Clinically relevant genetic variations in drug metabolizing enzymes.

In the field of pharmacogenetics, we currently have a few markers to guide physicians as to the best course of therapy for patients. For the most part, these genetic variants are within a drug metabolizing enzyme that has a large effect on the degree or rate at which a drug is converted to its metabolites. For many drugs, response and toxicity are multi-genic traits and understanding relationships between a patient's genetic variation in drug metabolizing enzymes and the efficacy and/or toxicity of a medication offers the potential to optimize therapies. This review will focus on variants in drug metabolizing enzymes with predictable and relatively large impacts on drug efficacy and/or toxicity; some of these drug/gene variant pairs have impacted drug labels by the United States Food and Drug Administration. The challenges in identifying genetic markers and implementing clinical changes based on known markers will be discussed. In addition, the impact of next generation sequencing in identifying rare variants will be addressed.

[1]  F Demard,et al.  Population study of dihydropyrimidine dehydrogenase in cancer patients. , 1994, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[2]  J. Idle,et al.  POLYMORPHIC HYDROXYLATION OF DEBRISOQUINE IN MAN , 1977, The Lancet.

[3]  M. Kato,et al.  Intestinal first-pass metabolism of CYP3A4 substrates. , 2008, Drug metabolism and pharmacokinetics.

[4]  W. Weber,et al.  Diverse point mutations in the human gene for polymorphic N-acetyltransferase. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[5]  J. Lafitte,et al.  Evidence for CYP2D6 expression in human lung. , 1997, Biochemical and biophysical research communications.

[6]  E. Schuetz,et al.  Genetic contribution to variable human CYP3A-mediated metabolism. , 2002, Advanced drug delivery reviews.

[7]  U. Klotz,et al.  Thiopurine Treatment in Inflammatory Bowel Disease , 2007, Clinical pharmacokinetics.

[8]  J. O’Connell,et al.  Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. , 2009, JAMA.

[9]  J. Schenkman,et al.  Dissection of cytochrome P-450 isozymes (RLM) from fractions of untreated rat liver microsomal proteins. , 1982, Biochemical and biophysical research communications.

[10]  N. Sládek,et al.  Induction of drug metabolism. I. Differences in the mechanisms by which polycyclic hydrocarbons and phenobarbital produce their inductive effects on microsomal N-demethylating systems. , 1969, Molecular pharmacology.

[11]  J. S. Miles,et al.  Identification of the primary gene defect at the cytochrome P450 CYP2D locus , 1990, Nature.

[12]  R. Kim,et al.  CYP2C9 allelic variants: ethnic distribution and functional significance. , 2002, Advanced drug delivery reviews.

[13]  C. Clayman,et al.  4. TOXICITY OF PRIMAQUINE IN NEGROES , 1952 .

[14]  D. Bartel MicroRNAs Genomics, Biogenesis, Mechanism, and Function , 2004, Cell.

[15]  G R Wilkinson,et al.  The major genetic defect responsible for the polymorphism of S-mephenytoin metabolism in humans. , 1994, The Journal of biological chemistry.

[16]  B. Lacarelle,et al.  DPD-based adaptive dosing of 5-FU in patients with head and neck cancer: impact on treatment efficacy and toxicity , 2010, Cancer Chemotherapy and Pharmacology.

[17]  M. Ratain,et al.  Genetic predisposition to the metabolism of irinotecan (CPT-11). Role of uridine diphosphate glucuronosyltransferase isoform 1A1 in the glucuronidation of its active metabolite (SN-38) in human liver microsomes. , 1998, The Journal of clinical investigation.

[18]  S. Hunt,et al.  Common VKORC1 and GGCX polymorphisms associated with warfarin dose , 2005, The Pharmacogenomics Journal.

[19]  N. Sládek,et al.  Induction of Drug Metabolism: II. Qualitative Differences in the Microsomal N-Demethylating Systems Stimulated by Polycyclic Hydrocarbons and by Phenobarbital , 1969 .

