The Impact of Cyp2c9 Genetics and Oral Contraceptives on Cytochrome P450 2c9 Phenotype

Abstract

ABSTRACT:CYP2C9-dependent drug metabolism is subject to large interindividual variation. To some extent, this is explained by genetic polymorphism with expression of enzyme variants that differ in catalytic activity. The aim of this study was to characterize the variation in CYP2C9 phenotype in relation to genotype, with further analysis of the CYP2C9 gene in metabolic outliers. A study population of 126 healthy white subjects were recruited and genotyped for the variant alleles, CYP2C9*1-3. In CYP2C9 phenotyping with losartan, three subpopulations were distinguished that differed in the number of CYP2C9*3 alleles (0, 1, or 2). A three-fold higher metabolic ratio (MR; urinary losartan/carboxymetabolite) was found comparing CYP2C9*1/*3 (n ‫؍‬ 20) to CYP2C9*1/*1 (n ‫؍‬ 81), but there was considerable variation within each genotype. Subjects genotyped as CYP2C9*1/*1, but with an unexpectedly slow oxidation of losartan, were selected for DNA-sequencing analysis of the CYP2C9 gene. Interestingly, single nucleotide polymorphisms (SNPs) could not be identified either in the 5-flanking region, the nine exons, or exon-intron boundaries. However, sequencing of the CYP2C9 gene was also carried out in patients genotyped as CYP2C9*1/*1 but with an exceptionally low steady-state clearance of S-warfarin. Here, five different SNPs were identified. In further analysis of the healthy volunteers, it became evident that women on oral contraceptives (OCs) had slower oxidation of losartan (MR of losartan: 1.7) than women without OCs (MR of losartan: 0.86). This novel finding was not explained by a different frequency of variant alleles. In summary, CYP2C9 genotype and oral contraceptives both contribute to a large interindividual variation in CYP2C9 activity.

Polymorphism of CYP2D6, CYP2C19, CYP2C9 and CYP2C8 in the Faroese population

“…This is in agreement with previous reported allele frequencies in other Caucasians [30]. 95% (95% CI 84.2-99.4%) of the subjects with CYP2C8*3 alleles also carried CYP2C9*2 alleles, while 75% (95% CI 61.0-85.3%) of the subjects having the CYP2C9*2 variant also carried CYP2C8*3 alleles.…”

CYP2C19 activity comparison between Swedes and Koreans: effect of genotype, sex, oral contraceptive use, and smoking

“…Furthermore previously it is reported that OC use inhibits CYP2C19 enzyme activity [18] and F o r P e e r R e v i e w 4 hence variation in OC use habit may also contribute to some extent. As to our knowledge no study has compared the enzyme activity between the two populations controlling for the effect of confounding factors such as oral contraceptive use and CYP2C19 genotype.…”

“…Christensen et al [18] developed the Karolinska cocktail based on five probe drugs to phenotype the enzymes CYP1A2, CYP2C9, CYP2D6, CYP3A4 and CYP2C19. In general previous studies reported lower CYP2C19 enzyme activity among Asians compared to White population.…”

“…Furthermore previously it is reported that OC use inhibits CYP2C19 enzyme activity [18] and hence variation in OC use habit may also contribute to some extent. As to our knowledge no study has compared the enzyme activity between the genotype phenotype relationship differences using the same methodology between healthy Swedish and Korean subjects having the same CYP2C19 genotype, OC use and smoking habit.…”

CYP2C8 and CYP2C9 polymorphisms in relation to tumour characteristics and early breast cancer related events among 652 breast cancer patients

“…CYP2C8*3 is defective in the metabolism of two important CYP2C8 substrates: the anticancer drug paclitaxel (Bahadur et al, 2002) and the physiologically important compound arachidonic acid (AA) (Dai et al, 2001). In addition, variants CYP2C8*4 and CYP2C9*2 and CYP2C9*3 also have a lower metabolic activity than the wildtype variants (Bahadur et al, 2002;Griskevicius et al, 2003;King et al, 2004;Sandberg et al, 2004).…”