Different Theoretical Approaches Essay

Examine how the different theoretical approaches have explained the changes that the family has historically gone through. The family is a universal institution present in every society throughout the world. For many, the family seems a familiar and comfortable institution, but this can appear in many different forms. A particular type of family is the ‘nuclear’ family; this consists of parents and children living together in the same household. The ‘conventional nuclear’ family comprises of a married man and woman with their biological children living together, this type of family is often dubbed ‘the cereal packet family’ where the male is the breadwinner and the female a homemaker. Another family type is the ‘extended’ family which includes all kin beyond the nuclear family e.g. Grandparents, Aunts or Uncles etc. Other family types include; Patriarchal families, Reconstituted or (step) families and Loan Parent Families, all of wh ich are alternatives to the traditional nuclear family. The family has been the focus of study for many different sociologists, all of which can be criticized in some form.Throughout this essay I am going to examine how the different theoretical approaches explain how family structures and the roles of individuals within them have changed in relation to each of the historical stages that Western society is said to have developed through. There is an underlying assumption amongst sociologists that ‘hunter-gatherer’ bands were the first forms of society. Although these were large communal groups the structure of the ‘nuclear’ family was seen to be present within them. In order to survive the need for team work was essential and therefore separate conjugal roles were necessary. Female mobility was limited due to the impact of child birth and child rearing so they were responsible for gathering nuts and berries from the land whilst the male role was go and hunt for food. Anthropologists studying ‘hunter-gathere r’ societies still in existence today such as The Hadza from Tanzania support this view and speculate this was once the way of life in every society. Functionalist Gary Lees believed the nuclear family unit was optimal within ‘hunter-gatherer’ societies as they needed to be mobile in order to move around and search for food. Marxist sociologist Friedrich Engels argued that because the means of production was owned communally then the family as such did not exist. He refers to this an era of ‘primitive  communism’ characterised by promiscuity. There were no rules limiting the number of sexual relationships so therefore society was in effect ‘the family’. (Holborn, 2004) Feminist sociologists tended to agree with the Marxist view but saw the roots of traditional conjugal roles such as childbirth and child-rearing as a disadvantage to women. The next stage in the development of society is referred to as the ‘pre-industrial’ stage. This stage of history saw a shift towards agricultural based societies. William Goode (1963) believed that the extended family was only appropriate with in this type of society due to the amount of Labour intensive work needed to be carried out. Functionalist Talcott Parsons agreed with this because the extended family system had more people available to carry out the wide variety of functions required. (Owens, n.d.) A study entitled ‘Family and community in Ireland’ (1968) Arensberg and Kimball found that kinship ties were still extremely strong but the basic unit was that of the extended family. They believe that the traditional Irish farming family is a ‘patriarchal extended family, due to considerable authority of the male head; the family is patrilineal because property is passed down the male family line. This has been criticised by Peter Laslett who examined parish records which provided evidence to indicate that in fact only 10% of pre-industrial families included kin beyond the nuclear family. (Owens, n.d.). Michael Young and Peter Wilmott conducted a study attempting to trace the development of the family from pre-industrial England to the 1970s. They suggest the family develops through four stages, they described the first stage family as one that works together as a unit of production; husband, wife and unmarried children work together as team. Materialist feminist Sylvia Walby believed that economic relations and inheritance of property were a major source of female disadvantage. The period of industrialisation is associated with urbanisation and the growth of factory based industry. Talcott Parsons argued that the family is ‘structurally isolated’ because relationships with other kin are a matter of choice and as the nuclear family contained the basic roles of mother, father and children needed to carry out the essential functions then the extended family of pre-industrial times was no longer required. He believed the family had emerged due to a process structural differentiation society had gone through and due to development of more specialised institutions there are fewer functions  needing to be perform ed by the family and therefore the family ceases to become an economic unit of production. (Holborn, 2004) However other sociologists such as Michael Anderson (1971) believed that industrialisation actually increased the need for extended family because as people moved into towns they moved in with relatives in order to find comfort and security. Community studies of working class neighbourhoods in the twentieth century such as Dennis et al’s study of a Yorkshire mining village (1956) and Jeremy Tunstall’s study of Hull trawler men (1962) all featured similar conclusions of extended family life and support. (Owens, n.d.) Wilmott and Young referred to this as their Stage two families which began with the industrial revolution. In this stage families cease to be a unit of production and become employed as individual wage earners. They believe due to low wages and high unemployment families extended their nuclear networks to include extended family networks, this provided them financial security against hardship. They believed this was the tie between mother and married daughter they used as a defence due to the conjugal bond within the nuclear family being so weak, due to the males in the relationship choosing to spend more time away from the family unit. Some people have argued that as industrialisation and modernisation proceeded, kinship-based society and the extended family broke up and the nuclear family emerged as the dominant form. This family has often been referred to as ‘the cereal packet family’. The role of father also saw a shift towards a more family based role and the conjugal bond was strong. Post-industrial times have seen a decline in factory based industry and a rise in people choosing to work within the service sector. The big question now is whether or not the ‘family is in decline?’ Patterns of family life have changed dramatically over recent years. One reason for this is the rise in divorce rates as changes to laws have meant that it is much easier for people to get divorced than it was in the past, also a change in attitude has meant that there is no longer the social stigma around attached with divorce. The development of the state and a rise in women workers means that women no longer have to rely on a male for financial support. Feminist Germaine Greer sees divorce has been good for women as they no longer have to accept living in an unhappy marriage. In conclusion I believe that there has been a widespread change in family structures over time, but I believe this is due more due to cultural changes  and a more widespread knowledge and acceptance of the different types of family that exists. Bibliography Holborn, H. a., 2004. Sociology themes and perspectives. 6th ed. s.l.:Harpercollins. Owens, R., n.d. Families and Households -Changing Structure. Sociology factsheet.

How is the culture and society ‘Of mice and men’ different from our own? Essay

The culture and society is extremely different from our own because the people in the book are less social, but nowadays people seem to socialize a lot more. The book is set in a time known as manual labour where there is very little machinery. This required a lot of strength. The machinery had to be worked by man and was less sophisticated than the machinery we have now. It was a society of which people had to travel to get work and were paid very little for the amount of hard labour they had to do. They only had a few possessions so that they could carry them around wherever they went to work. If they were to carry a lot of things with them they would not have been able to carry them. One similarity is that the people’s ambitions, dreams and hopes are very much the same to modern times. Most people wanted to settle down at a ranch, have pets and live life easily. In the time the book was set it did not matter what background you came from as long as you worked hard you would be able to make something of your life. This is very much the same as modern times in America. In England this was very different because what background you came from entirely depended on what sort of job you were going to have when you grow up. This is still kind of the same because if you come from a poor background you will not be able to have a good education to get a good job. The men in the book are trapped in the society they are in because they are not going to be able to get a good job. They are going to buck barley for the rest of their lives. Steinbeck makes a very strong racial element throughout the story. Crooks the stable buck is classed as less than human because he is physically disabled by getting kicked on the back by a horse. Also he is black so people class him as a lower being. He lives in a barn away from everyone else. Occasionally they let him join in, in some of the games they play. Curley’s wife is also part of the racial element because she is classed as an object and maybe a sex object to Curley. In the book Steinbeck does not give her a name which also means that she is an object. Curley restricts her from doing anything because she is not allowed out of the house or out of the ranch. She has to stay in the house else Curley will get annoyed and beat her. Candy is also discriminated because he is old and unable to do hard labour so they make him wash the floors for very little money. Lennie is discriminated against because he is mentally disabled rather than anyone else. Most of the people in the story are nomadic which means that they don not have a permanent base. They people on the ranch have a poor standard of living because they have shared accommodation and have absolutely no privacy. It is also quite sexist because the ranch is almost exclusively male. They have an abbreviated speech dialect which sounds very weird from a modern perspective. Also being nomadic means that they have a tendency to fight and have very aggressive attitudes to people that they dislike. In general the society in the book is very similar to our own. This is because they socialize and play games with each other.

The Hobbit, Supreme Ordeal Essay Example | Topics and Well Written Essays - 1000 words

The Hobbit, Supreme Ordeal - Essay Example Tasha Martin, the author builds the character in a series of hero journey steps that ultimately points out to the common path of heroes in the narrative. Bilbo lives a lavish life, enjoying seven meals per day, in this narrative; he wins this honor through a series of the ordeal that persistently depict his ultimate courage, pride, and persistence. His ordeal begins when he refuses to go with the wizard on adventure despite the arrival of the thirteen dwarves. In this episode, the wizard had tried his best to plead with him to accompany him on an adventure, after this he noticed that his mentor convinced him to accompany him for the adventure after the dwarves had gone (Tolkien 35). Initially, he is convinced that respectable Hobbits like him should not go for adventure. Elrond remarks â€Å"Ah, I shant be missed,† and Bilbo reply â€Å"The truth is most of them don’t think I should be on this journey,† reveals how other characters detested his presence in the journey. However, the change of mind to pursue dwarves becomes one of the biggest ordeal in his journey to be a hero. Later on, he realized that he had erred in judgment and decided to pursue the dwarves. On this journey, he meets both allies and enemies. It became a journey that shaped his personal stature and rise to be a recognized hero. Arguably, his pursuit of the dwarves is the best moment that helps bring out his heroism. Evidently, the most important event was the trial with the three trolls, the giant spiders and Gollum. Although he had encountered a number of trials during his pursuit, this special trial almost broke his stature.

