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In Vitro Assessment of 36 CYP 2 C 9 Allelic Isoforms Found in the C hinese Population on the Metabolism of Glimepiride
Author(s) -
Dai DaPeng,
Wang ShuangHu,
Geng PeiWu,
Hu GuoXin,
Cai JianPing
Publication year - 2014
Publication title -
basic and clinical pharmacology and toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.805
H-Index - 90
eISSN - 1742-7843
pISSN - 1742-7835
DOI - 10.1111/bcpt.12159
Subject(s) - microsome , population , gene isoform , allele , cytochrome p450 , glimepiride , isozyme , chemistry , enzyme , metabolism , biology , pharmacology , biochemistry , gene , endocrinology , medicine , type 2 diabetes , environmental health , diabetes mellitus
Of the 57 reported CYP 2 C 9 alleles, to date, 36 of them have been identified in the C hinese population. The aim of this study was to assess the catalytic characteristics of these allelic isoforms and their effects on the metabolism of glimepiride in vitro . Baculovirus‐mediated expressing system was used to highly express wild‐type and the 35 CYP 2 C 9 allelic variants in insect cell microsomes. Then, the enzymatic characteristics of each variant were evaluated using glimepiride as the substrate. Reactions were performed at 37°C with the insect microsomes and 0.125–10 μM glimepiride for 40 min. After termination, the products were extracted and used for signal collection by LC ‐ MS / MS . Of the 36 tested CYP 2 C 9 allelic isoforms, only four variants ( CYP 2 C 9.40, CYP 2 C 9.47, CYP 2 C 9.51 and CYP 2 C 9.54) exhibited similar relative clearance values to that of wild‐type CYP 2 C 9.1. In addition, one variant ( CYP 2 C 9.36) showed a higher intrinsic clearance value than the wild‐type protein, while the remaining 30 CYP 2 C 9 allelic isoforms exhibited significantly decreased clearance values (from 0.1% to 87.2%) compared to CYP 2 C 9.1. This study provided the most comprehensive data on the enzymatic activities of all reported CYP 2 C 9 variants in the C hinese population with regard to the commonly used antidiabetic drug, glimepiride. Our results indicate that most of the tested rare alleles significantly decrease the catalytic activity of CYP 2 C 9 variants towards glimepiride hydroxylation in vitro .