CYP2C9 allelic variants: ethnic distribution and functional significance
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.
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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)
- et al.
A 2.4-megabase physical map spanning the CYP2C gene cluster on chromosome 10q24
Genomics
(1995) - et al.
Gene structure and upstream regulatory regions of human CYP2C9 and CYP2C18
Biochem. Biophys. Res. Commun.
(1993) - et al.
Identification of a novel transcriptional silencer in the protein-coding region of the human CYP2C9 gene
Gene
(1998) - et al.
Rapid detection of CYP2C9∗3 alleles by real-time fluorescence PCR based on SYBR Green
Mol. Genet. Metab.
(1999) Substrate recognition sites in cytochrome P-450 family 2 (CYP2) proteins inferred from comparative analyses of amino acid and coding nucleotide sequences
J. Biol. Chem.
(1992)- et al.
Genetic polymorphism in exon 4 of cytochrome P450 CYP2C9 may be associated with warfarin sensitivity in Chinese patients
Blood
(2001) - et al.
Influence of cytochrome P-450 CYP2C9 polymorphisms on warfarin sensitivity and risk of over-anticoagulation in patients on long-term treatment
Blood
(2000) - et al.
Validation of methods for CYP2C9 genotyping: frequencies of mutant alleles in a Swedish population
Biochem. Biophys. Res. Commun.
(1999) - et al.
Allelic variants of human cytochrome P450 2C9:baculovirus-mediated expression, purification, structural characterization, substrate stereoselectivity, and prochiral selectivity of the wild-type and I359L mutant forms
Arch. Biochem. Biophys.
(1996) - et al.
Comparative studies on the catalytic roles of cytochrome P4502C9 and its Cys- and Leu-variants in the oxidation of warfarin, flurbiprofen, and diclofenac by human liver microsomes
Biochem. Pharmacol.
(1998)