[20]  J. Dungan,et al.  Association Between CYP2D6 Polymorphisms and Outcomes Among Women With Early Stage Breast Cancer Treated With Tamoxifen , 2010 .

[21]  C. Guillemette,et al.  Nomenclature update for the mammalian UDP glycosyltransferase (UGT) gene superfamily. , 2005, Pharmacogenetics and genomics.

[22]  V. McKusick,et al.  Genetic Control of Isoniazid Metabolism in Man , 1960, British medical journal.

[23]  Shufeng Zhou Polymorphism of Human Cytochrome P450 2D6 and Its Clinical Significance , 2009, Clinical pharmacokinetics.

[24]  R. Weinshilboum,et al.  Human thiopurine methyltransferase pharmacogenetics: Gene sequence polymorphisms , 1997, Clinical pharmacology and therapeutics.

[25]  R. Preisig,et al.  Pharmacogenetics of mephenytoin: A new drug hydroxylation polymorphism in man , 2004, European Journal of Clinical Pharmacology.

[26]  C. Clayman,et al.  Toxicity of primaquine in Caucasians. , 1952, Journal of the American Medical Association.

[27]  C. Gieger,et al.  Sequence variants at CHRNB3–CHRNA6 and CYP2A6 affect smoking behavior , 2010, Nature Genetics.

[28]  M. Farmen,et al.  Genetic Variation in Metabolizing Enzyme and Transporter Genes: Comprehensive Assessment in 3 Major East Asian Subpopulations With Comparison to Caucasians and Africans , 2010, Journal of clinical pharmacology.

[29]  N. Benowitz,et al.  Association of Nicotine Metabolite Ratio and CYP2A6 Genotype With Smoking Cessation Treatment in African‐American Light Smokers , 2009, Clinical pharmacology and therapeutics.

[30]  J. Boullata,et al.  Handbook of drug-nutrient interactions. , 2004 .

[31]  M Schwab,et al.  Predictive Value of Known and Novel Alleles of CYP2B6 for Efavirenz Plasma Concentrations in HIV‐infected Individuals , 2007, Clinical pharmacology and therapeutics.

[32]  T. Jiang,et al.  Meta-analysis of the association between the monoamine oxidase-A gene and mood disorders , 2010, Psychiatric Genetics.

[33]  D. Flockhart,et al.  Drug Interactions and the Cytochrome P450 System , 1995, Clinical pharmacokinetics.

[34]  C. Clayman,et al.  3. TOXICITY OF PRIMAQUINE IN CAUCASIANS , 1952 .

[35]  J. Menke Drug interactions and the cytochrome P-450 system. , 2000, South Dakota journal of medicine.

[36]  G. Hitchings,et al.  STUDIES ON ANALOGS OF PURINES AND PYRIMIDINES , 1950, Annals of the New York Academy of Sciences.

[37]  C. Day,et al.  Genetic association studies in drug-induced liver injury. , 2009, Seminars in liver disease.

[38]  E. Beutler,et al.  Molecular genetics of the glucose-6-phosphate dehydrogenase (G6PD) Mediterranean variant and description of a new G6PD mutant, G6PD Andalus1361A. , 1990, American journal of human genetics.

[39]  M. Eichelbaum,et al.  Defective N-oxidation of sparteine in man: A new pharmacogenetic defect , 1979, European Journal of Clinical Pharmacology.

[40]  L. H. Schmidt,et al.  Metabolism of isoniazid in man as related to the occurrence of peripheral neuritis. , 1954, American review of tuberculosis.

[41]  U. Meyer,et al.  The human CYP2D locus associated with a common genetic defect in drug oxidation: a G1934----A base change in intron 3 of a mutant CYP2D6 allele results in an aberrant 3' splice recognition site. , 1990, American journal of human genetics.

