title: Assessment of 25 CYP2D6 alleles found in the Chinese population on propafenone metabolism in vitro.
abstract: Cytochrome P450 enzyme 2D6 (CYP2D6) is an important member of the cytochrome P450 enzyme superfamily, with more than 100 CYP2D6 allelic variants being previously reported. The aim of this study was to assess the catalytic characteristics of 25 alleles (CYP2D6.1 and 24 CYP2D6 variants) and their effects on the metabolism of propafenone in vitro. Twenty-five CYP2D6 alleles were expressing in 21 Spodoptera frugiperda (Sf) insect cells, and each variant was evaluated using propafenone as the substrate. Reactions were performed at 37 °C with 1-100 μmol/L propafenone for 30 min. After termination, the product 5-OH-propafenone was extracted and used for signal collection by ultra-performance liquid chromatography (UPLC). Compared with wild type CYP2D6.1, the intrinsic clearance (Vmax and Km) values of all variants were significantly altered. Three variants (CYP2D6.87, CYP2D6.90, CYP2D6.F219S) exhibited markedly increased intrinsic clearance values (129% to 165%), whereas 21 variants exhibited significantly decreased values (16% to 85%) due to increased Km and (or) decreased Vmax values. These results indicated that the majority of tested alleles had significantly altered catalytic activity towards propafenone hydroxylation in this expression system. Attention should be paid to subjects carrying these rare alleles when treated with propafenone.
authors.affiliation: a The Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, Wenzhou Medical University, Wenzhou, Zhejiang 325000, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Su
authors.affiliation: b School of Pharmacy, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
authors.forename: Bing-Qing
authors.initials: BQ
authors.lastname: Liang
authors.affiliation: b School of Pharmacy, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
authors.forename: Yan-Lin
authors.initials: YL
authors.lastname: Feng
authors.affiliation: b School of Pharmacy, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
authors.forename: Yunyun
authors.initials: Y
authors.lastname: Zhan
authors.affiliation: b School of Pharmacy, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
authors.forename: Ermin
authors.initials: E
authors.lastname: Gu
authors.affiliation: b School of Pharmacy, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
authors.forename: Xinxin
authors.initials: X
authors.lastname: Chen
authors.affiliation: c The Key Laboratory of Geriatrics, Beijing Hospital & Beijing Institute of Geriatrics, Ministry of Health, Beijing 100730, China.
authors.forename: Da-Peng
authors.initials: DP
authors.lastname: Dai
authors.affiliation: b School of Pharmacy, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
authors.forename: Guo-Xin
authors.initials: GX
authors.lastname: Hu
authors.affiliation: c The Key Laboratory of Geriatrics, Beijing Hospital & Beijing Institute of Geriatrics, Ministry of Health, Beijing 100730, China.
authors.forename: Jian-Ping
authors.initials: JP
authors.lastname: Cai
mesh_terms: D000483:Alleles; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000378:metabolism*; D044466:Asian People / Q000235:genetics*; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D006801:Humans; D007313:Insecta; D008861:Microsomes / Q000378:metabolism; D000071184:Pharmacogenomic Variants / Q000235:genetics*; D011405:Propafenone / Q000378:metabolism*
chemical_list: D000889:Anti-Arrhythmia Agents; D011405:Propafenone; D019389:Cytochrome P-450 CYP2D6
keywords: CYP2D6; metabolism; métabolisme; propafenone; propafénone; variants; vitro