Haenen G R, Jansen F P, Vermeulen N P, Bast A
Department of Pharmacochemistry, Faculty of Chemistry, Vrije Universiteit, Amsterdam, The Netherlands.
Arch Biochem Biophys. 1991 May 15;287(1):48-52. doi: 10.1016/0003-9861(91)90386-w.
Rat liver microsomes contain a membrane-bound GSH S-transferase (GSH-tr), an enzyme that is involved in the detoxication of xenobiotics. Also located on rat liver microsomes is the cytochrome P450 system, an enzyme complex that catalyzes the conversion of several xenobiotics into reactive intermediates. In this study, it was demonstrated that reactive products from alpha-methyldopa formed by the cytochrome P450 system are able to stimulate microsomal GSH-tr. Also, products formed from alpha-methyldopa that are generated by H2O2-horseradish peroxidase and tyrosinase are able to stimulate the activity of microsomal GSH-tr. GSH was able to prevent the activation of microsomal GSH-tr. Our results indicate that the ortho-quinone or semi-ortho-quinone radical of alpha-methyldopa is responsible for the stimulation of microsomal GSH-tr, probably via arylation of the free sulfhydryl group of microsomal GSH-tr. This conclusion was supported by the observation that 4-methyl-ortho-quinone itself was able to stimulate microsomal GSH-tr via sulfhydryl arylation. Our results are in conformity with the hypothesis that reactive products formed by the cytochrome P450 complex are able to stimulate microsomal GSH-tr and possibly in this way enhance their detoxication.
大鼠肝脏微粒体含有一种膜结合型谷胱甘肽S-转移酶（GSH-tr），该酶参与外源性物质的解毒过程。细胞色素P450系统也存在于大鼠肝脏微粒体中，这是一种酶复合物，可催化多种外源性物质转化为反应性中间体。在本研究中，已证明细胞色素P450系统形成的α-甲基多巴反应产物能够刺激微粒体GSH-tr。此外，由H2O2-辣根过氧化物酶和酪氨酸酶产生的α-甲基多巴形成的产物也能够刺激微粒体GSH-tr的活性。谷胱甘肽能够阻止微粒体GSH-tr的激活。我们的结果表明，α-甲基多巴的邻醌或半邻醌自由基可能通过微粒体GSH-tr游离巯基的芳基化作用来刺激微粒体GSH-tr。4-甲基邻醌本身能够通过巯基芳基化作用刺激微粒体GSH-tr这一观察结果支持了这一结论。我们的结果与细胞色素P450复合物形成的反应产物能够刺激微粒体GSH-tr并可能以此方式增强其解毒作用的假说一致。
