Pharmacogenetics and Individualized Therapy E-Book

• Herausgeber: John Wiley & Sons
• Kategorie: Wissenschaft und neue Technologien
• Sprache: Englisch

Seitenzahl: 984

Veröffentlichungsjahr: 2012

Beschreibung

This resource provides thorough coverage of pharmacogenetics and its impact on pharmaceuticals, therapeutics, and clinical practice. It opens with the basics of pharmacogenetics, including drug disposition and pharmacodynamics. The following section moves into specific disease areas, including cardiovascular, psychiatry, cancer, asthma/COPD, adverse drug reactions, transplantation, inflammatory bowel disease, and pain medication. Clinical practice and ethical issues make up the third section, with the fourth devoted to technologies like genotyping, genomics, and proteomics. In the fifth part, chapters discuss the impact of key regulatory issues on the pharmaceutical industry.

Leseprobe

Contents

Cover

Title Page

Copyright

Preface

Contributors

Chapter 1: Pharmacogenetics: A Historical Perspective

1.1 Introduction

1.2 Early Pharmacogenetics Studies (from 1900 to 1970)

1.3 Pharmacogenetics of Drug Oxidation

1.4 Pharmacogenetics of Drug Conjugation

1.5 Pharmacogenetic Studies on Receptors and Transporters

1.6 Pharmacogenomics, Genomewide Studies, and Personalized Medicine

1.7 Conclusion

References

Part I: Pharmacogenetics: Relationship to Pharmacokinetics and Pharmacodynamics

Chapter 2: Pharmacogenetics in Drug Metabolism: Role of Phase I Enzymes

2.1 Introduction

2.2 Cytochromes P450

2.3 Non-P450 Phase I Enzymes

References

Chapter 3: Pharmacogenetics of Phase II Drug Metabolizing Enzymes

3.1 Introduction

3.2 Arylamine N-Acetyltransferases

3.3 Thiopurine-S-Methyltransferase (TPMT)

3.4 Glutathione S-Transferases

3.5 UDP Glucuronosyltransferases

3.6 Sulfotransferases

References

Chapter 4: Pharmacogenetics of Drug Transporters

4.1 Introduction

4.2 Pharmacogenetics of Uptake Transporters

4.3 Pharmacogenetics of Efflux Transporters

4.4 Conclusion

References

Chapter 5: Pharmacogenetics of Drug Targets

5.1 Introduction

5.2 Receptors

5.3 Enzymes

5.4 Transporters

5.5 Concluding Remarks

References

Part II: Pharmacogenetics: Therapeutic Areas

Chapter 6: Cardiovascular Pharmacogenetics

6.1 Introduction

6.2 Cardiovascular Disease

6.3 Cardiovascular Therapy

6.4 Genetic Determinants of Response to Cardiovascular Drugs

6.5 Clinical Implications

6.6 Future Directions

6.7 Conclusion

References

Chapter 7: Pharmacogenetics in Psychiatry

7.1 Introduction

7.2 Pharmacogenetics of Antipsychotic Treatment

7.3 Pharmacogenetics of Antidepressant Treatment

7.4 Pharmacogenetics of Lithium Treatment

7.5 Conclusions

References

Chapter 8: Pharmacogenetics in Cancer

8.1 Introduction

8.2 Personalized Therapy

8.3 Pharmacogenomic Markers

8.4 Conclusions

References

Chapter 9: Pharmacogenetics of Asthma and COPD

9.1 Introduction

9.2 Asthma and Copd

9.3 Asthma and COPD Treatment

9.4 Studies of Asthma and COPD Pharmacogenetics

9.5 Challenges in Asthma and COPD Pharmacogenetics

9.6 Future Directions

References

Chapter 10: Pharmacogenetics of Adverse Drug Reactions

10.1 Introduction

10.2 Drug-Induced Liver Injury

10.3 Drug-Induced QT Interval Prolongation

10.4 Drug-Induced Muscle Toxicity

10.5 Hypersensitivity Reactions (Including Severe Skin Rash)

10.6 Concluding Remarks

References

Chapter 11: Pharmacogenomics of Inflammatory Bowel Diseases

11.1 Introduction

11.2 Susceptibility Genes in IBD

11.4 Conclusion

11.5 Acknowledgments

References

Chapter 12: Pharmacogenetics of Pain Medication

12.1 Introduction

12.2 Genetic Modulation of the Effects of Classical Analgesics

12.3 Genetics of Drug Addiction

12.4 Pharmacogenetics of Drug Interactions

12.5 Conclusions and Future Perspectives

References

Part III: Pharmacogenetics: Implementation in Clinical Practice

Chapter 13: Ethical and Social Issues in Pharmacogenomics Testing

13.1 Introduction

13.2 The Rise of Genomics Research

13.3 Ethical Principles in the Era of Genomics

13.4 “Informed” Consent?

13.5 Individual and Collective Implications

13.6 Pharmacogenomics Applications in HealthCare

13.7 Lost in Translation

13.8 Integration into the Clinic and Pharmacy

13.9 Direct-to-Consumer (DTC) Pharmacogenetic Testing

13.10 The Need for Partnerships to Build the Necessary Evidence

13.11 Pharmacogenomics in Low-Resource Settings

13.12 Conclusions

References

Part IV: Developments in Pharmacogenetic Research

Chapter 14: High-Throughput Genotyping Technologies for Pharmacogenetics

14.1 Introduction

14.2 TaqMan OpenArray Genotyping System

14.3 Sequenom

14.4 Commercial High-Density Arrays

14.5 Conclusion

References

Chapter 15: Developments in Analyses in Pharmacogenetic Datasets

15.1 Introduction

15.2 Defining Drug Response Phenotype

15.3 Establishing the Heritability of Drug Response Phenotypes

15.4 Appropriate Study Designs for Pharmacogenomics Studies

15.5 Traditional Methods For Genetic Mapping

15.6 Novel Methodology for Complex Predictive Models

15.7 Developing an Analysis Plan

15.8 Conclusions

References

Part V: Pharmacogenetics: Industry and Regulatory Affairs

Chapter 16: Applications of Pharmacogenetics in Pharmaceutical Research and Development

16.1 Introduction

16.2 Enabling Genetic Developments

16.3 Pharmacogenetics and the Pharmaceutical R&D Pipeline

16.4 Nonpharmaceutical Industry Drivers of Pharmacogenetics

16.5 Conclusion

References

Chapter 17: Role of Pharmacogenetics in Registration Processes

17.1 Introduction

17.2 Critical Path Initiatives

17.3 Guidance for Industry

17.4 Voluntary Exploratory Data Submission (VXDS)

17.5 Biomarker Qualification Process

17.6 Labeling and Pharmacogenomics

17.7 Level of Evidence in Pharmacogenomics and Pharmacogenetics

17.8 Genetics and Genomic Tests

17.9 Education and Training

17.10 Conclusion

References

Part VI: Conclusions

Chapter 18: Pharmacogenetics: Possibilities and Pitfalls

18.1 Introduction

18.2 Pharmacogenetics in Clinical Practice

18.3 Safety

18.4 GWAS

18.5 New Developments

18.6 Conclusion

References

Color Plates

Index

Copyright © 2012 by John Wiley & Sons, Inc. All rights reserved.

