title: P450 (Cytochrome) Oxidoreductase Gene (POR) Common Variant (POR*28) Significantly Alters CYP2C9 Activity in Swedish, But Not in Korean Healthy Subjects.
abstract: CYP2C9 enzyme contributes to the metabolism of several pharmaceuticals and xenobiotics and yet displays large person-to-person and interethnic variation. Understanding the mechanisms of CYP2C9 variation is thus of immense importance for personalized medicine and rational therapeutics. A genetic variant of P450 (cytochrome) oxidoreductase (POR), a CYP450 redox partner, is reported to influence CYP2C9 metabolic activity in vitro. We investigated the impact of a common variant, POR*28, on CYP2C9 metabolic activity in humans. 148 healthy Swedish and 146 healthy Korean volunteers were genotyped for known CYP2C9 defective variant alleles (CYP2C9*2, *3). The CYP2C9 phenotype was determined using a single oral dose of 50 mg losartan. Excluding oral contraceptive (OC) users and carriers of 2C9*2 and *3 alleles, 117 Korean and 65 Swedish were genotyped for POR*5, *13 and *28 using Taqman assays. The urinary losartan to its metabolite E-3174 metabolic ratio (MR) was used as an index of CYP2C9 metabolic activity. The allele frequency of the POR*28 variant allele in Swedes and Koreans was 29% and 44%, respectively. POR*5 and *13 were absent in both study populations. Considering the CYP2C9*1/*1 genotypes only, the CYP2C9 metabolic activity was 1.40-fold higher in carriers of POR*28 allele than non-carriers among Swedes (p = 0.02). By contrast, no influence of the POR*28 on CYP2C9 activity was found in Koreans (p = 0.68). The multivariate analysis showed that ethnicity, POR genotype, and smoking were strong predictors of CYP2C9 MR (p < 0.05). This is the first report to implicate the importance of POR*28 genetic variation for CYP2C9 metabolic activity in humans. These findings contribute to current efforts for global personalized medicine and using medicines by taking into account pharmacogenetic and phenotypic variations.
authors.affiliation: 1 Department of Laboratory Medicine, Karolinska Institutet, Division of Clinical Pharmacology, Karolinska University Hospital , Huddinge, Sweden .|2 Faculty of Pharmacy, Universiti Teknologi MARA , Selangor, Malaysia .
authors.forename: Fazleen H M
authors.initials: FH
authors.lastname: Hatta
authors.affiliation: 1 Department of Laboratory Medicine, Karolinska Institutet, Division of Clinical Pharmacology, Karolinska University Hospital , Huddinge, Sweden .
authors.forename: Eleni
authors.initials: E
authors.lastname: Aklillu
mesh_terms: D000483:Alleles; D044466:Asian People / Q000235:genetics*; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics* / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism*; D004789:Enzyme Activation; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D056910:Republic of Korea; D013548:Sweden; D044465:White People / Q000235:genetics*
chemical_list: C000602470:POR protein, human; D003577:Cytochrome P-450 Enzyme System; D065729:Cytochrome P-450 CYP2C9