Final year project computing with business Dissertation

Final year project computing with business - Dissertation Example 40 Appendix C 40 Abstract A search through literature from various secondary sources shows that there is not much focus on the salon business when it comes to electronic commerce. Even though there are isolated sources that talk about different and independent components of the subject of e-commerce and the salon businesses, there cannot be found much specific literature that relates e-commerce directly to the salon business. There could be a number of reasons accounting for such gaps in literature. E-commerce has actually been appreciated as a platform that makes the conduct of businesses very rapid and forthcoming. This is because it generally ensures that the small working place of a particular business venture gains a global status by having its presence registered in every corner of the world where internet services can be accessed. The study was conducted to bring out the problem with the numerous cases of congestion at salons and the frequent disappointments that customers enc ountered. The study was conducted with the notion that if the identified problem was adequately dealt with, salon operators and customers could adequately plan their times to ensure that customers are placed at the best times they could receive service. Once this is done on the wings of e-commerce, there can be the assurance that there will be improved satisfaction of work. This can also increase profitability for salon owners. Chapter 1 INTRODUCTION 1.1 Background to the Study The impact of technology on human life is certainly overwhelming, specifically when mention is made of computers and for that matter the internet. Today, the internet has become a one stop centre where almost everything a person needs in a day to make his life complete can be found (Winner, 2008). But even as the popularity and usefulness of the internet advances, businesses and business operators in various industry sectors have taken advantage of the situation to advance their trade and make their revenues grow. One of the most crucial and important ways in which businesses make use of the internet is through electronic commerce, commonly referred to as e-commerce. Through e-commerce, a lot of activities take place on the internet, including advertisement of products and services, window shopping, search for products and services, sale and purchase of products and services, the booking of appointment services, and the payment of products and services (Virilio, 2008). It would however be noted that most e-commerce that take place among various companies and business ventures; no matter how large or small they are, take place via the use of specific websites. Such websites

Semco Company Essay Example | Topics and Well Written Essays - 5000 words

Semco Company - Essay Example What would be the likely consequences of the changes in the short and medium term? It may help your answer if you consider key differences between your chosen case and Semco. One of the most important characteristics of the firm’s human resources management is the freedom related with the participation of employees in the organizational projects. Employees can choose the type of work that suits better to their needs and their time – referring to the time available on a daily basis for work, an issue particularly important for women with children. Furthermore, the firm’s top management is not accurately informed on the personal details of employees – a fact that could be criticized negatively by theorists and practitioners in the HR management sector. In accordance with the comments of the firm’s owner, R. Semler, ‘we could decide to find out which is which and who is who, but for two good reasons we never bother; first, the employment and contractual relationships are so complex that describing them all would take too much time and trouble; second, we think it’s all useless information’ (case study, p.64). The structure of the firm’s HR management can be compared to the open-source software – everyone can enter the firm and participate in its profits – the performance of each employee is depended on his/ her own ambitions and targets. Rather than trying to monitor employees in all their activities within the organization managers in Semco try to communicate with them quite often and give them the chance to participate actively in the firm’s key strategic decisions. The structure of the firm’s HR framework is not similar with others in the market. In fact, people with limited time or those that were working for the firm in the past have equal chances to participate in the development of the firm’s projects. The firm supports the development of industrial democracy giving the chance to

Company Strategic Analysis - General Mills Research Paper

Company Strategic Analysis - General Mills - Research Paper Example The company has strong brand equity in the market place. The company’s financial position is strengthening even at the time of recession. The company has a diversified product portfolio. The company’s brands have strong brand identity. The company’s internal processes for acquiring raw materials for its products are very strong. Weaknesses: The scale of companies operations are hiding inefficiencies in its operations. General Mills is not taking enough measures to raise its productivity. Opportunities: Recent social trends have created a market for convenience food items. General Mills can export its product to the Asian Markets. Threats: The environment of recession is creating unprecedented operating challenges for the company. Kraft and Kellogg are formidable competitors of the company, having strong brands of their own. Suppressed consumer demand is threatening company’s revenues. Porter’s Five Forces Analysis: Threat of Substitutes: This dimens ion falls on the higher end of the spectrum because consumers have the option to buy convenience food items from food stalls and cheap hotels. Moreover, consumers can even decide to cook themselves fresh meals. So it can be concluded that there are alternatives available to consumers. Rivalry amongst competitors: This dimension is also ending up on the higher end of the spectrum because as mentioned earlier Kraft Food and Kellogg, both are formidable competitors having strong management and brand portfolio. In addition to this these companies also have strong capital base to support their operations. Suppliers Bargaining Power: This dimension also falls on the higher end of the spectrum because there are few quality suppliers of raw material in the marketplace. Companies who want to gain quality raw materials have to adhere to suppliers’ terms and conditions. Moreover, the price of the raw material is also very elastic, which leads companies to the future markets; in order to protect themselves from price risk and inflationary pressure. Customers Bargaining Power: This dimension again lies on the higher end of the spectrum because recessionary pressure has made consumers to curtail their expenditure. Consumers are demanding higher value at lower price from companies, in order to draw them to spend. Companies therefore have to adhere to the demands of consumers in order to utilize their huge asset base. Threat of New Entrant: This dimension falls on the lower end of the spectrum because the market conditions are not that encouraging for any new entrant to enter this market. Since the industry is engulfed by recession and has strong competitors in it, therefore no new entrant will be able to operate effectively in this marketplace. Firm’s overall Performance: Even at the time of recession the company has managed to perform exceptionally well. Almost all of its financial indicators are on the positive side of the spectrum, reflecting the fact that t he company has been successful in implementing its year start strategy. The company’s 2010 sales figure is up by 1 percent as compared to its 2009 sales figure (General Mills e, 2011). Operating profits have increased substantially, that is by 8 percent. Net income of the come has also increased drastically (17 percent) (General Mills e, 2011). The company’s asset utilization has also increased as reflected by the head of â€Å"Return on Average Total Capital†. This figure is up by 150 basis points, which is very encouraging. For the share

Job Selection Process Assignment Example | Topics and Well Written Essays - 2500 words

Job Selection Process - Assignment Example So, we need to ponder on the different meanings regarding "validity". One renowned and cited one is: "An account is valid or true if it represents accurately those features of the phenomena, that it is intended to describe, explain or theories" (Hamersley in 1987) (1) It means that what we are trying to measure is accurate or not. And the other is that whether the means of assessment is actually measuring what it needs to measure. Face validity, part of validity, is seeing to it that a particular test really measuring the criteria and phenomena. For the selection of an employee, there is a process which includes Job Analysis, Recruitment and Selection. Job analysis is the analysis of the job and to see what the job needs, Ability, skills, work experience that a job needs and the nature of the job. The job analysis is there to make job description list and job specification list so that a perfect employee could be found for the organization. So the question is how to find a good employee. Well, there are different procedures and ways to test the ability of the person regarding the job. Now these tests are very important but we don't know that do these tests really give you of what you looking for So to check the test's ability to measure is done b y validity. We will discuss this more after discussing reliability so that both are clear in your mind. Now coming to the definition of the "Reliability", we talk in our ... Now coming to the definition of the "Reliability", we talk in our every day life that this is reliable and that is reliable. Isn't it We say that is this source of the news is reliable or not We say that my friend is a reliable person or that thing is reliable, meaning that some thing is dependable, reliable or trustworthy. But this meaning can not fit into the research meaning of reliability. So in research the word reliability means to be consistent and repeated like if you are giving a test than you would get same answer again and again. Let's take an example of a non reliable measuring device. The measuring of the characteristics of the people is needed in the personnel selection to determine that who will be accepted for the job openings and who will be not. For instance we might be interested in knowing the physical characteristics of the applicant. For example we want to measure the height of the applicant; we might start of with a 12 inch ruler. The first applicant turns out to be 6feet and 1 inch tall. It would not be shocking to see that another person who measures the same applicant's height gives the result of 6 feet 1 and 12/16 inches an hour later. Than the same candidate when measured the other day comes out to be 6 feet 1 and 14/16 inches tall. Now although the person's height is stable but we are getting different answers. Why This is because the measurement device is not perfectly reliable. And there are slight errors in the results. (Writer: William M.K. Trochim. Last revised on: 10/20/2006) We can now achieve a formal definition: "the variance of the measure" (William M.K. Trochim, last revised on 20th October 2006). (3) Here we can also look at different definition cited by different writes around the world. For instance Black and

Detection, Control And Prevention Of Rape Term Paper

Detection, Control And Prevention Of Rape - Term Paper Example Rape-related incidents or sexual assaults are taking place not only in open societies but in closed societies like prisons or correctional facilities also. Kaiser & Stannow have pointed out that â€Å"more than 216,600 people were sexually abused in prisons and jails and, in the case of at least 17,100 of them, in juvenile detention. Overall, that’s almost six hundred people a day—twenty-five an hour†. In fact, many of the criminals believe that rape or sexual abuse is part of their prison life and it cannot be avoided, even though rape in prisons was prevented by the 2003 Prison Rape Elimination Act. In short, rape is a social evil which should be detected, controlled and prevented by implementing stiff laws against rape.Detection, control, and prevention of rapeDetection of rape crimes is important in taking preventive measures. In some countries or cultures, victims often try to hide their bitter experiences because of the fear of consequences from the society . In male-dominated societies, females have many things to lose than males, in rape cases. They may face social isolation, harassing, teasing etc. In order to avoid such things, victims quite often try to hide the rape attempts made by the males. The failure of victims in reporting their bitter experiences related to rape, encourage the offenders further and they will repeat their activities again and again. There are many rape cases reported from different countries in which the offender was none other than the father himself.... l abuse is part of their prison life and it cannot be avoided, even though rape in prisons was prevented by the 2003 Prison Rape Elimination Act (PREA). In short, rape is a social evil which should be detected, controlled and prevented by implementing stiff laws against rape. Detection, control and prevention of rape Detection of rape crimes is important in taking preventive measures. In some countries or cultures, victims often try to hide their bitter experiences because of the fear of consequences from the society. In male dominated societies, females have many things to loss than males, in rape cases. They may face social isolation, harassing, teasing etc. In order to avoid such things, victims quiet often try to hide the rape attempts made by the males. The failure of victims in reporting their bitter experiences related to rape, encourage the offenders further and they will repeat their activities again and again. There are many rape cases reported from different countries in w hich the offender was none other than the father himself. In such cases, the victim (female children) will not disclose their experience most of the times because of their fear of their father. â€Å"In one study, seventy-four percent of women who had intercourse before age fourteen and sixty percent of those who had sex before age fifteen report having had a forced sexual experience (Colb, 2004, p.2). The above statistics show the depth of the problem quiet clearly. It is an accepted fact that teenagers are vulnerable to sex related crimes than adults because of various reasons. Molesting a teenager is easy than molesting an adult because of genetic or psychological reasons. Teenage is a period during which sex hormones develop rapidly and therefore teenagers have a strong desire for sexual