Published by John Wiley & Sons, Inc., Hoboken, New Jersey

Published simultaneously in Canada

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Library of Congress Cataloging-in-Publication Data:

Pharmacogenetics and individualized therapy / edited by Anke-Hilse Mailand-van der Zee, Ann K. Daly.

p.; cm.

Includes bibliographical references and index.

ISBN 978-0-470-43354-6 (cloth)

1. Pharmacogenetics. I. Maitland-van der Zee, Anke-Hilse. II. Daly, Ann K.

[DNLM: 1. Pharmacogenetics–methods. 2. Drug Therapy–methods. 3. Individualized Medicine–methods. QV 38]

RM301.3.G45P396 2011

615′.19–dc23

2011015209

Preface

Pharmacogenetics and individualized therapy is a rapidly evolving field that is likely to have important consequences for clinical practice in the coming decades. This book is aimed at a general audience including advanced undergraduate and graduate students in medicine, pharmacy, pharmacology, and other related disciplines as well as researchers based in either academia or the pharmaceutical industry. Some familiarity with basic pharmacology and genetics is assumed.

This book is organized in five parts. Part I describes the basic principles of pharmacogenetics including factors relevant to drug disposition (phase I and phase II metabolizing enzymes, and drug transporters) and the role of pharmacodynamics (drug targets).

Part II includes discussions of state-of-the art pharmacogenetics in many important therapeutic areas [cardiovascular, psychiatry, cancer, asthma/chronic obstructive pulmonary disease (COPD), adverse drug reactions, transplantation, inflammatory bowel disease, pain medication].

Part III describes ethical and related issues in implementing pharmacogenetics into clinical practice.

In Part IV important developments in the techology supporting pharmacogenetics research are discussed. More recent developments in genotyping techniques provide opportunities for genotyping over 1 million single-nucleotide polymorphisms in many patients at affordable prices. Further developments in analysis techniques provide investigators with the opportunity to consider gene–environment and epistatic interactions as well as the possibility of whole-genome sequencing.

Part V discusses the impact of pharmacogenetics in the pharmaceutical industry and also the role that pharmacogenetics currently plays in the registration process.

It has been a privilege to interact with the distinguished expert authors who have provided chapters for this book, and we would like to express our sincere gratitude to them for their excellent contributions. We also wish to thank Lisa Gilhuijs-Pederson, PhD for assistance in editing this book.

ANN K. DALY, PhDANKE-HILSE MAITLAND-VAN DER ZEE, PharmD PhD

Contributors

Katherine J. Aitchison, Institute of Psychiatry, King's College London, London, UK

Martin Armstrong, Clinical Development and Medical Affairs, Shire AG, Geneva, Switzerland

Maria Arranz, Institute of Psychiatry, King's College London, London, UK

Anthonius de Boer, Faculty of Science, Utrecht Institute for Pharmaceutical Sciences (UIPS), Division of Pharmacoepidemiology and Pharmacotherapy, Utrecht University, Utrecht, The Netherlands

Daniel K. Burns, Deane Drug Discovery Institute, Duke University, Durham, North Carolina, USA

Angel Carracedo, Galician Foundation of Genomic Medicine (SERGAS), University of Santiago de Compostela, Santiago de Compostela, Spain

Ingolf Cascorbi, Institute of Experimental and Clinical Pharmacology, University Hospital Schleswig–Holstein, Kiel, Germany

Martina Cornel, Department of Human Genetics/EMGO Institute for Health Care and Research, VU University Medical Center, Amsterdam, The Netherlands and Center for Society and Genomics, Radboud University, Nijmegen, The Netherlands

Sarah Curran, Institute of Psychiatry, King's College London, London, UK

Ann K. Daly, Institute of Cellular Medicine, Newcastle University Medical School, Newcastle upon Tyne, UK

Vita Dolžan, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia

Markus Grube, Department of Pharmacology, Ernst Moritz Arndt-University of Greifswald, Greifswald, Germany

Shiew-Mei Huang, Office of Clinical Pharmacology, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, USA

Susanne Karner, Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany

Myong-Jin Kim, Office of Clinical Pharmacology, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, USA

Olaf H. Klungel, Faculty of Science, Utrecht Institute of Pharmaceutical Sciences (UIPS), Division of Pharmacoepidemiology and Pharmacotherapy, Utrecht University, Utrecht, The Netherlands

Gerard H. Koppelman, Pediatric Pulmonology and Pediatric Allergology, Beatrix Childrens Hospital, University Medical Center Groningen, Groningen, The Netherlands

Ellen S. Koster, Faculty of Science, Utrecht Institute of Pharmaceutical Sciences (UIPS), Division of Pharmacoepidemiology and Pharmacotherapy, Utrecht University, Utrecht, The Netherlands

Heyo K. Kroemer, Department of Pharmacology, Ernst Moritz Arndt-University of Greifswald, Greifswald, Germany

Lawrence J. Lesko, Office of Clinical Pharmacology, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, USA

Jörn Lötsch, Pharmazentrum Frankfurt and Department of Clinical Pharmacology, Johann Wolfgang Goethe-University Hospital, Frankfurt, Germany

Anke-Hilse Maitland-van der Zee, Faculty of Science, Utrecht Institute of Pharmaceutical Sciences (UIPS), Division of Pharmacoepidemiology and Pharmacotherapy, Utrecht University, Utrecht, The Netherlands

Sharon Marsh, Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada

Henriette E. Meyer zu Schwabedissen, Department of Pharmacology, Ernst Moritz Arndt-University of Greifswald, Greifswald, Germany

Alison A. Motsinger-Reif, Bioinformatics Research Center, Department of Statistics, North Carolina State University, Raleigh, North Carolina, USA

