Dansette Patrick M, Bertho Gildas, Mansuy Daniel
Université Paris Descartes, UFR Biomédicale, CNRS UMR 8601, 45 Rue des Saints-Pères, 75270 Paris Cedex 06, France.
Biochem Biophys Res Commun. 2005 Dec 9;338(1):450-5. doi: 10.1016/j.bbrc.2005.08.091. Epub 2005 Aug 22.
Oxidation of 2-phenylthiophene (2PT) by rat liver microsomes, in the presence of NADPH and glutathione (GSH), led to three kinds of metabolites whose structures were established by 1H NMR and mass spectrometry. The first ones were 2PT-S-oxide dimers formed by Diels-Alder type dimerization of 2PT-S-oxide, while the second ones were GSH adducts derived from the 1,4-Michaël-type addition of GSH to 2PT-S-oxide. The third metabolites were GSH adducts resulting from a nucleophilic attack of GSH to the 4,5-epoxide of 2PT. Oxidation of 2PT by recombinant, human cytochrome P4501A1, in the presence of NADPH and GSH, also led to these three kinds of metabolites. These results provide the first evidence that cytochrome P450 may catalyze the oxidation of thiophene compounds with the simultaneous formation of two reactive intermediates, a thiophene-S-oxide and a thiophene epoxide.
在存在还原型辅酶Ⅱ（NADPH）和谷胱甘肽（GSH）的情况下，大鼠肝脏微粒体对2-苯基噻吩（2PT）的氧化作用产生了三种代谢产物，其结构通过核磁共振氢谱（1H NMR）和质谱分析得以确定。第一种是由2PT-S-氧化物通过狄尔斯-阿尔德（Diels-Alder）型二聚化形成的2PT-S-氧化物二聚体，而第二种是谷胱甘肽通过1,4-迈克尔（Michaël）型加成到2PT-S-氧化物上形成的谷胱甘肽加合物。第三种代谢产物是谷胱甘肽对2PT的4,5-环氧化物进行亲核攻击产生的谷胱甘肽加合物。在存在NADPH和GSH的情况下，重组人细胞色素P4501A1对2PT的氧化作用也产生了这三种代谢产物。这些结果首次证明细胞色素P450可能催化噻吩化合物的氧化，同时形成两种反应性中间体，即噻吩-S-氧化物和噻吩环氧化物。