Comparative Aanalysis of Dell And Apple Laptop Marketing Essay

Comparative Aanalysis of Dell And Apple Laptop Marketing - Essay Example Apple’s brand personality is about removing complexity from consumer lifestyle through technology and the humanistic governance structure of Apple as a consumer-centric brand. 2. Market review Apple is much more transparent and accountable for its failures and successes associated with tangible product as part of the marketing mix. Apple performs what is referred to as movement marketing, a new marketing model that is strongly customer-centric, using corporate values as a foundation of sharing with consumers and being able to tap into their pre-existing values and lifestyle beliefs. Apple embraces social media as one platform by which to perform this movement marketing, using this forum to enhance customer relationship management and also to consistently reiterate what Apple believes in rather than simply expressing to target consumers the tangible benefits of various laptop products. This is the genuine key to brand loyalty (Goodson 2011). Making use of social media, such as Twitter and Facebook, provides Apple with unique opportunities to illustrate its belief in establishing effective, long-term customer relationships in key target demographics. Having established brand loyalty founded on years of consumer-accepted innovation launches that revolutionized the computing experience and with strict focus on customer relationship management philosophy. This provides Apple significant advantages over competition as once brand loyalty is established, it allows companies to position the brand under a premium pricing model (Chaudhuri and Holbrook 2001). Loyal customers are more apt to spend higher resources on their favourite brands and will be more active... This paper stresses that using values and principles at the corporate level as a promotional tool is unique in this technology industry and continues to provide greater sales volumes and the ability to expand various Apple branded product lines to include new innovation or supplementary service offerings. The report makes a conclusion that Dell must accept its current market position as a value-conscious brand that is aligned with consumer expectations for quality and excellence in service and support as it cannot justify premiumisation at this time. Dell unfortunately must rely on costly promotional ventures in order to produce greater revenues, however these efforts continue to put Dell back on the proverbial competitive map as a brand that can adjust with consumer needs and changing market conditions. The author of the paper declares that Apple gains much market loyalty and positive brand sentiment in its key target markets by extolling genuine, heartfelt connections between business and consumer which leads to brand attachments and avoids the risk of brand defection in dedicated target markets. Dell is missing opportunities to add a humanistic element into the marketing mix that can be accomplished, at low cost, through social media outlets. Apple, on the other hand, can benefit f rom Dell’s customization strategy, offering similar customized offerings based on aesthetics. Apple is currently differentiated from lower-priced competitors such as Dell.

Voice over Internet Protocol Security Vulnerability and Risk Analysis Literature review

Voice over Internet Protocol Security Vulnerability and Risk Analysis - Literature review Example In modern times different means and mechanisms are being introduced for establishing communication with one another. The aim behind all of them has been to work on those lines that ensure reliable, fast and economical sources that can enable connecting people from across the borders and shores. The progress so made is so immense that people sitting across the continent can get in touch and see each other in matter of few seconds. Different means exist for such concepts. All those means of communication that have existed in history were conducted with a concern and consideration of privacy in them. This is achieved through encryption of data that is being exchanged between the two points. Voice over I.P (VOIP) is one of them. It has gained popularity in recent times and is being widely used .Like every other system in the field of telecommunications; VOIP has its strengths as well as weaknesses. Like every other internet utility, it has its own vulnerabilities and security concerns. This paper looks into the vulnerabilities and risks affiliated with it, further touching on the features being provided by it along with its working principles in brief. The paper also looks into the role of Voice over I.P Security Alliance and its efforts to meeting the demands in terms of narrowing down the vulnerabilities that exist in various forms. Keywords: VoIP, Open standard, Vulnerability, Denial of Service. ... VOIP is established on the concept of open standards to maximum its use and accessibility (Ellis, Pursell & Rahman,pg 250, 2003). Interoperability is another feature that is making inroads across the platform all over. Having mentioned the features that are being provided by VOIP, a serious concern is being raised about its security aspect. Many a times it is being tagged as vulnerable in terms of security aspects. For this purpose efforts are needed to be in place which will insure the safety of all parameters involved in this. This is possible through study of all those areas which have loop holes in them and further working on those areas will make this a safe source of communication for customers to use. VOIP is a generic term for number of applications intended for establishing connection (Persky 2007); it could be the chat client establishment, the phone call conversation, the SMS service establishment. VOIP makes use of number of protocols that contain both the open protocols and proprietary protocols. Through the use of single broadband line, VOIP enables sending voice signals, data that includes textual format and video format information. The vulnerabilities are not just limited to its usage and application, rather operating systems, and protocols used (McGann & Sicker 2005). Types of calls possible with VOIP: Unicast calls: This kind of calling conversation involves the minimum number of parties, one at each end. It is the SIP or H.323 based call. Mostly the traffic and conversation is not encrypted and hence unsafe. Multi cast calls (limited number of callers): This includes more than two users involved in a conversation at one time. Usually a conference call where the first two establish a

Growth and Decline Essay Example for Free

Growth and Decline Essay Areas of growth and decline in the primary, secondary and tertiary classifications of business activities Firstly the primary sector, obtain or produces raw goods. The secondary sector manufactures and constructs goods. Finally the tertiary sector provides services to businesses and/or individuals. Over time whole sectors can grow or decline. Absolute growth or decline means that on its own a sector is getting bigger or smaller. If this type of decline happened continuously, one day a sector would disappear. Relative growth or decline means a sector is doing better or worse compared with other sectors. It may be growing relative to other sectors but still not doing very well. Or it may be declining relative to other sectors, but doing quite well on its own. Overall the primary and secondary sector is declining and the tertiary sector is growing. This is because we as a country are becoming more of a service culture. The primary and secondary sector has decreased because we can now use machinery to do certain jobs that people used to do and so people have to find work elsewhere in the tertiary sector. The primary sector has decreased rapidly through time from 1980 to 2002 and the employment rate for primary industries has decreased by over 65% going from 3. 6% to 1. 4%. This is because people no longer produce their own food or own animals for meat and so as the years went on people started to trade the food that they produced and the animals they owned for other products which leads on to the tertiary sector. However within the sector the output has risen from. Fishing fleets, coal mining and quarrying are all examples of areas in the primary sector that has declined. This is because machinery can do most jobs that people used to do, foreign industries also became more competitive and imports such as coal became more affordable. As the availability of coal declined in the UK, and also became more expensive to extract more coal was imported. This led to a further decline in primary sector employment in the UK. The primary sector has although increased in its organic food production, wind farming, fish farming and oil and natural gas extraction. The number of organic producers has risen from 6,038 organic producers in 2004 to 7,567 organic producers in 2009 this is because the demand for organic food has increased as more and more people want to eat food without artificial fertilizers and pesticides. However even with this increase the primary sector is declining compared to the secondary and tertiary sectors as employment for the primary sector in 2008 is only 1. 6% of the UK whereas the secondary sector has an employment rate of 17. 6% in 2008 and the tertiary sector has an employment rate of 80. % in 2008. This shows that the primary sector is declining along with the secondary sector but at a much more drastic rate. The secondary sector is doing better than the primary sector as pointed out in my last paragraph however is declining largely compared to the tertiary sector. Between 2005 and 2008 the secondary sector was on the rise as employment in manufacturing increased and the output of the secondary sector increased. H owever as the recession hit, the secondary sector saw a decline of output from 23% in 2008 to 6. 5% at the start of 2009. The areas hit most were industries metal products, transport (engineering) and construction. Over 140,000 jobs were lost in the motor industry, BAE systems cut 500 jobs and SANYO closed its factory which made televisions – ever since no factory in Britain made televisions. Later in 2009 the decline started to slow down but hasn’t improved much since as companies are still making cut backs. Going back to 2005-2008 the areas that were most successful in the secondary sector were the food and drink industry, drugs and pharmaceuticals, weapons, ammunitions, energy, electrical and optical equipment and finally paper and publishing.