Ruth I. Ohlsen, Institute of Psychiatry, King's College London, London, UK

Bas J. M. Peters, Faculty of Science, Utrecht Institute for Pharmaceutical Sciences (UIPS), Division of Pharmacoepidemiology and Pharmacotherapy, Utrecht University, Utrecht, The Netherlands

Toine Pieters, Faculty of Science, Utrecht Institute for Pharmaceutical Sciences (UIPS), Division of Pharmacoepidemiology and Pharmacotherapy, Utrecht University, Utrecht, The Netherlands; and Department of Medical Humanities, VU University Medical Center, Amsterdam, The Netherlands

Munir Pirmohamed, Institute of Translational Medicine, University of Liverpool, Liverpool, UK

Jan A. M. Raaijmakers, Faculty of Science, Utrecht Institute of Pharmaceutical Sciences (UIPS), Division of Pharmacoepidemiology and Pharmacotherapy, Utrecht University, Utrecht, The Netherlands

Elke Schaeffeler, Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany

Tom Schalekamp, Faculty of Science, Utrecht Institute for Pharmaceutical Sciences (UIPS), Division of Pharmacoepidemiology and Pharmacotherapy, Utrecht University, Utrecht, The Netherlands

Matthias Schwab, Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany and Institute of Experimental and Clinical Pharmacology and Toxicology, University Hospital, Tübingen, Germany

Beatriz Sobrino, Galician Foundation of Genomic Medicine (SERGAS), University of Santiago de Compostela, Santiago de Compostela, Spain

Scott S. Sundseth, Cabernet Pharmaceuticals, Durham, North Carolina, USA

Alexander Teml, Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany

Evangelia M. Tsapakis, Institute of Psychiatry, King's College London, London, UK

Susanne Vijverberg, Faculty of Science, Utrecht Institute for Pharmaceutical Sciences (UIPS), Division of Pharmacoepidemiology and Pharmacotherapy, Utrecht University, Utrecht, The Netherlands

Nora S. Vyas, Institute of Psychiatry, King's College London, London, UK

Issam Zineh, Office of Clinical Pharmacology, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, USA

Chapter 1

Pharmacogenetics: A Historical Perspective

Ann K. Daly

Newcastle University, Newcastle upon Tyne, UK

1.1 Introduction

It has been known for thousands of years that some individuals show toxic responses following consumption of fava beans, especially in countries bordering the Mediterranean. This is probably the earliest pharmacogenetic observation, although the biological basis for this has been established only quite recently (see Section 1.2). The foundation for much of modern pharmacogenetics came from experiments on chemical metabolism during the 19th century. These studies included the establishment that benzoic acid undergoes conjugation with glycine in vivo in both humans and animals, that benzene is oxidized to phenol in both dogs and humans and that some compounds can undergo conjugation with acetate (for a review, see Ref. 1).

1.2 Early Pharmacogenetics Studies (from 1900 to 1970)

The development of genetics and Mendelian inheritance together with observations by Archibald Garrod on the possibility of variation in chemical metabolism in the early 20th century has been well reviewed elsewhere see [2]. Probably the first direct pharmacogenetic study was reported in 1932 when Synder's study on the ability to taste phenylthiocarbamide within families showed that this trait was genetically determined [3]. The gene responsible for this variation and common genetic polymorphisms have only recently been identified (for a perspective, see Ref. 4). Although not a prescribed drug, phenylthiocarbamide shows homology to drugs such as propylthiouracil.

The initial drug-specific pharmacogenetics observations appeared in the literature during the 1950s. These were concerned with three widely used drugs at that time, that are all still used today: isoniazid, primaquine, and succinylcholine. The earliest observation concerned primaquine, which was found by Alf Alving to be associated with acute hemolysis in a small number of individuals [5]. Subsequent work by Alving and colleagues found that this toxicity was due to absence of the enzyme glucose-6-phosphate dehydrogenase in red blood cells of affected individuals [6]. The molecular genetic basis of this deficiency was later established by Ernest Beutler and colleagues in 1988 [7].

Isoniazid was first used against tuberculosis in the early 1950s, although it had been developed originally a number of years previously as an antidepressant. As reviewed recently, its use in tuberculosis patients represented an important advance in treatment of this disease [8]. Variation between individuals in urinary excretion profiles was described by Hettie Hughes [9], who soon afterwards also found an association between the metabolic profile and the incidence of a common adverse reaction, peripheral neuritis, with those showing slow conversion of the parent drug to acetylisoniazid more susceptible [10]. Further studies by several different workers, particularly Mitchell and Bell [11], Harris [12], and David Price Evans [13], led to the conclusion that isoniazid acetylation was subject to a genetic polymorphism and that some individuals (~10% of East Asians but 50% of Europeans) were slow acetylators. Slow acetylation was shown to be a recessive trait. As summarized in Section 1.4, the biochemical and genetic basis of slow acetylation is now well understood.

Also during the 1950s, a rare adverse response to the muscle relaxant succinylcholine was found to be due to an inherited deficiency in the enzyme cholinesterase [14]. Succinylcholine is used as a muscle relaxant during surgery, and those with the deficiency show prolonged paralysis (succinylcholine apnea). This observation was then further developed by Werner Kalow, who showed that the deficiency is inherited as an autosomal recessive trait and devised a biochemical test to screen for the deficiency, as he described in a description of his early work [15]. The gene encoding this enzyme, which is now usually referred to as butyrylcholinesterase, has been well studied, and a number of different mutations responsible for the deficiency have been identified. However, the original biochemical test is still the preferred method for identifying those affected by succinylcholine apnea due to the rarity of both the problem and the number of different mutations.

While these initial studies showing the clear role for genetics in determining adverse responses to primaquine, isoniazid, and succinylcholine were in progress, the general importance of the area was increasingly recognized. Arno Motulsky published a key review on the relationship between biochemical genetics and drug reactions that highlighted the adverse reactions to primaquine and succinylcholine in 1957 [16]. The term pharmacogenetics was first used in 1959 by Friedrich Vogel in an article on human genetics written in German [17] and was soon adopted by others working in the field.

