Elsevier

Advanced Drug Delivery Reviews

Volume 54, Issue 10, 18 November 2002, Pages 1257-1270
Advanced Drug Delivery Reviews

CYP2C9 allelic variants: ethnic distribution and functional significance

https://doi.org/10.1016/S0169-409X(02)00076-5Get rights and content

Abstract

Cytochrome P-450 (CYP) 2C9 CYP2C9 is a polymorphically expressed enzyme responsible for the metabolism of several clinically important drugs, some with a low therapeutic index. This review summarizes the structure–function relationship of the CYP2C9 promoter and coding regions, known polymorphisms, the functional significance of various CYP2C9 alleles in vitro and in vivo, and their population frequencies. In addition, possible molecular mechanisms underlying ethnic variability in the metabolism of CYP2C9 substrate drugs are discussed.

Introduction

Human cytochrome P-450 (CYP) enzymes catalyzing drug biotransformation include three families, CYP1, CYP2, and CYP3 that play a critical role in the oxidative metabolism of a wide range of endogenous substances, drugs and other xenobiotics [1], [2]. Among them, the CYP2 family, especially CYP2C subfamily, is large and complex [3]. CYP2C9, a major isozyme of the CYP2C subfamily in human liver, constitutes approximately 20% of the total human liver microsome P-450 content [4], [5], and metabolizes ∼10% of therapeutically important drugs, some such as warfarin with a narrow therapeutic index [6], [7], [8]. CYP2C9 exhibits marked inter-individual variability in its expression and catalytic activity due to functionally significant genetic variations that can result in either clinically relevant drug toxicity (e.g., warfarin-induced bleeding complications) in some patients who take standard doses of CYP2C9 substrate drugs, or inadequate drug efficacy and therapeutic failure in others.

Section snippets

CYP2C9 promoter region

The CYP2C9 gene is located at chromosomal region 10q24 [9], spanning approximately 55-kb with nine exons (GenBank accession numbers: L16877 to L16883) and encodes a protein of 490 amino acid residues [10]. CYP2C9 is 92% homologous to CYP2C19, the expressed product of its neighboring gene (CYP2C19) [11], differing by only 43 of 490 amino acids. However, the two enzymes have completely different substrate specificity.

Control of gene expression occurs principally at the level of transcription.

Population frequencies of the CYP2C9 allelic variants

Population frequencies of the CYP2C9∗2 and CYP2C9∗3 variant alleles are summarized in Table 2, Table 3 and meta-analyzed quantitatively. CYP2C9∗2 is absent in East Asian populations (Chinese, Japanese and Korean). African-Americans and Ethiopians, on the other hand, carry CYP2C9∗2 with an overall allele frequency of 3.2%. A significant heterogeneity of CYP2C9∗2 allele frequency exists among various Caucasian populations (20×2 contingency table; χ2=50.935; P<0.0001) with a wide range of CYP2C9∗2

Ethnic variability of CYP2C9 activity and its molecular basis

CYP2C9 is a major drug-metabolizing enzyme in human liver and contributes to the metabolism of a wide array of clinically important drugs. The effects of polymorphically expressed enzyme have been studied in most major ethnic groups.

An early clinical investigation showed that Asian patients who were resident in South California required nearly a 40% smaller average warfarin dose than Caucasian and Hispanic patients (3.1 vs. 5.1 mg/day) [75]. A subsequent observation also indicated that Chinese

Conclusions and future directions

The human CYP2C9 gene is highly polymorphic in its promoter and coding regions, and allelic variants vary in frequency among different ethnic groups. These genetic polymorphisms are associated with wide inter-individual variability in the hepatic metabolism of affected drugs and can result in altered clinical effects. Compared with CYP2C9∗2, CYP2C9∗3 and ∗5 result in a greater impairment of catalytic activity, with effects being substrate-dependent. Some CYP2C9 substrates (for example,

Acknowledgements

This work was supported in part by grants HL04012, GM31304, and the NIH/NIGMS Pharmacogenetics Research Network and Database (U01GM61374, http://pharmgkb.org) under grant U01 HL65962. We thank Dr. Grant R. Wilkinson for critical reading of this manuscript.

References (83)

  • A.E Rettie et al.

    A common genetic basis for idiosyncratic toxicity of warfarin and phenytoin

    Epilepsy Res.

    (1999)
  • M.S Ogg et al.

    CYP2C9∗3 allelic variant and bleeding complications

    Lancet

    (1999)
  • G.P Aithal et al.

    Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications

    Lancet

    (1999)
  • L.S Kaminsky et al.

    Human P450 metabolism of warfarin

    Pharmacol. Ther.

    (1997)
  • B.D Freeman et al.