Genetic Polymorphism Governing the CYP2D6 Cytrochrome

Genetic Polymorphism Governing the CYP2D6 Cytrochrome Genetic Polymorphism Governing the CYP2D6 Cytrochrome P450 Enzyme Subfamily in Drug Metabolism I. Abstract The decoding of the human genome has opened up an immense opportunity for further research in designing treatment plans that can be more personalized. The composition of a persons genome varies amongst individuals and also within populations. Individual responses to drug are inherited. The clinical implication of inter-individual variations is implicit in Cytochrome P450 enzymes that are prominent in drug metabolism. Polymorphism of over 20 enzymes involved in drug metabolism has been characterized and most of these involve the Cytochrome P450 enzymes. The Cytochrome P450 enzymes have been subjected to numerous evolutionary pressures over time, consequently producing various isoforms. The frequency of variant alleles can alter the pharmacokinetic parameters of the drug, especially of a drug with a narrow therapeutic index. These alleles can either have heightened responses to certain drugs causing toxicity or show very low compliance leading to therapeutic failure. Specifically, CYP2 D6 is known to vary tremendously amongst different ethnic groups. Polymorphism of drug metabolizing enzymes such as CYP2D6 can severely affect the clinical outcome in regards to drug response. CYP2D6 gene is shown to have 74 variant alleles, when expressed in homozygous or heterozygous manners give rise to four distinct phenotypes. In this new era of genomic advancements, there is much hope to decipher variations pertaining to drug metabolism and gear the focus towards individualized medicine. Patient selection can be drastically improved by the employment of genotyping. Innovative technologies have made genotyping prevalent and we have come a long way since the advent of pharmacogenetic in the early 19th century. Sir William Osler (1849-1919) documented that variability is the law of life, and as no two faces are the same, no two bodies are alike, and no two individuals react alike, and behave alike under the abnormal conditions we know as disease. II. Personalized Medicine and Pharmacogenomics A. Pharmacogenomics The human genome project has it made possible for researchers to comprehend the complexity of biological pathways involved in disease states and focus on variations amongst individuals in regards to drug regimens (Ginsburg and Willard, 2009). The pharmacokinetic aspect of the bodys way of dealing with the drug such as adsorption, distribution, metabolism and elimination of the substrate factors into the variability of individual drug response (Kroemer and Meyer zu Schwabedissen, 2010). The pharmacogenetic variation in absorption and elimination are quite rare compared to the variation seen in drug elimination (Nebert, 1999). According to Nebert et al. (2004) Clinical pharmacology is any particular response seen after a drug is administered. However, this phenotypical drug response is rather ambiguous and has various biological and environmental influences as illustrated in Fig.1, which can lead to a gradient in drug efficacy and toxicity (D. R. Nelson et al., 2004). The phenomenon of genetic variability causing different reactions to drugs has been recognized for awhile as seen in Fig 2 but only recently has the idea become prevalent (March, 2000). In 1902, Sir Archibold Garrard regarded enzymes as vital endogenous biochemical substances required for detoxification in alkaptonuria (Hood, 2003). Sir Archibold Garrard later exemplified the enzyme deficit leading to adverse drug reactions as in born errors of metabolism (Hood, 2003). An inherited difference in tasting ability of phenylthiocarbamide was first discovered by a chemist, Arthur Fox in 1931. Arthur Foxs finding in 1931 on genetic variability was considered a breakthrough finding in the field of pharmacogenetic (Hood, 2003). During World War II, the antimalarial drug such as primaquine showed differing results in Caucasian soldiers compared to the African American soldiers; African American soldiers showed greater occurrences of hemolytic anemia when administered drug (March, 2000). Metabolism as a conce pt became prevalent in mid 19th century when scientists began to decipher the excretory metabolites of consumed substances (Nebert and Vesell, 2004). Pharmacogenomics, the term coined in 1995, focuses on a persons genetic composition, gene and respective gene products, and illustrates how this variability affects drug metabolism (Nebert and Vesell, 2004)(Maria Almira Correia, 2009). The two major aspects of pharmacogenomics are a) To recognize the genes that are affected in a disease state; and b) To focus on the variant alleles that alter our response to the drugs (Wolf, Smith, and Smith, 2000). Figure 1 Factors influencing individual drug response. Reprinted from Pharmacology, pharmacogenetics, and pharmacoepidemiology: three Ps of individualized therapy By S. Dawood , 2009, Cancer Investigation, 27, 809-815 Figure 2 Favism is implicit in certain population that consume fava beans A Greek philosopher Pythagoras first noted this phenomenon that was later found to be associated with acute hemolytic anemia in people who consume the legumes. These people have deficiency in glucose-6-phospahte dehydrogenase and can show altered response to antimalarial drug Reprinted from Pharmacogenomics: the promise of personalized medicine by Hood Emily, 2003, Environ Health Perspect.; Aug;111(11):A581-9. Pharmacogenomics encompasses the whole human genome, DNA, RNA and the associated gene products involved in the study of drug metabolism, drug transport, target proteins (receptor, ion channels, enzymes) and links these gene products to their affects on xenobiotics (Mini and Nobili, 2009). A drug that exhibits reduced efficacy does not always correlate with reduced levels of toxicity since remedial values and noxious side effects of a drug are often exerted via diverse biochemical pathways (Mini and Nobili, 2009). The study of pharmacogenomics, therefore, has vital therapeutic value because most disease states entail some sort of drug treatment (Kroemer and Meyer zu Schwabedissen, 2010). The study of genomics is now made it possible to predict safety, toxicity and efficacy of drugs and opt for a personalized treatment plan by targeting variant alleles (Dawood, 2009). The empirical notion of patients with a certain disease state reacting to drugs homogenously is flawed (Dawood, 2009). This conviction, however, does not account for genetic variation, which unfortunately leads to over 40% of patients either getting the incorrect drug or wrong dosage of the drug (Bordet, Gautier, Le Louet, Dupuis, and Caron, 2001). A Meta analysis study done in 1994, estimated that more than 2 million patients hospitalized in the US had fatalities related to adverse drug reactions (Lazarou, Pomeranz, and Corey, 1998). These results concluded that in 1994, the 106,000 fatalities associated with adverse drug effects ranked between fourth to sixth leading causes of death in the US(Lazarou et al., 1998). Regardless of strict and regulated standards for drug efficacy and prevention of toxicity, adverse drug reactions are prominent and a drug is never equivalently effective on a general population (Roses, 2000). Financially, neither the patients and/or the health insurance companies find it feasible to pay for drugs that are either ineffective or cause adverse effects (Roses, 2000). If a patient has blunted ability to metabolize a drug that is administered to them in normal doses this could easily lead to mortality due to toxic levels of the exogenous substance left in the system (Hood, 2003). Patients react to drugs in a heterogeneous manner compared to the notion of homogenous efficacy, which is particularly imminent in chemotherapeutic drugs (Dawood, 2009). Most chemotherapeutic drugs have narrow therapeutic index and any variability in metabolism of this drug can lead to adverse drug reaction (Dawood, 2009). The approach employed currently often leads to therapeutic failure and waste of time leading to expensive health care costs and valuable time (Hood, 2003). Therapeutic failure related to drug metabolism in diseases such as cancer, psychiatric disorders, and hypertension can be severely detrimental if the drugs do not take effect due to the presence of variantions in enzymes leading to high and low metabolizers (Hood, 2003). Although, genetic variability alon e does not account for all the adverse effects of drugs seen in a patient, pinpointing the altered gene can be beneficial in tailoring a more precise therapy that involves less adverse effects (Hood, 2003). Therefore, understanding the complex interaction of individuals with their environment and underlying genetic variation will allow for a gradual shift from one drug fits all perception to an embodiment of individualized medicine (Dawood, 2009). B. Individualized Medicine Individualized medicine encompasses many attributes such as clinical, genetic, and environmental factors all intertwined in a complex meshwork affecting a disease state (Ginsburg and Willard, 2009). Thorough understanding of these various attributes can aid in development of personalized treatment plans and medication types/dosages leading to an effective patient care, reduction in drug toxicity and increase in drug efficacy (Ginsburg and Willard, 2009). The ultimate goal of the drug is to have the most efficacious and least toxic effect on the patient (Dawood, 2009). However, clinical variables such as drug-drug interaction and metabolism of drug and drug transport show pronounced differences accounting for toxicity (Dawood, 2009). The statistics reveal that a certain drug is known to produce therapeutic effect only in 30% of the patients, whereas 30% of the patient show little or no advantageous effect to the drug, 10% are shown to have only deleterious effects (Maitland-van der Zee, de Boer, and Leufkens, 2000). For example if a patient is on an antidepressant, which usually take two weeks to take effect, predicting drug response for patients with a variant allele is advantageous in regards to predicting efficacy (Kirchheiner and Seeringer, 2007). Predicting drug response poses just as many challenges as do the study of inherited diseases related to genes (McCarthy and Hilfiker, 2000). The variant gene products involved in drug me tabolism are related to regulation at the level of gene expression, post translational modification and drug-drug interaction, all of which affects individual responses to xenobiotics (McCarthy and Hilfiker, 2000).Typically, drug doses are determined by body surface area and for certain group of individuals the systemic exposure is presumed to be homogenous if the surface area is similar The surface area is mainly determined based on height and weight (Dawood, 2009). The variation however stems not necessarily from differences in physical factors but rather from discrepancy in drug metabolism and drug clearance (Galpin and Evans, 1993). Although, systemic monitoring for drugs with low therapeutics indicies has been employed, it still is not efficient enough to prevent therapeutic failure (Nebert and Vesell, 2004). II. Genetic Polymorphism A. Introduction Genetic polymorphism is the variation in allele that is present at a locus and occurs in more than 1% of the population (Phillips, Veenstra, Oren, Lee, and Sadee, 2001). The allele is considered a mutation when it occurs in less than 1% of the population (Mini and Nobili, 2009). The human genome is 3 billion base pair long and the variation in one nucleotide sequence in the DNA occurs in every 100-300 bases (Hood, 2003). Single nucleotide polymorphism (SNP) is the most extensively studied genetic polymorphism, which accounts for most of the variation in drug metabolism (Schmith et al., 2003). The human genome has over 1.4 million single nucleotide polymorphisms 60, 000-100,000 is associated with drug effects ((Dawood, 2009)(Schmith et al., 2003). These SNP can gives rise to polygenic gene variants that can alter the pharmacokinetic and the pharmacodynamic portfolio of a drug leading to innate deviation in metabolism (W. E. Evans and McLeod, 2003). The gene loci that encodes for prote ins involved in drug metabolism are inherently shown to have about 47-61% polymorphism, which in turn correlates to the immense differences in substrate breakdown (Nebert, 1999). Genes that have SNPs in the coding region usually change the amino acid sequence of the protein whereas the SNP in the regulatory region are known to control the concentration of the proteins (McCarthy and Hilfiker, 2000). An exogenous substance relays its effect by interacting either on the cell membrane, cytoplasm or in the plasma (Mini and Nobili, 2009). However, a substance that is known to be efficacious in most