1.3 Pharmacogenetics of Drug Oxidation

As described in Section 1.1, studies in the 19th century had demonstrated oxidation of benzene to phenol in vivo [1]. Pioneering studies on drug metabolism, especially those in the laboratories of the Millers and of Brodie and Gillette during the 1950s, showed that many drugs undergo oxidative metabolism in the presence of NADPH and molecular oxygen in liver microsomes [18, 19]. In 1962, Omura and Sato described cytochrome P450 from a rat liver microsome preparation as a hemoprotein that showed a peak at 450 nm in the presence of carbon monoxide and dithionite [20]. Shortly afterwards Ron Estabrook, David Cooper, and Otto Rosenthal showed that cytochrome P450 had steroid hydroxylase activity [21], and further studies confirmed its role in the metabolism of drugs such as codeine, aminopyrene, and acetanilide [22]. At this time, it was still assumed that cytochrome P450 was a single enzyme, but evidence for multiple forms emerged in the late 1960s [23, 24] with purification of a range of rat and rabbit enzymes achieved during the 1970s [25, 26].

Independent metabolism studies on two newly developed drugs sparteine and debrisoquine in Germany by Michel Eichelbaum and in the United Kingdom by Robert Smith in the mid 1970s resulted in findings indicating that some individuals were unable to oxidize these drugs, although the majority of individuals showed normal metabolism [27, 28]. These studies estimated that 10% of Europeans showed absence of activity, and the term poor metabolizer was first used. At this time, the enzymes responsible for this absence of activity were not known, but further studies confirmed that the deficiency in metabolism of both drugs cosegregated [29] and that the trait was inherited recessively [30]. It became clear that a number of different drugs, including tricyclic antidepressants, were also metabolized by this enzyme [31]. Studies on human liver microsomes confirmed that the enzyme responsible was a cytochrome P450 [32, 33], and this enzyme was then purified to homogeneity [34]. The availability of antibodies to the purified protein facilitated the cloning of the relevant cDNA by Frank Gonzalez and colleagues, who initially termed the gene CYPIID1 [35]. On the basis of emerging data for cytochrome P450 genes in humans and other animal species, it was decided subsequently that the gene encoding the debrisoquine/sparteine hydroxylase should be termed CYP2D6. Studies on human genomic DNA led to the identification of several polymorphisms in CYP2D6 associated with the poor metabolizer phenotype, including the most common splice site variant, a large deletion, and a small deletion [36–40]. A major additional contribution to the field was made in 1993 by Johansson, Ingelman-Sundberg, and colleagues, who described the phenomenon of ultrarapid metabolizers with one or more additional copies of CYP2D6 present [41]. These ultrarapid metabolizers had been previously identified on the basis of poor response to tricyclic antidepressants, and this was one of the first accounts of copy number variation in the human genome. Agreement regarding the current nomenclature for variant alleles in CYP2D6 and other cytochromes P450 was reached in 1996 [42].

In an approach similar to that used in the discovery of the CYP2D6 polymorphism, Kupfer and Preisig found that some individuals showed absence of metabolism of the anticonvulsant S-mephenytoin [43]. It was demonstrated that S-mephenytoin metabolism did not cosegregate with that of debrisoquine and sparteine, as this polymorphism was due to a separate gene defect. Identification of the gene responsible for S-mephenytoin hydroxylase proved difficult initially, probably because the relevant enzyme was expressed at a low level in the liver. The gene, now termed CYP2C19, was cloned by Goldstein and Meyer and colleagues in 1994, and the two most common polymorphisms associated with absence of S-mephenytoin hydroxylase activity were identified [44, 45].

A number of other cytochrome P450 genes are now known to be subject to functionally significant polymorphisms. In the case of one of these, CYP2C9, which metabolizes a range of drugs, including warfarin, tolbutamide, and nonsteroidal antiinflammatory drugs, some evidence for the existence of a polymorphism appeared in 1979 when a trimodal distribution in the metabolism of tolbutamide was reported [46]. Subsequently, it was shown that tolbutamide metabolism was distinct from debrisoquine metabolism [47]. The enzyme involved was purified and cloned and later named CYP2C9 [48, 49]. Analysis of CYP2C9 cDNA sequences provided evidence for the presence of coding region polymorphisms resulting in amino acid substitutions, and expression studies suggested these were functionally significant [48, 50, 51]. Genotyping of patients undergoing warfarin treatment confirmed the functional importance of the two most common coding region CYP2C9 polymorphisms [52–54].

Using a similar approach involving comparison of cloned cDNA sequences, evidence for a nonsynonymous polymorphism in CYP2A6 was obtained [55]. Following expression studies and population screening, it was demonstrated that this polymorphism was associated with a rare absence of CYP2A6 activity, but additional polymorphisms (including a large deletion) in CYP2A6 that also lead to loss of activity have been reported [56].

Biochemical studies on human liver demonstrated that some individuals express an additional cytochrome P450 with homology but not identity to the major drug metabolizing P450 CYP3A4 [57–59]. Expression of this isoform, now termed CYP3A5, is also determined by a common genetic polymorphism affecting splicing that was first identified by Erin Schutz and colleagues in 2001 [60].

From the early studies in the 1970s, it is now clear that at least four CYPs, namely, CYP2D6, CYP2C19, CYP2A6, and CYP3A5, are subject to polymorphisms leading to absence of enzyme activity in significant numbers of individuals and that CYP2C9 activity is very low (although not completely absent) in some individuals. There are also a large number of polymorphisms leading to smaller changes in cytochrome P450 activities (see Chapter 3 for more details). Current knowledge of phenotype–genotype relationships within the cytochrome P450 family is now more comprehensive than for the majority of human genes, although a better understanding of some aspects such as regulation of gene expression is still needed.

1.4 Pharmacogenetics of Drug Conjugation

As discussed in Section 1.2, a polymorphism affecting conjugation of drugs such as isoniazid with acetyl CoA had been known to exist since the 1950s. Other conjugation polymorphisms were subsequently described from phenotyping studies. In particular, Richard Weinshilboum identified several polymorphisms affecting methylation of xenobiotics and endogenous compounds by measurement of enzymatic activities in blood cells. He described the most pharmacologically important of these polymorphisms, in thiopurine methyltransferase (TPMT), in 1980 [61]. Approximately 1 in every 300 Europeans lacks this enzyme with lower activity observed in heterozygotes. Other conjugation polymorphisms identified by phenotypic approaches included a deficiency in the glutathione S-transferase M1 (GSTM1), which affects 50% of Europeans and was originally detected by measurement of trans-stilbene oxide conjugation in lymphocytes [62]. The classic paper by Motulsky on genetic variability in metabolism [16] mentioned the mild hyperbilirubinemia described previously by Gilbert in 1901 and usually referred to as Gilbert's syndrome [63]. This was later shown to relate to impaired activity in glucuronidation by a form of the enzyme UDP-glucuronosyltransferase, and there were suggestions that glucuronidation of prescribed drugs might also be affected in this syndrome [64].