    Cytochrome P450 polymorphisms are associated with reduced warfarin dose

    Surgery

    (2000)
  • R.H White et al.

    Major bleeding after hospitalization for deep-venous thrombosis

    Am. J. Med.

    (1999)
  • S Rendic et al.

    Human cytochrome P450 enzymes: a status report summarizing their reactions, substrates, inducers, and inhibitors

    Drug Metab. Rev.

    (1997)
  • H.G Xie et al.

    Molecular basis of ethnic differences in drug disposition and response

  • D.R Nelson et al.

    P450 superfamily: update on new sequences, gene mapping, accession numbers and nomenclature

    Pharmacogenetics

    (1996)
  • T Shimada et al.

    Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians

    J. Pharmacol. Exp. Ther.

    (1994)
  • K Inoue et al.

    Relationship between CYP2C9 and 2C19 genotypes and tolbutamide methyl hydroxylation and S-mephenytoin 4′-hydroxylation activities in livers of Japanese and Caucasian populations

    Pharmacogenetics

    (1997)
  • J.A Goldstein et al.

    Biochemistry and molecular biology of the human CYP2C subfamily

    Pharmacogenetics

    (1994)
  • J.O Miners et al.

    Cytochrome P4502C9: an enzyme of major importance in human drug metabolism

    Br. J. Clin. Pharmacol.

    (1998)
  • D.S Streetman et al.

    Phenotyping of drug-metabolizing enzymes in adults: a review of in-vivo cytochrome P450 phenotyping probes

    Pharmacogenetics

    (2000)
  • M Romkes et al.

    Cloning and expression of complementary DNAs for multiple members of the human cytochrome P450IIC subfamily

    Biochemistry

    (1991)
  • M Shintani et al.

    Genetic polymorphisms and functional characterization of the 5′-flanking region of the human CYP2C9 gene: in vitro and in vivo studies

    Clin. Pharmacol. Ther.

    (2001)
  • G.C Ibeanu et al.

    Transcriptional regulation of human CYP2C genes: functional comparison of CYP2C9 and CYP2C18 promoter regions

    Biochemistry

    (1995)
  • C Ged et al.

    Characterization of cDNAs, mRNAs, and proteins related to human liver microsomal cytochrome P450(s)-mephenytoin 4′-hydroxylase

    Biochemistry

    (1988)
  • S.-L Wang et al.

    Detection of CYP2C9 polymorphism based on the polymerase chain reaction in Chinese

    Pharmacogenetics

    (1995)
  • T.H Sullivan-Klose et al.

    The role of the CYP2C9-Leu359 allelic variant in the tolbutamide polymorphism

    Pharmacogenetics

    (1996)
  • M Margaglione et al.

    Genetic modulation of oral anticoagulation with warfarin

    Thromb. Haemost.

    (2000)
  • A Gaedigk et al.

    Cytochrome P4502C9 (CYP2C9) allele frequencies in Canadian Native Indian and Inuit populations

    Can. J. Physiol. Pharmacol.

    (2001)
  • J Imai et al.

    Polymorphism of the cytochrome P450 (CYP) 2C9 gene in Japanese epileptic patients: genetic analysis of the CYP2C9 locus

    Pharmacogenetics

    (2000)
  • L.J Dickmann et al.

    Identification and functional characterization of a new CYP2C9 variant (CYP2C9∗5) expressed among African Americans

    Mol. Pharmacol.

    (2001)
  • H.-G Xie et al.

    Frequency of the defective CYP2C9 variant alleles in different ethnic groups [abstract]

    Clin. Pharmacol. Ther.

    (2002)
  • A.R Strom et al.

    Allele frequency of a new CYP2C9 allele (CYP2C9∗4) in Caucasians and African-Americans

    Drug Metab. Rev.

    (2000)
  • G.P Aithal et al.

    Relationship of polymorphism in CYP2C9 to genetic susceptibility to diclofenac-induced hepatitis

    Pharmacogenetics

    (2000)
  • I Ieiri et al.

    Catalytic activity of three variants (Ile, Leu, and Thr) at amino acid residue 359 in human CYP2C9 gene and simultaneous detection using single-strand conformation polymorphism analysis

    Ther. Drug Monit.

    (2000)
  • R.S Kidd et al.

    Identification of a null allele of CYP2C9 in an African-American exhibiting toxicity to phenytoin

    Pharmacogenetics

    (2001)
  • U.I Schwarz et al.

    Identification of three new CYP2C9 variants

    Clin. Pharmacol. Ther. [abstr.]

    (2001)
  • M.J Stubbins et al.

    Genetic analysis of the human cytochrome P450 CYP2C9 locus

    Pharmacogenetics

    (1996)
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