[42]  A. V. van Kuilenburg Dihydropyrimidine dehydrogenase and the efficacy and toxicity of 5-fluorouracil. , 2004, European journal of cancer.

[43]  R. Knight,et al.  Comparison of isoniazid concentrations in the blood of people of Japanese and European descent; therapeutic and genetic implications. , 1958, American review of tuberculosis.

[44]  Hein Putter,et al.  Effect of concomitant CYP2D6 inhibitor use and tamoxifen adherence on breast cancer recurrence in early-stage breast cancer. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[45]  U. Meyer,et al.  Genotyping of poor metabolisers of debrisoquine by allele-specific PCR amplification , 1990, The Lancet.

[46]  B. Goh,et al.  Role of UGT1A1*6, UGT1A1*28 and ABCG2 c.421C>A polymorphisms in irinotecan‐induced neutropenia in Asian cancer patients , 2007, Cancer science.

[47]  B. Giusti,et al.  Cytochrome P450 2C19*2 polymorphism and cardiovascular recurrences in patients taking clopidogrel: a meta-analysis , 2011, The Pharmacogenomics Journal.

[48]  H. Jörnvall,et al.  Recommended nomenclature for the vertebrate alcohol dehydrogenase gene family. , 1999, Biochemical pharmacology.

[49]  A. Motulsky Drug reactions enzymes, and biochemical genetics. , 1957, Journal of the American Medical Association.

[50]  N. Geller,et al.  Prospective alpha allocation in the clarification of optimal anticoagulation through genetics (COAG) trial , 2010, Clinical trials.

[51]  R. Diasio,et al.  Decreased dihydropyrimidine dehydrogenase activity in a population of patients with breast cancer: implication for 5-fluorouracil-based chemotherapy. , 1998, Clinical cancer research : an official journal of the American Association for Cancer Research.

[52]  M. Rawlins,et al.  Gilbert’s Syndrome and Drug Metabolism , 1979, Clinical pharmacokinetics.

[53]  J. Idle,et al.  A family and population study of the genetic polymorphism of debrisoquine oxidation in a white British population. , 1980, Journal of medical genetics.

[54]  西尾 由貴子 D85N, a KCNE1 polymorphism, is a disease-causing gene variant in long QT syndrome , 2011 .

[55]  M. Gawaz,et al.  CYP2C19 and nongenetic factors predict poor responsiveness to clopidogrel loading dose after coronary stent implantation. , 2008, Pharmacogenomics.

[56]  M. Eichelbaum,et al.  Deletion of the entire cytochrome P450 CYP2D6 gene as a cause of impaired drug metabolism in poor metabolizers of the debrisoquine/sparteine polymorphism. , 1991, American journal of human genetics.

[57]  M. Boyd,et al.  Constitutive expression and localization of the major drug metabolizing enzyme, cytochrome P4502D in human brain. , 2002, Brain research. Molecular brain research.

[58]  C. Clayman,et al.  Toxicity of primaquine in Negroes. , 1952, Journal of the American Medical Association.

[59]  Y. Hasegawa,et al.  UGT1AI*6 and UGT1A1*27 for individualized irinotecan chemotherapy. , 2007, Current opinion in molecular therapeutics.

[60]  Fergus J Couch,et al.  Pharmacogenetics of tamoxifen biotransformation is associated with clinical outcomes of efficacy and hot flashes. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[61]  D. Grant,et al.  Changes in consensus arylamine N-acetyltransferase gene nomenclature. , 2008, Pharmacogenetics and genomics.

[62]  M. Ingelman-Sundberg,et al.  Inherited amplification of an active gene in the cytochrome P450 CYP2D locus as a cause of ultrarapid metabolism of debrisoquine. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[63]  A. Kastrati,et al.  Cytochrome 2C19*17 Allelic Variant, Platelet Aggregation, Bleeding Events, and Stent Thrombosis in Clopidogrel-Treated Patients With Coronary Stent Placement , 2010, Circulation.