With the development of molecular cloning techniques, the basis of the various conjugation polymorphisms known previously became clear during the late 1980s and early 1990s, and evidence also emerged for additional functionally significant polymorphisms by sequence comparisons. The molecular basis of the GSTM1 deficiency was established quite early in 1988, probably because it is due to a large gene deletion that was readily detectable by a number of different approaches [65]. Cloning of the NAT2 cDNA, encoding the enzyme responsible for isoniazid metabolism, was achieved in 1991 by Blum and Meyer with two common variant alleles with several base substitutions in their coding regions found to be associated with absence of activity [66]. Other inactive variants were identified elsewhere [67, 68], and, as in the case of the cytochrome P450 alleles, a standardized nomenclature system was developed [69]. In the case of TPMT, gene cloning and identification of two common alleles associated with absence of activity was achieved in 1996 [70, 71]. The most common variant allele giving rise to Gilbert's syndrome was identified in the same year and found to be a TA insertion in the promoter region of the UGT1A1 gene, which encodes the major UDP-glucuronosyltransferase responsible for bilirubin conjugation [72].

Genotyping for the TPMT polymorphisms in patients being prescribed 6-mercaptopurine or azathioprine and the UGT1A1 variant associated with Gilbert's disease in patients receiving irinotecan are now recommended but not mandated by the US Food and Drug Administration (FDA). Knowledge of genotype can enable either dose adjustment or an alternative drug to be prescribed.

1.5 Pharmacogenetic Studies on Receptors and Transporters

Progress on pharmacogenetics of drug receptors and other targets has been slower mainly because phenotypic evidence for the existence of functionally significant polymorphisms was generally not available. However, as discussed in Chapter 5, data from the human genome sequencing project have provided new insights into this area. Studies on polymorphisms in both the adrenergic receptor and dopamine receptor genes appeared in the early 1990s with Stephen Liggett leading in the area of adrenergic receptors [73]. As discussed in Chapter 6, polymorphisms in the various adrenergic receptors have been demonstated to be of considerable relevance to drug response, especially for the β2-receptor, but the overall pharmacological importance of polymorphisms in dopamine receptors is still less well established.

Among other drug targets, vitamin K epoxide reductase, the target for coumarin anticoagulants, which is also discussed in detail in Chapter 6, is another example of a gene with well-established pharmacogenetics. In particular, limited phenotypic data from the 1970s suggested that the target for warfarin was subject to interindividual variation in some individuals with resistance to the drug occurring in some families [74]. The gene encoding vitamin K epoxide reductase in humans was finally identified only in 2004 [75, 76], but this advance quickly led to identification of isolated mutations associated with warfarin resistance and also to common genetic polymorphisms affecting response to anticoagulants [77–79].

1.6 Pharmacogenomics, Genomewide Studies, and Personalized Medicine

As reviewed by Meyer [2], the term pharmacogenomics first appeared in the literature in 1997. One of the first articles using this term [80] described its relevance to personalized medicine. Pharmacogenomics is often described as the whole-genome application of pharmacogenetics. There is clearly a large overlap between the two disciplines, but pharmacogenomics is broader and may involve the development of new drugs to target specific genes as well as more effective use of existing medicines. Prior to the 1990s, pharmacogenetic studies were concerned with the effects of single genes, but in the era of pharmacogenomics, the combined effects of a number of genes on a particular phenotype is typically investigated.

Probably the best example of an area in which there has been some implementation of pharmacogenomics is in cancer chemotherapy. Although pharmacogenetic polymorphisms such as TPMT (see Section 1.4) are important in determining the metabolism of selected drugs used in chemotherapy and their possible toxicity, it was realised that tumor genotype and phenotype in addition to host genotype will be predictors of response. The licensing of trastuzumab (Herceptin) as a targeted therapy for breast tumors in 1998 is the earliest example of a drug used as a personalized medicine on the basis of tumor phenotype (for review, see Ref. 81). A test to determine estrogen receptor status is needed before the drug is prescribed as only tumors that are estrogen receptor–positive respond. Other similar drugs followed, most notably imatinib (Glivec) in 2001. Imatinib is a tyrosine kinase inhibitor effective only in tumors with a particular chromosomal translocation [81]. In a separate development, it is now possible to classify tumors by signature for expression of a number of different genes and to use this signature to predict the most appropriate cancer chemotherapy regimen. As discussed by Bonnefoi and colleagues [82], clinical trials are now in progress in breast cancer patients to confirm previous retrospective trials showing that determining mRNA expression levels for a set of either 21 or 70 genes in tumor tissue was of value in predicting whether patients with early-stage breast cancer should undergo chemotherapy or be treated only by hormone therapy.

Another area of pharmacogenomics that is currently developing is the use of genomewide association studies to identify genotypes associated with either drug response or drug toxicity. Such studies have been widely reported for complex polygenic diseases with some interesting novel genes affecting disease susceptibility already identified [83]. A number of genomewide association studies on drug response or adverse reactions have appeared since 2007 [84–86], but these have generally pointed to only one or two genes having a major effect rather than the larger number of genes each with a small effect typically seen in the complex polygenic disease studies. Further similar studies, especially on serious adverse drug reactions, are already in progress.

1.7 Conclusion

During 1957–1997, pharmacogenetics evolved to pharmacogenomics. There has been considerable further progress in the subsequent 12 years. Our understanding of single gene effects, especially in relation to drug metabolism, is now comprehensive, but our understanding of effects by multiple genes is still limited. In addition, we still need to translate the range of well-validated and clinically relevant pharmacogenetic discoveries that have been made over the years into more widespread use in patient care. Despite the predictions that we are entering an era of personalized medicine [80], except for the few examples discussed in Sections 1.5 and 1.6 in relation to cancer treatment, this has not yet occurred to any great extent.

References

1. Conti A, Bickel MH. History of drug-metabolism—discoveries of major pathways in 19th-century. Drug Metab. Rev. 1977;6: 1–50.

2. Meyer UA. Pharmacogenetics—five decades of therapeutic lessons from genetic diversity. Nat. Rev. Genet. 2004;5: 669–676.

3. Snyder LH. Studies in human inheritance IX. The inheritance of taste deficiency in man. Ohio J. Sci. 1932;32: 436–468.