individuals can cause detrimental effects in some if they are homozygous for the variant alleles as seen in Fig 3. This variation can affect any of the compartment of interaction a drug asserts its effects (Mini and Nobili, 2009). These alterations can manifest into phenotypes that can cause adverse effects by enhancing or inhibiting normal physiological activity (Mini and Nobili, 2009). The hu man genome project has simplified the identification of roughly 100,000 SNPs in the human genome, which can be employed to acquire accurate information on individual drug responses (Schmith et al., 2003). A haplotype is regarded as a blueprint in which not one but many SNP occur on the same chromosome (Hood, 2003). Although a single SNP may cause altered response to drugs, it is more likely the combination of SNPs on a single chromosome that may play a role in drug metabolism leading to polygenic phenotype (Hood, 2003). In the near future, clinical trials might be required to incorporate genotyping for potential drugs. The cost of genotyping for clinical trials has been predicted to cost approximately 1 million dollars (McCarthy and Hilfiker, 2000). Even though the additional cost to the trial is of concern, the overall end results might provide valuable information on drug metabolism amongst different ethnic groups, which would be beneficial in the long run. Characterization of genes of enzymes involved in drug metabolism are shown to have considerable variations; about 3 to 10 variant alleles are considered to be of the common type and over 12 to 100 variant alleles that are uncommon and occur rarely (Nebert and Vesell, 2004). Initially, when the Human Genome Project was undertaken, there was little concern about the difference in sequencing of chromosome amongst different ethnic groups (Nebert, 1999). Most scientists at the time believed there would be no substantial discrepancy between chromosomes of an individual who is of an Asian descent compared to an individual of European descent (Nebert, 1999). Graham and Smith in the 1999 study showed that there is significant variation in drug metabolism amongst individuals of different ethnic backgrounds, which effects the pharmacokinetic variability of the enzyme that are involved in drug metabolism (Graham and Peterson, 1999)(Maitland-van der Zee et al., 2000). Recent study on Asian, White s and Blacks showed that different ethnic populations differ in the frequency of alleles of a gene and this variant can result in altered drug responses (Limdi et al., 2010). The functional consequence on drug metabolism of the variant allele depends on the extension of mutation and frequency of occurrence in an individual subgroup (Maitland-van der Zee et al., 2000). To establish an accurate overall picture of variant alleles in different ethnic subgroups, an extensive SNP genotyping is needed, with an average group size of 1000 individuals in each subgroup (Nebert, 1999). The information derived from this can then be utilized for an extensive genotype-phenotype linkage study (Nebert, 1999). Figure 3 Polymorphism affecting the concentration of a drug leading to toxic doses and low efficacy in individuals who are homozygous for the variant gene. Reprinted from Pharmacogenetics: implementing personalized medicine By Enrico Mini; Stefania Nobili, Clinical Cases in Mineral and Bone Metabolism 2009; 6(1): 17-24 B. Adverse Drug Reaction Drug-drug interactions are common when numerous drugs are ingested simultaneously (Wolf et al., 2000). These drug-drug interactions can induce or inhibit enzymes in the common pathway of metabolism causing adverse effects (Oesch, 2009). An individual who has reduced ability to metabolize a substrate can easily accumulate the drug if an alternative route is not accessible (Oesch, 2009). The pharmacokinetic differences in individuals can cause poor metabolizers to have increased amounts of systemic exposure to the drug and fast metabolizers having less than normal amounts resulting in therapeutic failure or even toxicity. (Bailey, Bondar, and Furness, 1998). Comprehending this inherited genetic variability in drug metabolism can herald a new era in individualized therapy (Dawood, 2009)(Oesch, 2009)(Wolf et al., 2000). Study of pharmacogenomics allows for ways to reduce adverse drug reactions by identifying the nature of the drug, reaction to the drug and metabolic targets of the drug ( Phillips et al., 2001). All of the above can be utilized to create an extensive biomarker, which can then be employed by physicians to make appropriate dosing changes for individuals with variant alleles (Ginsburg, Konstance, Allsbrook, and Schulman, 2005). Alternatively, if reducing the dose is not a viable option, physicians can alter the treatment to include drugs that can by pass the deficient biochemical pathway (Ginsburg et al., 2005; Phillips et al., 2001). In order to utilize genotyping as a beneficial tool, physicians need to quantify variant drug responses to the specific gene unambiguously (Nebert, 1999). It is imperative that the candidate locus that is affected by the drug is identified and positive tests are employed for the variant alleles (Holmes et al., 2009). The Genetic polymorphism plays a major role in drug efficacy and also in adverse drug reactions (Dawood, 2009). Pharmacogenomic studies are hard to conduct because the variation in drug metabolism is only known after the administration of the exogenous substance, as compared to inherited diseases which have clear family linkage (McCarthy and Hilfiker, 2000). It is highly unlikely that an entire family would be prescribed a certain drug at the same time so the variation in the allele is only known under clinical trials (McCarthy and Hilfiker, 2000). SNP profiling can be beneficial if it can predict the drug response in patients and the demographics of people affected (McCarthy and Hilfiker, 2000). For example, a study by Drazen in 1999 showed that variation in ALOX5 was correlated 100% of the time with patients being non-receptive to an antiasthmatic drug (Drazen et. al, 1999). However, the prevalence of the non-variant gene in ALOX5 occurs in only 6-10 % of the patients; therefore, for a drug to be efficacious, the percent frequency of variant allele needs to be determined (Drazen et. al, 1999;McCarthy and Hilfiker, 2000). The major questions to be addressed then is how prevalent is the variant gene? How often are patients in a certain demographic group prescribed a drug that can cause adverse effects (Maitland-van der Zee et al., 2000)? A potential drug is marketed and distributed worldwide, however, most of the clinical trials are never encompass a broad range of population and most polymorphisms go undetected (McCarthy and Hilfiker, 2000). The clinical trials mainly consist of the Caucasian population in America and Europe, but a wider range of population is needed to pinpoint major variation amongst different ethnic groups (McCarthy and Hilfiker, 2000). Consequently, polymorphisms that are relevant in certain populations need to be studied and the target must be to address variant genes that are prevalent in drug metabolism (Maitland-van der Zee et al., 2000). Currently, there is little to no information on most of the drugs that are already in the market regarding genetic variability in drug metabolism (Maitland-van der Zee et al., 2000). In the future, potential drugs should include such population based studies in their clinical trials so fewer drugs would conform to one drug fits all motto (Maitland-van der Z ee et al., 2000). Polymorphism profiling can have major implication in drug safety because a drug that poses adverse effects on a large subgroup could be restricted from being launched into the market (Ginsburg et al., 2005). Genotyping can permit physicians to detect different polymorphism in individuals and allow them to create drug regimens that are not only efficacious but pose least toxic effects (Oesch, 2009). Preferential genotyping by clinicians for variant alleles could drastically reduce drug related adverse effects and in turn will be economically feasible and productive in the long run (March, 2000; Nebert and Vesell, 2004). Patient selection could be drastically improved by employment of genotyping. C. When is Genotyping Appropriate? Most drug targets are not key candidates for genotyping (Kirchheiner and Seeringer, 2007). The blood sample is collected from the patient after a day or two of administration of the drug. Therefore, drugs that require an immediate attention to dose adjustment or drugs that have a high therapeutic index may not be feasible for genotyping (Kirchheiner and Seeringer, 2007). In addition drugs that are metabolized via more than one overlying biochemical pathway pose extreme difficulties in pinpointing the variant allele and do not benefit from genotyping. However there are enzymes that have variant alleles such as the Cytochrome P450 enzymes which metabolize drugs such as warfarin, morphine, tamoxifen etc. and this polymorphism can lead to altered response to a drug (Kirchheiner and Seeringer, 2007). Adjusting the dose based on plasma level concentration of the drug is not always adequate for these patients (Dawood, 2009). Genotyping in these cases can lead to increased efficacy by identi fication of polymorphism, which can reduce the costly and time-consuming dose adjustment period. For example, CYP2D6 is a major enzyme involved in the breakdown of antidepressants. The therapeutic effects of antidepressants are only seen after a few weeks of treatment (Kirchheiner and Seeringer, 2007). Therefore, if a patient is a poor metabolizer they will accumulate the drug vs. a person who is an ultra rapid metabolizer, who will show no therapeutic value. In the case of antidepressants, genotyping for the CYP2D6 polymorphism may be beneficial prior to the start of therapy. Innovative technologies have made genotyping prevalent and we have come a long way since the advent of pharmacogenetic in the early 19th century. Pharmacogenetic disciplines if employed in pharmaceutical industry can aid in development of drugs that cater to the individual; this will allow for prospective drugs to be well suited for fewer people in comparison to drugs that assert mediocre efficacy in a vast group of individual. Food and Drug administration in 2004 permitted the employment of Chip technology known as AmpliChip by Rosche for identification of variant genes in the Cytochrome P450 pathway (http://www.roche-diagnostics.us/press_room/2005/011105.htm); (Ginsburg et al., 2005) Companies like Genelex Corporation of Seattle, Washington and Gentris are now enabling pharmaceutical companies and patients respectively to utilize Cytochrome P450 genotype profiling for CYP 2D6, CYP 2C9 and CYP2C19 enzymes (Hood, 2003). The marriage of genetics and medicine is going to become promine nt in the years to come and by the year 2020 pharmacogenomics will become a vital tool utilized to market drugs. The information derived from these test will allow patients to be on customized designer drugs(Collins and McKusick, 2001), allow physicians to set appropriate prescription amount for initial dosing and establish monitoring system for individuals with variant alleles (Tweardy and Belmont, 2009). III Cytochrome P450 Enzyme A. Background Variant alleles that lead to functional changes of gene product can have therapeutic consequences. These alleles can either have heightened responses to certain drugs causing toxicity or show none to very low compliance (Wolf et al., 2000). Polymorphism of over 20 enzymes involved in drug metabolism has been characterized and most of these involve the Cytochrome P450 enzymes (CYP) (Wolf et al., 2000). Cytochrome P450 enzymes are involved in metabolism of over 60% of drugs currently in the market today (Hood, 2003). Polymorphisms in the CYP enzymes are known to alter the pharmacokinetic aspects of exogenous substances affecting mainly the biotransformation of the substance (Kirchheiner and Seeringer, 2007). Polymorphism of the Cytochrome P450 enzyme was first discovered in relation to debrisoquine, a hypertension-correcting drug (March, 2000). Bob Smith, of Imperial College in London ingested debrisoquine and experienced severe hypotension after administration. In addition, his blood levels showed 20 fold decreased levels of drug metabolite compared to his colleagues (March, 2000; Nebert 1997). In 1988, Gonzalez and his group characterized and showed that the gene product that was causing the altered response to debrisoquine as CYP2D6; it was also found to be a liver microsomal enzyme. The cloning of this microsomal enzyme was the first look at genetic polymorphism at the molecular level (Gonzalez et al., 1988; Mini and Nobili, 2009). The study by Gonzales et al. and his group paved way for further studies geared to identify genetic polymorphism in a population that