[64]  J. W. Findlay,et al.  Analgesie drugs in breast milk and plasma * , 1981, Clinical pharmacology and therapeutics.

[65]  R. Neubig,et al.  International Union of Pharmacology. LXXII. Recommendations for Trace Amine Receptor Nomenclature , 2009, Pharmacological Reviews.

[66]  H. Edenberg The Genetics of Alcohol Metabolism: Role of Alcohol Dehydrogenase and Aldehyde Dehydrogenase Variants , 2007, Alcohol research & health : the journal of the National Institute on Alcohol Abuse and Alcoholism.

[67]  R. Weinshilboum,et al.  Mercaptopurine pharmacogenetics: monogenic inheritance of erythrocyte thiopurine methyltransferase activity. , 1980, American journal of human genetics.

[68]  I. Mlinarič-Raščan,et al.  Individualization of thiopurine therapy: thiopurine S-methyltransferase and beyond. , 2009, Pharmacogenomics.

[69]  L. Wienkers,et al.  Warfarin-fluconazole. II. A metabolically based drug interaction: in vivo studies. , 1996, Drug metabolism and disposition: the biological fate of chemicals.

[70]  K. Brøsen Drug interactions and the cytochrome P450 system. The role of cytochrome P450 1A2. , 1995, Clinical Pharmacokinetics.

[71]  M. J. Coon,et al.  Position-specific oxygenation of benzo(a)pyrene by different forms of purified cytochrome P-450 from rabbit liver. , 1975, Proceedings of the National Academy of Sciences of the United States of America.

[72]  B. Brodie,et al.  Enzymatic metabolism of drugs and other foreign compounds. , 1958, Annual review of biochemistry.

[73]  P. Gangadharam,et al.  Peripheral neuritis due to isoniazid. , 1960, Bulletin of the World Health Organization.

[74]  M. Pirmohamed,et al.  Drug-induced hypersensitivity reactions and pharmacogenomics: past, present and future. , 2010, Pharmacogenomics.

[75]  B. Carleton,et al.  Pharmacogenetics of Neonatal Opioid Toxicity Following Maternal Use of Codeine During Breastfeeding: A Case–Control Study , 2009, Clinical pharmacology and therapeutics.

[76]  L. Bertilsson,et al.  Pharmacogenetic covariation of defective N-oxidation of sparteine and 4-hydroxylation of debrisoquine , 1980, European Journal of Clinical Pharmacology.

[77]  P. Fasching,et al.  CYP2D6 Polymorphisms as Predictors of Outcome in Breast Cancer Patients Treated with Tamoxifen: Expanded Polymorphism Coverage Improves Risk Stratification , 2010, Clinical Cancer Research.

[78]  H. McLeod,et al.  Should DPD analysis be required prior to prescribing fluoropyrimidines? , 2007, European journal of cancer.

[79]  M. Goetz,et al.  The tamoxifen metabolite, endoxifen, is a potent antiestrogen that targets estrogen receptor alpha for degradation in breast cancer cells. , 2009, Cancer research.

[80]  E. Sim,et al.  N-acetyltransferase polymorphism. Comparison of phenotype and genotype in humans. , 1991, Biochemical pharmacology.

[81]  D. Flockhart,et al.  The Star‐Allele Nomenclature: Retooling for Translational Genomics , 2007, Clinical pharmacology and therapeutics.

[82]  L. Bertilsson,et al.  Nortriptyline and antipyrine clearance in relation to debrisoquine hydroxylation in man. , 1980, Life sciences.

[83]  Shiew-Mei Huang,et al.  A Regulatory Science Perspective on Warfarin Therapy: A Pharmacogenetic Opportunity , 2009, Journal of clinical pharmacology.

[84]  N. Sapeika,et al.  The Excretion of Drugs in Human Milk—A Review , 1947, The Journal of obstetrics and gynaecology of the British Empire.

