乙醇对重组人CYP2C9.1代谢S-华法林和双氯芬酸的影响。

Effect of ethanol on S-warfarin and diclofenac metabolism by recombinant human CYP2C9.1.

作者信息

Tatsumi Akitoshi, Ikegami Yuki, Morii Ryoko, Sugiyama Masatoshi, Kadobayashi Muneo, Iwakawa Seigo

机构信息

Educational Center for Clinical Pharmacy, Kobe Pharmaceutical University, Japan.

出版信息

Biol Pharm Bull. 2009 Mar;32(3):517-9. doi: 10.1248/bpb.32.517.

DOI:10.1248/bpb.32.517

PMID:19252308

Abstract

The effect of ethanol on the metabolism of S-warfarin and diclofenac by recombinant cytochrome P450 2C9.1 microsomes (CYP2C9.1) was studied. The 7-hydroxylation metabolism of S-warfarin was inhibited by as low as 0.1 vol% (17 mM) ethanol. Ethanol decreased the V(max)/K(m) and V(max) values of S-warfarin metabolism in a concentration-dependent manner, but the K(m) value was unchanged by ethanol. The inhibitory effect of ethanol on the 4'-hydroxylation metabolism of diclofenac was not observed even at 1.0 vol% (170 mM) ethanol. Ethanol at a concentration of 3.0 vol% (510 mM) increased the K(m) value of diclofenac metabolism without changes in the V(max), which indicates that diclofenac 4'-hydroxylation by CYP2C9.1 was competitively inhibited by ethanol. S-Warfarin metabolism by CYP2C9.1 was more sensitive to ethanol than diclofenac metabolism. These results suggest that ethanol inhibits the metabolism by CYP2C9.1 in a substrate-dependent manner.

摘要

研究了乙醇对重组细胞色素P450 2C9.1微粒体（CYP2C9.1）代谢S-华法林和双氯芬酸的影响。低至0.1体积%（17 mM）的乙醇即可抑制S-华法林的7-羟基化代谢。乙醇以浓度依赖性方式降低S-华法林代谢的V(max)/K(m)和V(max)值，但乙醇对K(m)值无影响。即使在1.0体积%（170 mM）乙醇浓度下，也未观察到乙醇对双氯芬酸4'-羟基化代谢的抑制作用。浓度为3.0体积%（510 mM）的乙醇增加了双氯芬酸代谢的K(m)值，而V(max)未改变，这表明乙醇竞争性抑制了CYP2C9.1介导的双氯芬酸4'-羟基化。CYP2C9.1对S-华法林的代谢比对双氯芬酸的代谢对乙醇更敏感。这些结果表明，乙醇以底物依赖性方式抑制CYP2C9.1的代谢。