title: The role of CYP2C9 genetic polymorphism in carvedilol O-desmethylation in vitro.
abstract: We aimed at investigating the role of CYP2C9 in carvedilol O-desmethylation and identifying the effect of 35 CYP2C9 allelic variants we found in Chinese Han population on the in vitro metabolism of carvedilol. Recombinant CYP2C9 and CYP2D6 microsomes of the wild type were used to test and verify the enzymes involved in carvedilol O-desmethylation. Recombinant CYP2C9 microsomes of distinguished genotypes were used to characterize the corresponding enzyme activity toward carvedilol. 2-100 μM carvedilol was incubated for 30 min at 37 °C. The products were detected using high-performance liquid chromatography. CYP2C9 plays a certain role in carvedilol metabolism. Compared with wild-type CYP2C9*1, the intrinsic clearance (V max/K m) values of all variants toward carvedilol O-desmethylation were significantly altered. The variants exhibited significantly decreased values (from 30 to 99.8 %) due to increased K m and/or decreased V max values. We conclude that recombinant system could be used to investigate the enzymes involved in drug metabolism and these findings complement the database where CYP2C9 polymorphism interacts with biotransformation of exogenous substances like drugs and toxins.
authors.affiliation: Department of Pharmacology, School of Pharmacy, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, People's Republic of China.
authors.forename: Pei-Pei
authors.initials: PP
authors.lastname: Pan
authors.affiliation: Department of Pharmacology, School of Pharmacy, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, People's Republic of China.
authors.forename: Qing-Hua
authors.initials: QH
authors.lastname: Weng
authors.affiliation: Department of Pharmacology, School of Pharmacy, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, People's Republic of China.
authors.forename: Chen-Jian
authors.initials: CJ
authors.lastname: Zhou
authors.affiliation: Department of Pharmacology, School of Pharmacy, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, People's Republic of China.
authors.forename: Yan-Li
authors.initials: YL
authors.lastname: Wei
authors.affiliation: Department of Pharmacology, School of Pharmacy, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, People's Republic of China.
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.affiliation: The Key Laboratory of Geriatrics, Beijing Hospital and Beijing Institute of Geriatrics, Ministry of Health, Beijing, China.
authors.forename: Da-Peng
authors.initials: DP
authors.lastname: Dai
authors.affiliation: The Key Laboratory of Geriatrics, Beijing Hospital and Beijing Institute of Geriatrics, Ministry of Health, Beijing, China.
authors.forename: Jian-Ping
authors.initials: JP
authors.lastname: Cai
authors.affiliation: Department of Pharmacology, School of Pharmacy, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, People's Republic of China. wzhHGX@163.com.
authors.forename: Guo-Xin
authors.initials: GX
authors.lastname: Hu
mesh_terms: D044466:Asian People / Q000235:genetics*; D002227:Carbazoles / Q000378:metabolism* / Q000494:pharmacology; D000077261:Carvedilol; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics* / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008745:Methylation; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D011110:Polymorphism, Genetic / Q000235:genetics*; D011412:Propanolamines / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D002227:Carbazoles; D011412:Propanolamines; D000077261:Carvedilol; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9
keywords: CYP2C9; CYP2D6; Carvedilol O-desmethylation; Enzymatic activity; Genetic polymorphism; Metabolism