[85]  Martin R. Johnson,et al.  Semi-automated radioassay for determination of dihydropyrimidine dehydrogenase (DPD) activity. Screening cancer patients for DPD deficiency, a condition associated with 5-fluorouracil toxicity. , 1997, Journal of chromatography. B, Biomedical sciences and applications.

[86]  H. McLeod,et al.  Clopidogrel pharmacogenomics and risk of inadequate platelet inhibition: US FDA recommendations. , 2009, Pharmacogenomics.

[87]  D. Waxman,et al.  Activation of oxazaphosphorines by cytochrome P450: application to gene-directed enzyme prodrug therapy for cancer. , 2006, Toxicology in vitro : an international journal published in association with BIBRA.

[88]  M. Tomšič,et al.  Genetic polymorphism of CYP1A2 and the toxicity of leflunomide treatment in rheumatoid arthritis patients , 2008, European Journal of Clinical Pharmacology.

[89]  J. Horowitz,et al.  Prasugrel vs. clopidogrel for cytochrome P450 2C19‐genotyped subgroups: integration of the TRITON‐TIMI 38 trial data , 2010, Journal of thrombosis and haemostasis : JTH.

[90]  R. Estabrook,et al.  Photochemical Action Spectrum of the Terminal Oxidase of Mixed Function Oxidase Systems , 1965, Science.

[91]  D. Flockhart,et al.  Clinical Significance of the Cytochrome P450 2C19 Genetic Polymorphism , 2002, Clinical pharmacokinetics.

[92]  J. Halperin,et al.  CYP2C9*8 is prevalent among African-Americans: implications for pharmacogenetic dosing. , 2009, Pharmacogenomics.

[93]  Tyson A. Clark,et al.  Genetic architecture of transcript-level variation in humans. , 2008, American journal of human genetics.

[94]  B. Alexanderson,et al.  Steady-state plasma levels of nortriptyline in twins: Influence of genetic factors and drug therapy , 1969, British medical journal.

[95]  M. Zhan,et al.  Profiles of tamoxifen-related side effects by race and smoking status in women with breast cancer. , 2007, Cancer detection and prevention.

[96]  David A. Flockhart,et al.  CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment. , 2005, Journal of the National Cancer Institute.

[97]  T. Langaee,et al.  Genetic and Clinical Predictors of Warfarin Dose Requirements in African Americans , 2010, Clinical pharmacology and therapeutics.

[98]  Noam Shomron,et al.  MicroRNAs and pharmacogenomics. , 2010, Pharmacogenomics.

[99]  T E Klein,et al.  Clinical Pharmacogenetics Implementation Consortium Guidelines for Thiopurine Methyltransferase Genotype and Thiopurine Dosing , 2011, Clinical pharmacology and therapy.

[100]  T. Nishiyama,et al.  Dihydropyrimidine Dehydrogenase Activity in 150 Healthy Japanese Volunteers and Identification of Novel Mutations , 2005, Clinical Cancer Research.

[101]  Christina N. Lessov-Schlaggar,et al.  CYP2A6 genotype and the metabolism and disposition kinetics of nicotine , 2006, Clinical pharmacology and therapeutics.

[102]  S. B. Koukouritaki,et al.  Flavin-containing monooxygenase genetic polymorphism: impact on chemical metabolism and drug development. , 2005, Pharmacogenomics.

[103]  R. Weinshilboum,et al.  Thiopurine pharmacogenetics in leukemia: Correlation of erythrocyte thiopurine methyltransferase activity and 6‐thioguanine nucleotide concentrations , 1987, Clinical pharmacology and therapeutics.

[104]  J. Sheller,et al.  Impact of ethnic origin and quinidine coadministration on codeine's disposition and pharmacodynamic effects. , 1999, The Journal of pharmacology and experimental therapeutics.

[105]  D W Nebert,et al.  The P450 gene superfamily: recommended nomenclature. , 1987, DNA.