linked variant genes to alteration in drug metabolism and drug response (Mini and Nobili, 2009). Cytochrome P450s are mainly found in endoplasmic reticulum and in the mitochondria of a cell, and are copious in the liver (Porter and Coon, 1991). The CYP enzymes consist of about 49 genes that function primarily in drug metabolism (Maitland-van der Zee et al., 2000; Porter and Coon, 1991). In humans the CYP enzymes are major constituents in metabolism of fatty acids, prostoglandins, steroids and xenobiotics (Graham and Peterson, 1999). Daily diet intake of mammals consists of many natural products such as terpenes, steroids, and alkoloids and the CYP enzymes are major catalysts in the biotransformation and breakdown of these exogenous substances (Guengerich, 1991). Cytochrome P450 enzymes comprise of a super family of gene that encompass proteins predominantly involved in metabolizing of xenobiotics as well as endogenous substrates such as steroids, fatty acids, prostaglandins and arachidonate metabolites as shown in Table 1, therefore genetic polymorphism in the CYP enzymes can lead to many health related risks such as hypertension and cancer (Graham and Peterson, 1999; Jiang et al., 2005; Mayer et al., 2005). CYP enzymes are monooxygenases that catalyze non-specific oxidations of many substrates (Guengerich, 1991), (Porter and Coon, 1991). The synthetic exogenous substrates of t he cytochrome enzymes range to approximately 200,000 entities, which can all have complex interplay amongst each other in inducing or inhibiting the various isoforms of the CYP enzymes (Porter and Coon, 1991). These enzymes however are capable of catalyzing novel substrates as well and therefore one cannot cap an upper limit on the number of possible potential substrates (Porter and Coon, 1991). Therefore, the evolutionary advantage in the immensity of the CYP isoform is a crucial survival tool for our cultivating environment as well as our dynamically changing physiological system. Table 1. Exogenous and endogenous substrates of Cytochrome P450 enzymes The substrate for the CYP enzymes are just as diverse for endogenous substance as they are for exogenous substances. The CYP enzymes are prominent catalytic enzymes involved in biotransformation of various substances. Reprinted from Miniereview: Cytochrome P450 By Todd D. Porter and Minor J. Coon, The Journal of Biological Chemistry, 1991; 266(21): 13649-13472 The rates of catalyzation of the CYP enzymes are relatively slow and this can provide further explanation into their pivotal role in drug disposition (Guengerich, 1991). In addition, most of the CYP enzymes are involved in rate-limiting steps of drug metabolism and this is a key determinant of the in vivo kinetics of the drug (Pelkonen, 2002). CYP enzymes are key players in the systemic exposure of a drug and the time period a drug can assert its action (Brockmoller, Kirchheiner, Meisel, and Roots, 2000). The CYP enzymes are involved in either forming the active metabolite of the drug from a prodrug or in metabolizing the drug into inactive by-products,both of which can influence the functional temporal aspect of a drug (Brockmoller et al., 2000). Metabolites created by the CYP enzymes can also be toxic; exerting their own mutagenic and allergenic effects (Brockmoller et al., 2000). The FDA requires pharmaceutical companies to identify on the product brochure one of twenty CYP enzyme s that are involved in the biotransformation of the drug (Brockmoller et al., 2000). Interactions of different drugs concerning CYP enzymes are good predictor of drug-drug interaction, therefore marketed drugs are required to indicate the CYP enzyme involved in biotransformation of the drug on the product information (Andersson, 1991)(Brockmoller et al., 2000). However, this information does not include the polymorphism prominent within these CYP enzymes. The need for such information is crucial since these enzymes are notorious for genetic polymorphism (Brockmoller et al., 2000). Functional variations in the CYP enzymes are known to show a gradient in efficacy and variation in the quantity of the substrate present in the subject (Maitland-van der Zee et al., 2000; Wolf et al., 2000). Allelic variants causing poor, fast and ultrarapid metabolizing enzymes have been identified in most of the CYP enzymes. Most of the CYP enzymes in the liver show some degree of polymorphism (Anzenbach erova et al., 2000). B. Cytochrome Gene Family Evolution CYP enzymes are ubiquitous as they are found in every domain of living organism from Bacteria, Archaea and Eukarya and known to have originated from an ancestral gene approximately three and half billion years ago. The modern cytochrome probably originated with the Prokaryotes 1.5 billion years before the prevalence of atmospheric oxygen (Graham and Peterson, 1999; Nebert and Gonzalez, 1987; Werck-Reichhart and Feyereisen, 2000). In early eukaryotes, these enzymes not only maintained membrane veracity but also were primarily involved in the biosynthesis of endogenous hydrophobic substances such as fatty acids, cholesterol (Nebert and Gonzalez, 1987). The CYP mutilgene family diverged again 900 hundred million years later giving rise to enzymes predominantly involved in biosynthesis of steroids (Nebert and Gonzalez, 1987). This expansion lead to the another divergence of the two most important mammalian CYP families implicit in drug and carcinogen metabolizing enzymes currently known as CYP1 and CYP2 gene family (Nebert and Gonzalez, 1987). Finally, 400 million years ago dramatic expansion ensued primarily in CYP2, CYP3 and CYP4 families (Nebert and Gonzalez, 1987). This current expansion correlates to the time frame when aquatic animals merged onto the terrestrial land and were exposed to many hydrocarbon-based combustion material in the environment along with toxic plant products in their diet (Gonzalez and Nebert, 1990; D. R. Nelson and Strobel, 1987) The generation of this multigene family is due to the multiple mechanistic changes over time that reflect the complexity and diversity of the CYP enzymes. Most of the changes are related to lack of intron conservation (Werck-Reichhart and Feyereisen, 2000), exon shuffling (Doolittle, 1985; Patthy, 1985), expression of redundant genes (Anderson et al., 1981; Barrell, Air, and Hutchison, 1976), alternative splicing, frame shit mutations and RNA editing (Andreadis, Gallego, and Nadal-Ginard, 1987; Atkins, Weiss, Genetic Polymorphism Governing the CYP2D6 Cytrochrome Genetic Polymorphism Governing the CYP2D6 Cytrochrome Genetic Polymorphism Governing the CYP2D6 Cytrochrome P450 Enzyme Subfamily in Drug Metabolism I. Abstract The decoding of the human genome has opened up an immense opportunity for further research in designing treatment plans that can be more personalized. The composition of a persons genome varies amongst individuals and also within populations. Individual responses to drug are inherited. The clinical implication of inter-individual variations is implicit in Cytochrome P450 enzymes that are prominent in drug metabolism. Polymorphism of over 20 enzymes involved in drug metabolism has been characterized and most of these involve the Cytochrome P450 enzymes. The Cytochrome P450 enzymes have been subjected to numerous evolutionary pressures over time, consequently producing various isoforms. The frequency of variant alleles can alter the pharmacokinetic parameters of the drug, especially of a drug with a narrow therapeutic index. These alleles can either have heightened responses to certain drugs causing toxicity or show very low compliance leading to therapeutic failure. Specifically, CYP2 D6 is known to vary tremendously amongst different ethnic groups. Polymorphism of drug metabolizing enzymes such as CYP2D6 can severely affect the clinical outcome in regards to drug response. CYP2D6 gene is shown to have 74 variant alleles, when expressed in homozygous or heterozygous manners give rise to four distinct phenotypes. In this new era of genomic advancements, there is much hope to decipher variations pertaining to drug metabolism and gear the focus towards individualized medicine. Patient selection can be drastically improved by the employment of genotyping. Innovative technologies have made genotyping prevalent and we have come a long way since the advent of pharmacogenetic in the early 19th century. Sir William Osler (1849-1919) documented that variability is the law of life, and as no two faces are the same, no two bodies are alike, and no two individuals react alike, and behave alike under the abnormal conditions we know as disease. II. Personalized Medicine and Pharmacogenomics A. Pharmacogenomics The human genome project has it made possible for researchers to comprehend the complexity of biological pathways involved in disease states and focus on variations amongst individuals in regards to drug regimens (Ginsburg and Willard, 2009). The pharmacokinetic aspect of the bodys way of dealing with the drug such as adsorption, distribution, metabolism and elimination of the substrate factors into the variability of individual drug response (Kroemer and Meyer zu Schwabedissen, 2010). The pharmacogenetic variation in absorption and elimination are quite rare compared to the variation seen in drug elimination (Nebert, 1999). According to Nebert et al. (2004) Clinical pharmacology is any particular response seen after a drug is administered. However, this phenotypical drug response is rather ambiguous and has various biological and environmental influences as illustrated in Fig.1, which can lead to a gradient in drug efficacy and toxicity (D. R. Nelson et al., 2004). The phenomenon of genetic variability causing different reactions to drugs has been recognized for awhile as seen in Fig 2 but only recently has the idea become prevalent (March, 2000). In 1902, Sir Archibold Garrard regarded enzymes as vital endogenous biochemical substances required for detoxification in alkaptonuria (Hood, 2003). Sir Archibold Garrard later exemplified the enzyme deficit leading to adverse drug reactions as in born errors of metabolism (Hood, 2003). An inherited difference in tasting ability of phenylthiocarbamide was first discovered by a chemist, Arthur Fox in 1931. Arthur Foxs finding in 1931 on genetic variability was considered a breakthrough finding in the field of pharmacogenetic (Hood, 2003). During World War II, the antimalarial drug such as primaquine showed differing results in Caucasian soldiers compared to the African American soldiers; African American soldiers showed greater occurrences of hemolytic anemia when administered drug (March, 2000). Metabolism as a conce pt became prevalent in mid 19th century when scientists began to decipher the excretory metabolites of consumed substances (Nebert and Vesell, 2004). Pharmacogenomics, the term coined in 1995, focuses on a persons genetic composition, gene and respective gene products, and illustrates how this variability affects drug metabolism (Nebert and Vesell, 2004)(Maria Almira Correia, 2009). The two major aspects of pharmacogenomics are a) To recognize the genes that are affected in a disease state; and b) To focus on the variant alleles that alter our response to the drugs (Wolf, Smith, and Smith, 2000). Figure 1 Factors influencing individual drug response. Reprinted from Pharmacology, pharmacogenetics, and pharmacoepidemiology: three Ps of individualized therapy By S. Dawood , 2009, Cancer Investigation, 27, 809-815 Figure 2 Favism is implicit in certain population that consume fava beans A Greek philosopher Pythagoras first noted this phenomenon that was later found to be associated with acute hemolytic anemia in people who consume the legumes. These people have deficiency in glucose-6-phospahte dehydrogenase and can show altered response to antimalarial drug Reprinted from Pharmacogenomics: the promise of personalized medicine by Hood Emily, 2003, Environ Health Perspect.; Aug;111(11):A581-9. Pharmacogenomics encompasses the whole human genome, DNA, RNA and the associated gene products involved in the study of drug metabolism, drug transport, target proteins (receptor, ion channels, enzymes) and links these gene products to their affects on xenobiotics (Mini and Nobili, 2009). A drug that exhibits reduced efficacy does not always correlate with reduced levels of toxicity since remedial values and noxious side effects of a drug are often exerted via diverse biochemical pathways (Mini and Nobili, 2009). The study of pharmacogenomics, therefore, has vital therapeutic value because most disease states entail some sort of drug treatment (Kroemer and Meyer zu Schwabedissen, 2010). The study of genomics is now made it possible to predict safety, toxicity and efficacy of drugs and opt for a personalized treatment plan by targeting variant alleles (Dawood, 2009). The empirical notion of patients with a