4. Wooding S. Phenylthiocarbamide: A 75-year adventure in genetics and natural selection. Genetics 2006;172: 2015–2023.

5. Clayman CB, Arnold J, Hockwald RS, Yount EH Jr, Edgcomb JH, Alving AS. Toxicity of primaquine in Caucasians. J. Am. Med. Assoc. (JAMA) 1952;149: 1563–1568.

6. Alving AS, Carson PE, Flanagan CL, Ickes CE. Enzymatic deficiency in primaquine-sensitive erythrocytes. Science 1956;124: 484–485.

7. Hirono A, Beutler E. Molecular cloning and nucleotide sequence of cDNA for human glucose-6-phosphate dehydrogenase variant A(−). Proc. Natl. Acad. Sci. USA 1988;85: 3951–3954.

8. Rieder HL. Fourth-generation fluoroquinolones in tuberculosis. Lancet 2009;373: 1148–1149.

9. Hughes HB. On the metabolic fate of isoniazid. J. Pharmacol. Exp. Ther. 1953;109: 444–452.

10. Hughes HB, Biehl JP, Jones AP, Schmidt LH. Metabolism of isoniazid in man as related to the occurrence of peripheral neuritis. Am. Rev. Tuberc. 1954;70: 266–273.

11. Mitchell RS, Bell JC. Clinical implications of isoniazid, PAS and streptomycin blood levels in pulmonary tuberculosis. Trans. Am. Clin. Climatol. Assoc. 1957;69: 98–102; discussion. 103–105.

12. Harris HW, Knight RA, Selin MJ. Comparison of isoniazid concentrations in the blood of people of Japanese and European descent; therapeutic and genetic implications. Am. Rev. Tuberc. 1958;78: 944–948.

13. Evans DAP, Manley KA, McKusick VA. Genetic control of isoniazid metabolism in man. Br. Med. J. 1960;2: 485–491.

14. Lehmann H, Ryan E. The familial incidence of low pseudocholinesterase level. Lancet 1956;271: 124.

15. Kalow W. The Pennsylvania State University College of Medicine 1990 Bernard B. Brodie Lecture. Pharmacogenetics: Past and future. Life Sci. 1990;47: 1385–1397.

16. Motulsky AG. Drug reactions enzymes, and biochemical genetics. J. Am. Med. Assoc. 1957;165: 835–837.

17. Vogel F. Moderne probleme der humangenetik. Ergebnisse der Innere Medizinische und Kinderheilkunde 1959;12: 52–62.

18. Conney AH, Miller EC, Miller JA. Substrate-induced synthesis and other properties of benzpyrene hydroxylase in rat liver. J. Biol. Chem. 1957;228: 753–766.

19. Brodie BB, Gillette JR, La Du BN. Enzymatic metabolism of drugs and other foreign compounds. Annu. Rev. Biochem. 1958;27: 427–454.

20. Omura T, Sato R. A new cytochrome in liver microsomes. J. Biol. Chem. 1962;237: 1375–1376.

21. Cooper DY, Estabrook RW, Rosenthal O. The stoichiometry of C21 hydroxylation of steroids by adrenocortical microsomes. J. Biol. Chem. 1963;238: 1320–1323.

22. Cooper DY, Levin S, Narasimhulu S, Rosenthal O. Photochemical action spectrum of the terminal oxidase of mixed function oxidase systems. Science 1965;147: 400–402.

23. Sladek NE, Mannering GJ. Induction of drug metabolism. I. Differences in the mechanisms by which polycyclic hydrocarbons and phenobarbital produce their inductive effects on microsomal N-demethylating systems. Mol. Pharmacol. 1969;5: 174–185.

24. Alvares AP, Schilling G, Levin W, Kuntzman R. Studies on the induction of CO-binding pigments in liver microsomes by phenobarbital and 3-methylcholanthrene. Biochem. Biophys. Res. Commun. 1967;29: 521–526.

25. Cheng KC, Schenkman JB. Purification and characterization of two constitutive forms of rat liver microsomal cytochrome P-450. J. Biol. Chem. 1982;257: 2378–2385.

26. Wiebel FJ, Selkirk JK, Gelboin HV, Haugen DA, van der Hoeven TA, Coon MJ. Position-specific oxygenation of benzo(a)pyrene by different forms of purified cytochrome P-450 from rabbit liver. Proc. Natl. Acad. Sci. USA 1975;72: 3917–3920.

27. Eichelbaum M, Spannbrucker N, Steincke B, Dengler HJ. Defective N-oxidation of sparteine in man: A new pharmacogenetic defect. Eur. J. Clin. Pharmacol. 1979;17: 153–155.

28. Mahgoub A, Idle JR, Dring LG, Lancaster R, Smith RL. Polymorphic hydroxylation of debrisoquine in man. Lancet 1977;ii: 584–586.

29. Bertilsson L, Dengler HJ, Eichelbaum M, Schulz HU. Pharmacogenetic covariation of defective N-oxidation of sparteine and 4-hydroxylation of debrisoquine. Eur. J. Clin. Pharmacol. 1980;17: 153–155.

30. Evans DAP, Mahgoun A, Sloan TP, Idle JR, Smith RL. A family and population study of the genetic polymorphism of debrisoquine oxidation in a white British population. J. Med. Genet. 1980;17: 102–105.

31. Bertilsson L, Eichelbaum M, Mellstrom B, Sawe J, Schultz NV, Sjoqvist F. Nortryptyline and antipyrine clearance in relation to debrisoquine hydroxylation in man. Life Sci. 1980;27: 1673–1677.

32. Kahn GC, Boobis AR, Murray S, Brodie MJ, Davies DS. Assay and characterisation of debrisoquine 4-hydroxylase activity of microsomal fractions of human liver. Br. J. Clin. Pharmacol. 1982;13: 637–645.

33. Meier PJ, Mueller HK, Dick B, Meyer UA. Hepatic monooxygenase activities in subjects with a genetic defect in drug oxidation. Gastroenterology 1983;85: 682–692.

34. Distelrath LM, Reilly PEB, Martin MV, Davis GG, Wilkinson GR, Guengerich FP. Purification and characterisation of the human liver cytochromes P450 involved in debrisoquine 4-hydroxylation and phenacetin O-deethylation, two prototypes for genetic polymorphism in oxidative drug metabolism. J. Biol. Chem. 1985;260: 9057–9067.