[106]  Magnus Ingelman-Sundberg,et al.  Influence of cytochrome P450 polymorphisms on drug therapies: pharmacogenetic, pharmacoepigenetic and clinical aspects. , 2007, Pharmacology & therapeutics.

[107]  A. Daly Significance of the Minor Cytochrome P450 3A Isoforms , 2006, Clinical pharmacokinetics.

[108]  R. Levy Cytochrome P450 Isozymes and Antiepileptic Drug Interactions , 1995, Epilepsia.

[109]  E. Beutler,et al.  Molecular cloning and nucleotide sequence of cDNA for human glucose-6-phosphate dehydrogenase variant A(-). , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[110]  Guoying Tai,et al.  The pharmocogenomics of warfarin: closing in on personalized medicine. , 2006, Molecular interventions.

[111]  Martin R. Johnson,et al.  Rapid Identification of Dihydropyrimidine Dehydrogenase Deficiency by Using a Novel 2-13C-Uracil Breath Test , 2004, Clinical Cancer Research.

[112]  R. Altman,et al.  Estimation of the warfarin dose with clinical and pharmacogenetic data. , 2009, The New England journal of medicine.

[113]  T. Prueksaritanont,et al.  (+)-bufuralol 1'-hydroxylation activity in human and rhesus monkey intestine and liver. , 1995, Biochemical pharmacology.

[114]  D W Nebert,et al.  The P450 superfamily: update on new sequences, gene mapping, and recommended nomenclature. , 1991, DNA and cell biology.

[115]  J. Cashman,et al.  A nomenclature for the mammalian flavin-containing monooxygenase gene family based on amino acid sequence identities. , 1994, Archives of biochemistry and biophysics.

[116]  R. Diasio,et al.  Dihydropyrimidine dehydrogenase deficiency in an Indian population , 2006, Cancer Chemotherapy and Pharmacology.

[117]  J. Miller,et al.  Substrate-induced synthesis and other properties of benzpyrene hydroxylase in rat liver. , 1957, The Journal of biological chemistry.

[118]  B. Burchell,et al.  Genetic variation in bilirubin UDP-glucuronosyltransferase gene promoter and Gilbert's syndrome , 1996, The Lancet.

[119]  Interethnic dissociation between debrisoquine and desipramine hydroxylation. , 1985, Journal of clinical psychopharmacology.

[120]  K. Brøsen,et al.  Drug Interactions and the Cytochrome P450 System , 1995 .

[121]  Knight Ra,et al.  Comparison of isoniazid concentrations in the blood of people of Japanese and European descent; therapeutic and genetic implications. , 1958 .

[122]  D. Grant,et al.  Molecular mechanism of slow acetylation of drugs and carcinogens in humans. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[123]  L. Goodman,et al.  The Pharmacological Basis of Therapeutics , 1941 .

[124]  R. Tyndale,et al.  Genetic variability in CYP2A6 and the pharmacokinetics of nicotine. , 2007, Pharmacogenomics.

[125]  Lang Li,et al.  CYP2D6 genotype and tamoxifen response , 2005, Breast Cancer Research.

[126]  J. Ferrières,et al.  Genetic determinants of response to clopidogrel and cardiovascular events. , 2009, The New England journal of medicine.

[127]  F. Sjöqvist,et al.  Plasma levels of monomethylated tricyclic antidepressants during treatment with imipramine-like compounds. , 1967, Life sciences.

[128]  M. Leider Goodman & Gilman's The Pharmacological Basis of Therapeutics , 1985 .

[129]  Nicole Soranzo,et al.  A Genome-Wide Association Study Confirms VKORC1, CYP2C9, and CYP4F2 as Principal Genetic Determinants of Warfarin Dose , 2009, PLoS genetics.

[130]  Elizabeth Pennisi,et al.  Genomics. 1000 Genomes Project gives new map of genetic diversity. , 2010, Science.

[131]  D. Holdstock Past, present--and future? , 2005, Medicine, conflict, and survival.

