AIM: CYP2C8 represents 7% of the hepatic cytochrome system and metabolizes around 5% of drugs in phase I processes. It also plays a significant role in metabolism of endogenous compounds. More than 20 single-nucleotide polymorphisms (SNPs) have been noted, mainly in exons 3, 5, and 8. The most studied SNPs may lead to decreased enzyme activity and may have impact on drug metabolism. Variant alleles are called CYP2C8*2 (I269F), CYP2C8*3 (R139K, K399R), and CYP2C8*4(I264M). Our aim was to investigate the frequency of major functional SNPs among the Czech population. MATERIAL AND METHODS: DNA was isolated from whole blood of 161 healthy, young, and unrelated subjects (94 men and 67 women, aged from 23 to 28 years). The genotypes of polymorphic positions CYP2C8*2, CYP2C8*3 (G416A, A1196G), and CYP2C8*4 were determined by polymerase chain reaction-restriction fragment length polymorphism. RESULTS AND CONCLUSION: Observed allele frequencies were 10.9%, 5.9%, and 0.3% for the alleles CYP2C8*3, CYP2C8*4, and CYP2C8*2, respectively. Both CYP2C8*3 (G416A, A1196G) alleles have been found in complete linkage disequilibrium. The allele distribution complies well with Hardy-Weinberg equilibrium. Allele frequencies of functionally important CYP2C8 variants in the Czech population are similar to that of other Caucasian populations.

Clinical Pharmacology Unit Department of Pharmacology 1st Faculty of Medicine Charles University Prague Czech Republic

See more in PubMed

Bahadur N. Leathart JB. Mutch E, et al. CYP2C8 polymorphisms in Caucasians and their relationship with paclitaxel 6alpha-hydroxylase activity in human liver microsomes. Biochem Pharmacol. 2002;64:1579–1589. PubMed

Capdevila J. Chacos N. Werringloer J, et al. Liver microsomal cytochrome P-450 and the oxidative metabolism of arachidonic acid. Proc Natl Acad Sci U S A. 1981;78:5362–5366. PubMed PMC

Cavaco I. Stromberg-Norklit J. Kaneko A, et al. CYP2C8 polymorphism frequencies among malaria patients in Zanzibar. Eur J Clin Pharmacol. 2005;61:15–18. PubMed

Dai D. Zeldin DC. Blaisdell JA, et al. Polymorphisms in human CYP2C8 decrease metabolism of the anticancer drug paclitaxel and arachidonic acid. Pharmacogenetics. 2001;11:597–607. PubMed

Daily EB. Aquilante CL. Cytochrome P450 2C8 pharmacogenetics: a review of clinical studies. Pharmacogenomics. 2009;10:1489–1510. PubMed PMC

Evans WE. Relling MV. Clinical pharmacokinetics-pharmacodynamics of anticancer drugs. Clin Pharmacokinet. 1989;16:327–336. PubMed

Garcia-Martin E. Martinez C. Ladero JM, et al. Interethnic and intraethnic variability of CYP2C8 and CYP2C9 polymorphisms in healthy individuals. Mol Diagn Ther. 2006;10:29–40. PubMed

Garcia-Martin E. Martinez C. Tabares B, et al. Interindividual variability in ibuprofen pharmacokinetics is related to interaction of cytochrome P450 2C8 and 2C9 amino acid polymorphisms. Clin Pharmacol Ther. 2004;76:119–127. PubMed

Halling J. Petersen MS. Damkier P, et al. Polymorphism of CYP2D6, CYP2C19, CYP2C9 and CYP2C8 in the Faroese population. Eur J Clin Pharmacol. 2005;61:491–497. PubMed

Hanioka N. Matsumoto K. Saito Y, et al. Influence of CYP2C8*13 and CYP2C8*14 alleles on amiodarone N-deethylation. Basic Clin Pharmacol Toxicol. 2010;108:359–362. PubMed

Hanioka N. Matsumoto K. Saito Y, et al. Influence of CYP2C8*13 and CYP2C8*14 alleles on amiodarone N-deethylation. Basic Clin Pharmacol Toxicol. 2011;108:359–362. PubMed

Jiang H. Zhong F. Sun L, et al. Structural and functional insights into polymorphic enzymes of cytochrome P450 2C8. Amino Acids. 2010;40:1195–1204. PubMed

Klose TS. Blaisdell JA. Goldstein JA. Gene structure of CYP2C8 and extrahepatic distribution of the human CYP2Cs. J Biochem Mol Toxicol. 1999;13:289–295. PubMed

Kudzi W. Dodoo AN. Mills JJ. Characterisation of CYP2C8, CYP2C9 and CYP2C19 polymorphisms in a Ghanaian population. BMC Med Genet. 2009;10:124. PubMed PMC

Lapple F. von Richter O. Fromm MF, et al. Differential expression and function of CYP2C isoforms in human intestine and liver. Pharmacogenetics. 2003;13:565–575. PubMed

Muthiah YD. Lee WL. Teh LK, et al. Genetic polymorphism of CYP2C8 in three Malaysian ethnics: CYP2C8*2 and CYP2C8*3 are found in Malaysian Indians. J Clin Pharm Ther. 2005;30:487–490. PubMed

Nakajima M. Fujiki Y. Noda K, et al. Genetic polymorphisms of CYP2C8 in Japanese population. Drug Metab Dispos. 2003;31:687–690. PubMed

Soyama A. Hanioka N. Saito Y, et al. Amiodarone N-deethylation by CYP2C8 and its variants, CYP2C8*3 and CYP2C8 P404A. Pharmacol Toxicol. 2002;91:174–178. PubMed

Soyama A. Saito Y. Hanioka N, et al. Non-synonymous single nucleotide alterations found in the CYP2C8 gene result in reduced in vitro paclitaxel metabolism. Biol Pharm Bull. 2001;24:1427–1430. PubMed

Totah RA. Rettie AE. Cytochrome P450 2C8: substrates, inhibitors, pharmacogenetics, and clinical relevance. Clin Pharmacol Ther. 2005;77:341–352. PubMed

Weise A. Grundler S. Zaumsegel D, et al. Development and evaluation of a rapid and reliable method for cytochrome P450 2C8 genotyping. Clin Lab. 2004;50:141–148. PubMed

Yasar U. Bennet AM. Eliasson E, et al. Allelic variants of cytochromes P450 2C modify the risk for acute myocardial infarction. Pharmacogenetics. 2003;13:715–720. PubMed

Zeldin DC. Moomaw CR. Jesse N, et al. Biochemical characterization of the human liver cytochrome P450 arachidonic acid epoxygenase pathway. Arch Biochem Biophys. 1996;330:87–96. PubMed