35. Gonzalez FJ, Vilbois F, Hardwick JP, McBride OW, Nebert DW, Gelboin HV, et al. Human debrisoquine 4-hydroxylase (P450IID1): cDNA and deduced amino acid sequence and assignment of the CYP2D locus to chromosome 22. Genomics 1988;2: 174–179.

36. Heim M, Meyer UA. Genotyping of poor metabolisers by allele-specific PCR amplification. Lancet 1990;2: 529–532.

37. Gough AC, Miles JS, Spurr NK, Moss JE, Gaedigk A, Eichelbaum M, et al. Identification of the primary gene defect at the cytochrome P450 CYP2D locus. Nature 1990;347: 773–776.

38. Hanioka N, Kimura S, Meyer UA, Gonzalez FJ. The human CYP2D locus associated with a common genetic defect in drug oxidation: a G1934 to A base change in intron 3 of a mutant CYP2D6 allele results in an aberrant 3′ splice recognition site. Am. J. Hum. Genet. 1990;47: 994–1001.

39. Kagimoto M, Heim M, Kagimoto K, Zeugin T, Meyer UA. Multiple mutations of the human cytochrome P450IID6 gene (CYP2D6) in poor metabolisers of debrisoquine. J. Biol. Chem. 1990;265: 17209–17214.

40. Gaedigk A, Blum M, Gaedigk R, Eichelbaum M, Meyer UA. Deletion of the entire cytochrome P450 gene as a cause of impaired drug metabolism in poor metabolizers of the debrisoquine/sparteine polymorphism. Am. J. Hum. Genet. 1991;48: 943–950.

41. Johansson I, Lundqvist E, Bertilsson L, Dahl M-L, Sjoqvist F, Ingelman-Sundberg M. Inherited amplification of an active gene in the cytochrome P450 CYP2D locus as a cause of ultrarapid metabolism of debrisoquine. Proc. Natl. Acad. Sci. USA 1993;90: 11825–11829.

42. Daly AK, Brockmoller J, Broly F, Eichelbaum M, Evans WE, Gonzalez FJ, et al. Nomenclature for human CYP2D6 alleles. Pharmacogenetics 1996;6: 193–211.

43. Kupfer A, Preisig R. Pharmacogenetics of mephenytoin: A new drug hydroxylation polymorphism in man. Eur. J. Clin. Pharmacol. 1984;26: 753–759.

44. de Morais SMF, Wilkinson GR, Blaisdell J, Meyer UA, Nakamura K, Goldstein JA. Identification of a new genetic defect responsible for the polymorphism of (S)-mephenytoin metabolism in Japanese. Mol. Pharmacol. 1994;46: 594–598.

45. de Morais SMF, Wilkinson GR, Blaisdell J, Nakamura K, Meyer UA, Goldstein JA. The major genetic defect responsible for the polymorphism of S-mephenytoin metabolism in humans. J. Biol. Chem. 1994;269: 15419–15422.

46. Scott J, Poffenbarger PL. Pharmacogenetics of tolbutamide metabolism in humans. Diabetes 1978;28: 41–51.

47. Miners JO, Smith KJ, Robson RA, McManus ME, Veronese ME, Birkett DJ. Tolbutamide hydroxylation by human liver microsomes. Kinetic characterisation and relationship to other cytochrome P-450 dependent xenobiotic oxidations. Biochem. Pharmacol. 1988;37: 1137–1144.

48. Kimura S, Pastewka J, Gelboin HV, Gonzalez FJ. cDNA and amino acid sequences of two members of the human P450IIC gene subfamily. Nucleic Acids Res. 1987;15: 10053–10054.

49. Meehan RR, Gosden JR, Rout D, Hastie ND, Friedberg T, Adesnik M, et al. Human cytochrome P450 PB-1: A multigene family involved in mephenytoin and steroid oxidations that maps to chromosome 10. Am. J. Hum. Genet. 1988;42: 26–37.

50. Rettie AE, Wienkers LC, Gonzalez FJ, Trager WF, Korzekwa KR. Impaired (S)-warfarin metabolism catalysed by the R144C allelic variant of CYP2C9. Pharmacogenetics 1994;4: 39–42.

51. Sullivan-Close TH, Ghanayem BI, Bell DA, Zhang Z-Y, Kaminsky LS, Shenfield GM, et al. The role of the CYP2C9-Leu359 allelic variant in the tolbutamide polymorphism. Pharmacogenetics 1996;6: 341–349.

52. Furuya H, FernandezSalguero P, Gregory W, Taber H, Steward A, Gonzalez FJ, et al. Genetic polymorphism of CYP2C9 and its effect on warfarin maintenance dose requirement in patients undergoing anticoagulation therapy. Pharmacogenetics 1995;5: 389–392.

53. Steward DJ, Haining RL, Henne KR, Davis G, Rushmore TH, Trager WF, et al. Genetic association between sensitivity to warfarin and expression of CYP2C9*3. Pharmacogenetics 1997;7: 361–367.

54. Aithal GP, Day CP, Kesteven PJL, Daly AK. Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications. Lancet 1999;353: 717–719.

55. Fernandez-Salguero P, Hoffman SMG, Cholerton S, Mohrenweiser H, Raunio H, Pelkonen O, et al. A genetic polymorphism in coumarin 7-hydroxylation: Sequence of the human CYP2A genes and identification of variant CYP2A6 alleles. Am. J. Hum. Genet. 1995;57: 651–660.

56. Oscarson M, McLellan RA, Gullsten H, Yue QY, Lang MA, Bernal ML, et al. Characterisation and PCR-based detection of a CYP2A6 gene deletion found at a high frequency in a Chinese population. FEBS Lett 1999;448: 105–110.

57. Aoyama T, Yamano S, Waxman DJ, Lapenson DP, Meyer UA, Fischer V, et al. Cytochrome P450 hPCN3, a novel cytochrome P450 IIA gene product that is differentially expressed in adult human liver. J. Biol. Chem. 1989;264: 10388–10395.

58. Schuetz JD, Molowa DT, Guzelian PS. Characterization of a cDNA encoding a new member of the glucocorticoid-responsive cytochromes P450 in human liver. Arch. Biochem. Biophys. 1989;274: 355–365.

59. Wrighton SA, Ring BJ, Watkins PB, VandenBranden M. Identification of a polymorphically expressed member of the human cytochrome P-450III family. Mol. Pharmacol. 1989;36: 97–105.

60. Kuehl P, Zhang J, Lin Y, Lamba J, Assem M, Schuetz J, et al. Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nat. Genet. 2001;27: 383–391.

