Ethanol oxidation into acetaldehyde by 16 recombinant human cytochrome P450 isoforms: Role of CYP2C isoforms in human liver microsomes
Ethanol oxidation into acetaldehyde by 16 recombinant human cytochrome P450 isoforms: Role of CYP2C isoforms in human liver microsomes
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DOI：
10.1016/j.toxlet.2006.09.011
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发表时间：
2006-12-15
影响因子：
3.5
通讯作者：
Lucas, D.
中科院分区：
文献类型：
--
作者：
Hamitouche, S.;Poupon, J.;Lucas, D.
利用16个重组人CYP异构体研究了细胞色素P450 （CYP）参与乙醇氧化成乙醛的过程。测定CYP1A1、CYP1A2、CYP1B1、CYP2A6、CYP2B6、CYP2C8、CYP2C9*1、CYP2C9*2、CYP2C9*3、CYP2C18、CYP2C19、CYP2D6、CYP2E1、CYP2J2、CYP3A4和CYP4A11的表观K-m和V-m。除CYP2A6和CYP2C18外，所有测试的CYPs都将乙醇代谢成大量的乙醛，并显示出10 mM左右的K-m值。在一组人肝微粒体中，发现乙醇氧化与CYP2E1、CYP3A4和CYP1A2的催化活性之间存在显著相关性，证实了这些CYPs在乙醇代谢中的重要意义。在肝脏中，CYP2C异构体在CYP3A4之后最为丰富，我们利用重组CYP2C异构体或人肝微粒体的选择性抑制剂研究了CYP2C异构体的作用。基于机制的CYP2C9和CYP2C19抑制剂替尼酸（100 μ M）和噻氯匹定（20 μ M）分别使人肝微粒体样品中的乙醇氧化降低8 +/- 1.2%和7.6 +/- 1.6%，而CYP2E1 （DEDTC 100 μ M）、CYP3A4 （TAO 50 μ M）和CYP1A2（呋喃茶碱25 μ M）的选择性抑制剂分别使乙醇氧化降低11.9 +/- 2.1%、19.8 +/- 1.9%和16.3 +/- 3.9%。由于乙醇可以被大多数CYPs代谢，它有助于解释或预测酒精与外源性药物的相互作用，这在医学处方中具有重要意义。2006爱思唯尔爱尔兰有限公司版权所有。
The involvement of cytochromes P450 (CYPs) in the oxidation of ethanol into acetaldehyde was investigated by using 16 recombinant human CYP isoforms. Apparent K-m and V-m were determined for CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2B6, CYP2C8, CYP2C9*1, CYP2C9*2, CYP2C9*3, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2J2, CYP3A4 and CYP4A11. All of the tested CYPs, except CYP2A6 and CYP2C18, metabolized ethanol into significant amounts of acetaldehyde and displayed K-m values around 10 mM. The significant correlation found between ethanol oxidation and CYP2E1, CYP3A4 and CYP1A2 catalytic activities in a panel of human liver microsomes confirmed the strong implication of these CYPs in ethanol metabolism. The contribution of CYP2C isoforms which are the most abundant in the liver after CYP3A4, was studied using selective inhibitors either with recombinant CYP2C isoforms or in human liver microsomes. Tienilic acid (100 mu M) and ticlopidine (20 mu M), mechanism-based inhibitors of CYP2C9 and CYP2C19, respectively, decreased ethanol oxidation by 8 +/- 1.2% and 7.6 +/- 1.6% in human liver microsomal samples while selective inhibitors of CYP2E1 (DEDTC 100 mu M), CYP3A4 (TAO 50 mu M) and CYP1A2 (furafylline 25 mu M) decreased it by 11.9 +/- 2.1%, 19.8 +/- 1.9% and 16.3 +/- 3.9%, respectively. As ethanol can be metabolized by most of CYPs, it helps to explain or predict alcohol-xenobiotics interactions which are of high importance in medical prescription. (c) 2006 Elsevier Ireland Ltd. All rights reserved.