certain disease state reacting to drugs homogenously is flawed (Dawood, 2009). This conviction, however, does not account for genetic variation, which unfortunately leads to over 40% of patients either getting the incorrect drug or wrong dosage of the drug (Bordet, Gautier, Le Louet, Dupuis, and Caron, 2001). A Meta analysis study done in 1994, estimated that more than 2 million patients hospitalized in the US had fatalities related to adverse drug reactions (Lazarou, Pomeranz, and Corey, 1998). These results concluded that in 1994, the 106,000 fatalities associated with adverse drug effects ranked between fourth to sixth leading causes of death in the US(Lazarou et al., 1998). Regardless of strict and regulated standards for drug efficacy and prevention of toxicity, adverse drug reactions are prominent and a drug is never equivalently effective on a general population (Roses, 2000). Financially, neither the patients and/or the health insurance companies find it feasible to pay for drugs that are either ineffective or cause adverse effects (Roses, 2000). If a patient has blunted ability to metabolize a drug that is administered to them in normal doses this could easily lead to mortality due to toxic levels of the exogenous substance left in the system (Hood, 2003). Patients react to drugs in a heterogeneous manner compared to the notion of homogenous efficacy, which is particularly imminent in chemotherapeutic drugs (Dawood, 2009). Most chemotherapeutic drugs have narrow therapeutic index and any variability in metabolism of this drug can lead to adverse drug reaction (Dawood, 2009). The approach employed currently often leads to therapeutic failure and waste of time leading to expensive health care costs and valuable time (Hood, 2003). Therapeutic failure related to drug metabolism in diseases such as cancer, psychiatric disorders, and hypertension can be severely detrimental if the drugs do not take effect due to the presence of variantions in enzymes leading to high and low metabolizers (Hood, 2003). Although, genetic variability alon e does not account for all the adverse effects of drugs seen in a patient, pinpointing the altered gene can be beneficial in tailoring a more precise therapy that involves less adverse effects (Hood, 2003). Therefore, understanding the complex interaction of individuals with their environment and underlying genetic variation will allow for a gradual shift from one drug fits all perception to an embodiment of individualized medicine (Dawood, 2009). B. Individualized Medicine Individualized medicine encompasses many attributes such as clinical, genetic, and environmental factors all intertwined in a complex meshwork affecting a disease state (Ginsburg and Willard, 2009). Thorough understanding of these various attributes can aid in development of personalized treatment plans and medication types/dosages leading to an effective patient care, reduction in drug toxicity and increase in drug efficacy (Ginsburg and Willard, 2009). The ultimate goal of the drug is to have the most efficacious and least toxic effect on the patient (Dawood, 2009). However, clinical variables such as drug-drug interaction and metabolism of drug and drug transport show pronounced differences accounting for toxicity (Dawood, 2009). The statistics reveal that a certain drug is known to produce therapeutic effect only in 30% of the patients, whereas 30% of the patient show little or no advantageous effect to the drug, 10% are shown to have only deleterious effects (Maitland-van der Zee, de Boer, and Leufkens, 2000). For example if a patient is on an antidepressant, which usually take two weeks to take effect, predicting drug response for patients with a variant allele is advantageous in regards to predicting efficacy (Kirchheiner and Seeringer, 2007). Predicting drug response poses just as many challenges as do the study of inherited diseases related to genes (McCarthy and Hilfiker, 2000). The variant gene products involved in drug me tabolism are related to regulation at the level of gene expression, post translational modification and drug-drug interaction, all of which affects individual responses to xenobiotics (McCarthy and Hilfiker, 2000).Typically, drug doses are determined by body surface area and for certain group of individuals the systemic exposure is presumed to be homogenous if the surface area is similar The surface area is mainly determined based on height and weight (Dawood, 2009). The variation however stems not necessarily from differences in physical factors but rather from discrepancy in drug metabolism and drug clearance (Galpin and Evans, 1993). Although, systemic monitoring for drugs with low therapeutics indicies has been employed, it still is not efficient enough to prevent therapeutic failure (Nebert and Vesell, 2004). II. Genetic Polymorphism A. Introduction Genetic polymorphism is the variation in allele that is present at a locus and occurs in more than 1% of the population (Phillips, Veenstra, Oren, Lee, and Sadee, 2001). The allele is considered a mutation when it occurs in less than 1% of the population (Mini and Nobili, 2009). The human genome is 3 billion base pair long and the variation in one nucleotide sequence in the DNA occurs in every 100-300 bases (Hood, 2003). Single nucleotide polymorphism (SNP) is the most extensively studied genetic polymorphism, which accounts for most of the variation in drug metabolism (Schmith et al., 2003). The human genome has over 1.4 million single nucleotide polymorphisms 60, 000-100,000 is associated with drug effects ((Dawood, 2009)(Schmith et al., 2003). These SNP can gives rise to polygenic gene variants that can alter the pharmacokinetic and the pharmacodynamic portfolio of a drug leading to innate deviation in metabolism (W. E. Evans and McLeod, 2003). The gene loci that encodes for prote ins involved in drug metabolism are inherently shown to have about 47-61% polymorphism, which in turn correlates to the immense differences in substrate breakdown (Nebert, 1999). Genes that have SNPs in the coding region usually change the amino acid sequence of the protein whereas the SNP in the regulatory region are known to control the concentration of the proteins (McCarthy and Hilfiker, 2000). An exogenous substance relays its effect by interacting either on the cell membrane, cytoplasm or in the plasma (Mini and Nobili, 2009). However, a substance that is known to be efficacious in most individuals can cause detrimental effects in some if they are homozygous for the variant alleles as seen in Fig 3. This variation can affect any of the compartment of interaction a drug asserts its effects (Mini and Nobili, 2009). These alterations can manifest into phenotypes that can cause adverse effects by enhancing or inhibiting normal physiological activity (Mini and Nobili, 2009). The hu man genome project has simplified the identification of roughly 100,000 SNPs in the human genome, which can be employed to acquire accurate information on individual drug responses (Schmith et al., 2003). A haplotype is regarded as a blueprint in which not one but many SNP occur on the same chromosome (Hood, 2003). Although a single SNP may cause altered response to drugs, it is more likely the combination of SNPs on a single chromosome that may play a role in drug metabolism leading to polygenic phenotype (Hood, 2003). In the near future, clinical trials might be required to incorporate genotyping for potential drugs. The cost of genotyping for clinical trials has been predicted to cost approximately 1 million dollars (McCarthy and Hilfiker, 2000). Even though the additional cost to the trial is of concern, the overall end results might provide valuable information on drug metabolism amongst different ethnic groups, which would be beneficial in the long run. Characterization of genes of enzymes involved in drug metabolism are shown to have considerable variations; about 3 to 10 variant alleles are considered to be of the common type and over 12 to 100 variant alleles that are uncommon and occur rarely (Nebert and Vesell, 2004). Initially, when the Human Genome Project was undertaken, there was little concern about the difference in sequencing of chromosome amongst different ethnic groups (Nebert, 1999). Most scientists at the time believed there would be no substantial discrepancy between chromosomes of an individual who is of an Asian descent compared to an individual of European descent (Nebert, 1999). Graham and Smith in the 1999 study showed that there is significant variation in drug metabolism amongst individuals of different ethnic backgrounds, which effects the pharmacokinetic variability of the enzyme that are involved in drug metabolism (Graham and Peterson, 1999)(Maitland-van der Zee et al., 2000). Recent study on Asian, White s and Blacks showed that different ethnic populations differ in the frequency of alleles of a gene and this variant can result in altered drug responses (Limdi et al., 2010). The functional consequence on drug metabolism of the variant allele depends on the extension of mutation and frequency of occurrence in an individual subgroup (Maitland-van der Zee et al., 2000). To establish an accurate overall picture of variant alleles in different ethnic subgroups, an extensive SNP genotyping is needed, with an average group size of 1000 individuals in each subgroup (Nebert, 1999). The information derived from this can then be utilized for an extensive genotype-phenotype linkage study (Nebert, 1999). Figure 3 Polymorphism affecting the concentration of a drug leading to toxic doses and low efficacy in individuals who are homozygous for the variant gene. Reprinted from Pharmacogenetics: implementing personalized medicine By Enrico Mini; Stefania Nobili, Clinical Cases in Mineral and Bone Metabolism 2009; 6(1): 17-24 B. Adverse Drug Reaction Drug-drug interactions are common when numerous drugs are ingested simultaneously (Wolf et al., 2000). These drug-drug interactions can induce or inhibit enzymes in the common pathway of metabolism causing adverse effects (Oesch, 2009). An individual who has reduced ability to metabolize a substrate can easily accumulate the drug if an alternative route is not accessible (Oesch, 2009). The pharmacokinetic differences in individuals can cause poor metabolizers to have increased amounts of systemic exposure to the drug and fast metabolizers having less than normal amounts resulting in therapeutic failure or even toxicity. (Bailey, Bondar, and Furness, 1998). Comprehending this inherited genetic variability in drug metabolism can herald a new era in individualized therapy (Dawood, 2009)(Oesch, 2009)(Wolf et al., 2000). Study of pharmacogenomics allows for ways to reduce adverse drug reactions by identifying the nature of the drug, reaction to the drug and metabolic targets of the drug ( Phillips et al., 2001). All of the above can be utilized to create an extensive biomarker, which can then be employed by physicians to make appropriate dosing changes for individuals with variant alleles (Ginsburg, Konstance, Allsbrook, and Schulman, 2005). Alternatively, if reducing the dose is not a viable option, physicians can alter the treatment to include drugs that can by pass the deficient biochemical pathway (Ginsburg et al., 2005; Phillips et al., 2001). In order to utilize genotyping as a beneficial tool, physicians need to quantify variant drug responses to the specific gene unambiguously (Nebert, 1999). It is imperative that the candidate locus that is affected by the drug is identified and positive tests are employed for the variant alleles (Holmes et al., 2009). The Genetic polymorphism plays a major role in drug efficacy and also in adverse drug reactions (Dawood, 2009). Pharmacogenomic studies are hard to conduct because the variation in drug metabolism is only known after the administration of the exogenous substance, as compared to inherited diseases which have clear family linkage (McCarthy and Hilfiker, 2000). It is highly unlikely that an entire family would be prescribed a certain drug at the same time so the variation in the allele is only known under clinical trials (McCarthy and Hilfiker, 2000). SNP profiling can be beneficial if it can predict the drug response in patients and the demographics of people affected (McCarthy and Hilfiker, 2000). For example, a study by Drazen in 1999 showed that variation in ALOX5 was correlated 100% of the time with patients being non-receptive to an antiasthmatic drug (Drazen et. al, 1999). However, the prevalence of the non-variant gene in ALOX5 occurs in only 6-10 % of the patients; therefore, for a drug to be efficacious, the percent frequency of variant allele needs to be determined (Drazen et. al, 1999;McCarthy and Hilfiker, 2000). The major questions to be addressed then is how prevalent is the variant gene? How often are patients in a certain demographic