61. Weinshilboum R, Sladek SL. Mercaptopurine pharmacogenetics: Monogenic inheritance of erythrocyte thiopurine methyltransferase activity. Am. J. Hum. Genet. 1980;32: 651–662.

62. Seidegard J, Pero RW. The hereditary transmission of high glutathione transferase-activity towards trans-stilbene oxide in human mononuclear leukocytes. Hum. Genet. 1985;69: 66–68.

63. Gilbert C, Lereboullet P. La cholemie simple familiale. Semaine Med. 1901;21: 241–243.

64. Macklon AF, Savage RL, Rawlins MD. Gilbert syndrome and drug metabolism. Clin. Pharmacokin. 1979;4: 223–232.

65. Seidegard J, Vorachek WR, Pero RW, Pearson WR. Hereditary differences in the expression of the human glutathione S-transferase active on trans-stilbene oxide are due to a gene deletion. Proc. Natl. Acad. Sci. USA 1988;85: 7293–7297.

66. Blum M, Demierre A, Grant DM, Heim M, Meyer UA. Molecular mechanism of slow acetylation of drugs and carcinogens in humans. Proc. Natl. Acad. Sci. USA 1991;88: 5237–5241.

67. Vatsis KP, Martell KJ, Weber WW. Diverse point mutations in the human gene for polymorphic N-acetyltransferase. Proc. Natl. Acad. Sci. USA 1991;88: 6333–6337.

68. Hickman D, Sim E. N-acetyltransferase polymorphism. Comparison of phenotype and genotype in humans. Biochem. Pharmacol. 1991;42: 1007–1014.

69. Vatsis KP, Weber WW, Bell DA, Dupret J-M, Evans DAP, Grant DM, et al. Nomenclature for N-acetyltransferases. Pharmacogenetics 1995;5: 1–17.

70. Szumlanski C, Otterness D, Her C, Lee D, Brandriff B, Kelsell D, et al. Thiopurine methyltransferase pharmacogenetics: Human gene cloning and characterization of a common polymorphism. DNA Cell Biol. 1996;15: 17–30.

71. Tai H-L, Krynetski EY, Yates CR, Loennechen T, Fessing MY, Krynetskaia NF, et al. Thiopurine S-methyltransferase deficiency: two nucleotide transitions define the most prevalent mutant allele associated with loss of catalytic activity in Caucasians. Am. J. Hum. Genet. 1996;58: 694–702.

72. Monaghan G, Ryan M, Seddon R, Hume R, Burchell B. Genetic variation in bilirubin UDP-glucuronosyltransferase gene promoter and Gilbert's syndrome. Lancet 1996;347: 578–581.

73. Green SA, Cole G, Jacinto M, Innis M, Liggett SB. A polymorphism of the human beta 2-adrenergic receptor within the fourth transmembrane domain alters ligand binding and functional properties of the receptor. J. Biol. Chem. 1993;268: 23116–23121.

74. O'Reilly RA. The second reported kindred with hereditary resistance to oral anticoagulant drugs. New Engl. J. Med. 1970;282: 1448–1451.

75. Rost S, Fregin A, Ivaskevicius V, Conzelmann E, Hortnagel K, Pelz HJ, et al. Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2. Nature 2004;427: 537–541.

76. Li T, Chang CY, Jin DY, Lin PJ, Khvorova A, Stafford DW. Identification of the gene for vitamin K epoxide reductase. Nature 2004;427: 541–544.

77. D'Andrea G, D'Ambrosio RL, Di Perna P, Chetta M, Santacroce R, Brancaccio V, et al. A polymorphism in VKORC1 gene is associated with an inter-individual variability in the dose-anticoagulant effect of warfarin. Blood 2005;105: 645–649.

78. Rieder MJ, Reiner AP, Gage BF, Nickerson DA, Eby CS, McLeod HL, et al. Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose. N. Engl. J. Med. 2005;352: 2285–2293.

79. Sconce EA, Khan TI, Wynne HA, Avery P, Monkhouse L, King BP, et al. The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements: Proposal for a new dosing regimen. Blood 2005;106: 2329–2333.

80. Marshall A. Laying the foundations for personalized medicines. Nat. Biotechnol. 1997;15: 954–957.

81. Ross JS, Schenkein DP, Pietrusko R, Rolfe M, Linette GP, Stec J, et al. Targeted therapies for cancer 2004. Am. J. Clin. Pathol. 2004;122: 598–609.

82. Bonnefoi H, Underhill C, Iggo R, Cameron D, Predictive signatures for chemotherapy sensitivity in breast cancer: Are they ready for use in the clinic? Eur. J. Cancer 2009;45: 1733–1743.

83. Burton PR, Clayton DG, Cardon LR, Craddock N, Deloukas P, Duncanson A, et al., Genome-wide association study of 14,000 cases of seven common diseases and 3, 000 shared controls. Nature 2007;447: 661–678.

84. Cooper GM, Johnson JA, Langaee TY, Feng H, Stanaway IB, Schwarz UI, et al. A genome-wide scan for common genetic variants with a large influence on warfarin maintenance dose. Blood 2008;112: 1022–1027.

85. Link E, Parish S, Armitage J, Bowman L, Heath S, Matsuda F, et al. SLCO1B1 variants and statin-induced myopathy—a genomewide study. N. Engl. J. Med. 2008;359: 789–799.

86. Daly AK, Donaldson PT, Bhatnagar P, Shen Y, Pe'er I, Floratos A, et al. HLA-B*5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin. Nat. Genet. 2009;41: 816–819.

Part I

Pharmacogenetics: Relationship to Pharmacokinetics and Pharmacodynamics

Chapter 2

Pharmacogenetics in Drug Metabolism: Role of Phase I Enzymes

Vita Dolžan

Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia

2.1 Introduction

Phase I drug metabolizing enzymes (DMEs) catalyze the first step in metabolism of xenobiotics such as drugs and carcinogens. Most of these enzymes, especially cytochromes P450 (P450s or CYPs), metabolically activate xenobiotics to reactive electrophilic forms that are then conjugated to endogenous compounds by phase II DMEs: UDP-glucuronosyltransferases (UGTs), -acetyltransferases (NATs), glutathione--transferases (GSTs), or others (reviewed in Chapter 3). All these metabolic processes transform the xenobiotic to a more water-soluble form that can be transported from the cells (as reviewed in Chapter 4) to be eliminated from the body.