Functional Characterization of Allelic Variants of Polymorphic Human Cytochrome P450 2A6 (CYP2A6*5, *7, *8, *18, *19, and *35)
作者： Songhee Han , Seunghye Choi , Young-Jin Chun , Chul-Ho Yun , Chang Hoon Lee
DOI: 10.1248/BPB.35.394
关键词:
摘要: Cytochrome P450 2A6 (CYP2A6) catalyzes important metabolic reactions of many xenobiotic compounds, including coumarin, nicotine, cotinine, and clinical drugs. Genetic polymorphisms CYP2A6 can influence its activities. This study analyzed the functional activities six allelic variants (CYP2A6*5, *7, *8, *18, *19, *35) containing nonsynonymous single-nucleotide polymorphisms. Recombinant variant enzymes CYP2A6*7, *35 were successfully expressed in Escherichia coli purified. However, a holoenzyme spectrum was not detected for CYP2A6*5 (G479V). Structural analysis shows that G479V mutation may alter interaction between A helix F—G helices. Enzyme kinetic analyses indicated effects mutations on drug metabolism are dependent substrates. In case coumarin 7-hydroxylation, CYP2A6*8 displayed increased Km values whereas CYP2A6*18 *19 showed decreased kcat values, which resulted lower catalytic efficiencies (kcat/Km). nicotine 5-oxidation, CYP2A6*19 exhibited an value, much greater decreases values. These results suggest individuals carrying these likely to have different metabolisms Functional characterization help determine importance
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