group prescribed a drug that can cause adverse effects (Maitland-van der Zee et al., 2000)? A potential drug is marketed and distributed worldwide, however, most of the clinical trials are never encompass a broad range of population and most polymorphisms go undetected (McCarthy and Hilfiker, 2000). The clinical trials mainly consist of the Caucasian population in America and Europe, but a wider range of population is needed to pinpoint major variation amongst different ethnic groups (McCarthy and Hilfiker, 2000). Consequently, polymorphisms that are relevant in certain populations need to be studied and the target must be to address variant genes that are prevalent in drug metabolism (Maitland-van der Zee et al., 2000). Currently, there is little to no information on most of the drugs that are already in the market regarding genetic variability in drug metabolism (Maitland-van der Zee et al., 2000). In the future, potential drugs should include such population based studies in their clinical trials so fewer drugs would conform to one drug fits all motto (Maitland-van der Z ee et al., 2000). Polymorphism profiling can have major implication in drug safety because a drug that poses adverse effects on a large subgroup could be restricted from being launched into the market (Ginsburg et al., 2005). Genotyping can permit physicians to detect different polymorphism in individuals and allow them to create drug regimens that are not only efficacious but pose least toxic effects (Oesch, 2009). Preferential genotyping by clinicians for variant alleles could drastically reduce drug related adverse effects and in turn will be economically feasible and productive in the long run (March, 2000; Nebert and Vesell, 2004). Patient selection could be drastically improved by employment of genotyping. C. When is Genotyping Appropriate? Most drug targets are not key candidates for genotyping (Kirchheiner and Seeringer, 2007). The blood sample is collected from the patient after a day or two of administration of the drug. Therefore, drugs that require an immediate attention to dose adjustment or drugs that have a high therapeutic index may not be feasible for genotyping (Kirchheiner and Seeringer, 2007). In addition drugs that are metabolized via more than one overlying biochemical pathway pose extreme difficulties in pinpointing the variant allele and do not benefit from genotyping. However there are enzymes that have variant alleles such as the Cytochrome P450 enzymes which metabolize drugs such as warfarin, morphine, tamoxifen etc. and this polymorphism can lead to altered response to a drug (Kirchheiner and Seeringer, 2007). Adjusting the dose based on plasma level concentration of the drug is not always adequate for these patients (Dawood, 2009). Genotyping in these cases can lead to increased efficacy by identi fication of polymorphism, which can reduce the costly and time-consuming dose adjustment period. For example, CYP2D6 is a major enzyme involved in the breakdown of antidepressants. The therapeutic effects of antidepressants are only seen after a few weeks of treatment (Kirchheiner and Seeringer, 2007). Therefore, if a patient is a poor metabolizer they will accumulate the drug vs. a person who is an ultra rapid metabolizer, who will show no therapeutic value. In the case of antidepressants, genotyping for the CYP2D6 polymorphism may be beneficial prior to the start of therapy. Innovative technologies have made genotyping prevalent and we have come a long way since the advent of pharmacogenetic in the early 19th century. Pharmacogenetic disciplines if employed in pharmaceutical industry can aid in development of drugs that cater to the individual; this will allow for prospective drugs to be well suited for fewer people in comparison to drugs that assert mediocre efficacy in a vast group of individual. Food and Drug administration in 2004 permitted the employment of Chip technology known as AmpliChip by Rosche for identification of variant genes in the Cytochrome P450 pathway (http://www.roche-diagnostics.us/press_room/2005/011105.htm); (Ginsburg et al., 2005) Companies like Genelex Corporation of Seattle, Washington and Gentris are now enabling pharmaceutical companies and patients respectively to utilize Cytochrome P450 genotype profiling for CYP 2D6, CYP 2C9 and CYP2C19 enzymes (Hood, 2003). The marriage of genetics and medicine is going to become promine nt in the years to come and by the year 2020 pharmacogenomics will become a vital tool utilized to market drugs. The information derived from these test will allow patients to be on customized designer drugs(Collins and McKusick, 2001), allow physicians to set appropriate prescription amount for initial dosing and establish monitoring system for individuals with variant alleles (Tweardy and Belmont, 2009). III Cytochrome P450 Enzyme A. Background Variant alleles that lead to functional changes of gene product can have therapeutic consequences. These alleles can either have heightened responses to certain drugs causing toxicity or show none to very low compliance (Wolf et al., 2000). Polymorphism of over 20 enzymes involved in drug metabolism has been characterized and most of these involve the Cytochrome P450 enzymes (CYP) (Wolf et al., 2000). Cytochrome P450 enzymes are involved in metabolism of over 60% of drugs currently in the market today (Hood, 2003). Polymorphisms in the CYP enzymes are known to alter the pharmacokinetic aspects of exogenous substances affecting mainly the biotransformation of the substance (Kirchheiner and Seeringer, 2007). Polymorphism of the Cytochrome P450 enzyme was first discovered in relation to debrisoquine, a hypertension-correcting drug (March, 2000). Bob Smith, of Imperial College in London ingested debrisoquine and experienced severe hypotension after administration. In addition, his blood levels showed 20 fold decreased levels of drug metabolite compared to his colleagues (March, 2000; Nebert 1997). In 1988, Gonzalez and his group characterized and showed that the gene product that was causing the altered response to debrisoquine as CYP2D6; it was also found to be a liver microsomal enzyme. The cloning of this microsomal enzyme was the first look at genetic polymorphism at the molecular level (Gonzalez et al., 1988; Mini and Nobili, 2009). The study by Gonzales et al. and his group paved way for further studies geared to identify genetic polymorphism in a population that linked variant genes to alteration in drug metabolism and drug response (Mini and Nobili, 2009). Cytochrome P450s are mainly found in endoplasmic reticulum and in the mitochondria of a cell, and are copious in the liver (Porter and Coon, 1991). The CYP enzymes consist of about 49 genes that function primarily in drug metabolism (Maitland-van der Zee et al., 2000; Porter and Coon, 1991). In humans the CYP enzymes are major constituents in metabolism of fatty acids, prostoglandins, steroids and xenobiotics (Graham and Peterson, 1999). Daily diet intake of mammals consists of many natural products such as terpenes, steroids, and alkoloids and the CYP enzymes are major catalysts in the biotransformation and breakdown of these exogenous substances (Guengerich, 1991). Cytochrome P450 enzymes comprise of a super family of gene that encompass proteins predominantly involved in metabolizing of xenobiotics as well as endogenous substrates such as steroids, fatty acids, prostaglandins and arachidonate metabolites as shown in Table 1, therefore genetic polymorphism in the CYP enzymes can lead to many health related risks such as hypertension and cancer (Graham and Peterson, 1999; Jiang et al., 2005; Mayer et al., 2005). CYP enzymes are monooxygenases that catalyze non-specific oxidations of many substrates (Guengerich, 1991), (Porter and Coon, 1991). The synthetic exogenous substrates of t he cytochrome enzymes range to approximately 200,000 entities, which can all have complex interplay amongst each other in inducing or inhibiting the various isoforms of the CYP enzymes (Porter and Coon, 1991). These enzymes however are capable of catalyzing novel substrates as well and therefore one cannot cap an upper limit on the number of possible potential substrates (Porter and Coon, 1991). Therefore, the evolutionary advantage in the immensity of the CYP isoform is a crucial survival tool for our cultivating environment as well as our dynamically changing physiological system. Table 1. Exogenous and endogenous substrates of Cytochrome P450 enzymes The substrate for the CYP enzymes are just as diverse for endogenous substance as they are for exogenous substances. The CYP enzymes are prominent catalytic enzymes involved in biotransformation of various substances. Reprinted from Miniereview: Cytochrome P450 By Todd D. Porter and Minor J. Coon, The Journal of Biological Chemistry, 1991; 266(21): 13649-13472 The rates of catalyzation of the CYP enzymes are relatively slow and this can provide further explanation into their pivotal role in drug disposition (Guengerich, 1991). In addition, most of the CYP enzymes are involved in rate-limiting steps of drug metabolism and this is a key determinant of the in vivo kinetics of the drug (Pelkonen, 2002). CYP enzymes are key players in the systemic exposure of a drug and the time period a drug can assert its action (Brockmoller, Kirchheiner, Meisel, and Roots, 2000). The CYP enzymes are involved in either forming the active metabolite of the drug from a prodrug or in metabolizing the drug into inactive by-products,both of which can influence the functional temporal aspect of a drug (Brockmoller et al., 2000). Metabolites created by the CYP enzymes can also be toxic; exerting their own mutagenic and allergenic effects (Brockmoller et al., 2000). The FDA requires pharmaceutical companies to identify on the product brochure one of twenty CYP enzyme s that are involved in the biotransformation of the drug (Brockmoller et al., 2000). Interactions of different drugs concerning CYP enzymes are good predictor of drug-drug interaction, therefore marketed drugs are required to indicate the CYP enzyme involved in biotransformation of the drug on the product information (Andersson, 1991)(Brockmoller et al., 2000). However, this information does not include the polymorphism prominent within these CYP enzymes. The need for such information is crucial since these enzymes are notorious for genetic polymorphism (Brockmoller et al., 2000). Functional variations in the CYP enzymes are known to show a gradient in efficacy and variation in the quantity of the substrate present in the subject (Maitland-van der Zee et al., 2000; Wolf et al., 2000). Allelic variants causing poor, fast and ultrarapid metabolizing enzymes have been identified in most of the CYP enzymes. Most of the CYP enzymes in the liver show some degree of polymorphism (Anzenbach erova et al., 2000). B. Cytochrome Gene Family Evolution CYP enzymes are ubiquitous as they are found in every domain of living organism from Bacteria, Archaea and Eukarya and known to have originated from an ancestral gene approximately three and half billion years ago. The modern cytochrome probably originated with the Prokaryotes 1.5 billion years before the prevalence of atmospheric oxygen (Graham and Peterson, 1999; Nebert and Gonzalez, 1987; Werck-Reichhart and Feyereisen, 2000). In early eukaryotes, these enzymes not only maintained membrane veracity but also were primarily involved in the biosynthesis of endogenous hydrophobic substances such as fatty acids, cholesterol (Nebert and Gonzalez, 1987). The CYP mutilgene family diverged again 900 hundred million years later giving rise to enzymes predominantly involved in biosynthesis of steroids (Nebert and Gonzalez, 1987). This expansion lead to the another divergence of the two most important mammalian CYP families implicit in drug and carcinogen metabolizing enzymes currently known as CYP1 and CYP2 gene family (Nebert and Gonzalez, 1987). Finally, 400 million years ago dramatic expansion ensued primarily in CYP2, CYP3 and CYP4 families (Nebert and Gonzalez, 1987). This current expansion correlates to the time frame when aquatic animals merged onto the terrestrial land and were exposed to many hydrocarbon-based combustion material in the environment along with toxic plant products in their diet (Gonzalez and Nebert, 1990; D. R. Nelson and Strobel, 1987) The generation of this multigene family is due to the multiple mechanistic changes over time that reflect the complexity and diversity of the CYP enzymes. Most of the changes are related to lack of intron conservation (Werck-Reichhart and Feyereisen, 2000), exon shuffling (Doolittle, 1985; Patthy, 1985), expression of redundant genes (Anderson et al., 1981; Barrell, Air, and Hutchison, 1976), alternative splicing, frame shit mutations and RNA editing (Andreadis, Gallego, and Nadal-Ginard, 1987; Atkins, Weiss,