[132]  U. Klotz,et al.  Thiopurine treatment in inflammatory bowel disease: clinical pharmacology and implication of pharmacogenetically guided dosing. , 2007, Clinical pharmacokinetics.

[133]  J. Sludden,et al.  Evaluation of dihydropyrimidine dehydrogenase activity in South-west Asian, Kenyan and Ghanaian populations. , 2000, British journal of clinical pharmacology.

[134]  P. Carson,et al.  Enzymatic deficiency in primaquine-sensitive erythrocytes. , 1956, Science.

[135]  Zeruesenay Desta,et al.  Active tamoxifen metabolite plasma concentrations after coadministration of tamoxifen and the selective serotonin reuptake inhibitor paroxetine. , 2003, Journal of the National Cancer Institute.

[136]  C. Gieger,et al.  Sequence variants at CHRNB 3 – CHRNA 6 and CYP 2 A 6 affect smoking behavior , 2010 .

[137]  R. Estabrook,et al.  The stoichiometry of C21 hydroxylation of steroids by adrenocortical microsomes. , 1963, The Journal of biological chemistry.

[138]  C. Hirschhäuser,et al.  Paraoxonase-1 is a major determinant of clopidogrel efficacy , 2011, Nature Medicine.

[139]  Magnus Ingelman-Sundberg,et al.  The human genome project and novel aspects of cytochrome P450 research. , 2005, Toxicology and applied pharmacology.

[140]  W. Evans,et al.  Thiopurine S-methyltransferase deficiency: two nucleotide transitions define the most prevalent mutant allele associated with loss of catalytic activity in Caucasians. , 1996, American journal of human genetics.

[141]  L. Alger,et al.  Codeine and the Breastfed Neonate , 1993, Journal of human lactation : official journal of International Lactation Consultant Association.

[142]  L. Luzzatto,et al.  Both mutations in G6PD A- are necessary to produce the G6PD deficient phenotype. , 1992, Human molecular genetics.

[143]  S. Yin,et al.  Effect of the allelic variants of aldehyde dehydrogenase ALDH2*2 and alcohol dehydrogenase ADH1B*2 on blood acetaldehyde concentrations , 2009, Human Genomics.

[144]  T. Omura,et al.  A new cytochrome in liver microsomes. , 1962, The Journal of biological chemistry.

[145]  A. Bairoch,et al.  Human aldehyde dehydrogenase genes: alternatively spliced transcriptional variants and their suggested nomenclature , 2009, Pharmacogenetics and genomics.

[146]  A. V. van Kuilenburg,et al.  Pharmacogenetic and clinical aspects of dihydropyrimidine dehydrogenase deficiency. , 2003, Annals of clinical biochemistry.

[147]  Gideon Koren,et al.  Safety of codeine during breastfeeding: fatal morphine poisoning in the breastfed neonate of a mother prescribed codeine. , 2007, Canadian family physician Medecin de famille canadien.

[148]  F. Mach,et al.  Biological effect of increased maintenance dose of clopidogrel in cardiovascular outpatients and influence of the cytochrome P450 2C19*2 allele on clopidogrel responsiveness. , 2008, Thrombosis research.

[149]  P. Vreken,et al.  Genotype and phenotype in patients with dihydropyrimidine dehydrogenase deficiency , 1999, Human Genetics.

[150]  G. Aithal,et al.  Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications , 1999, The Lancet.

[151]  R. Weinshilboum,et al.  Thiopurine methyltransferase pharmacogenetics: human gene cloning and characterization of a common polymorphism. , 1996, DNA and cell biology.

[152]  G. Milano,et al.  A Rapid and Inexpensive Method for Anticipating Severe Toxicity to Fluorouracil and Fluorouracil-based Chemotherapy , 2006, Therapeutic drug monitoring.

[153]  F. Vogel Moderne Probleme der Humangenetik , 1959 .