Incorporation of an oxygen from water into troglitazone quinone by cytochrome P450 and myeloperoxidase.
نویسندگان
چکیده
Troglitazone (TGZ) was the first glitazone used for the treatment of type II diabetes mellitus. TGZ undergoes an oxidative chroman ring-opening reaction to form a quinone product. Recently, cytochrome P450 (P450) was shown to be able to catalyze the formation of TGZ quinone. TGZ quinone was the major metabolite formed by dexamethasone-induced rat liver microsomes or myeloperoxidase (MPO) incubated with TGZ. The ultimate source for the quinone carbonyl oxygen atom of TGZ quinone was investigated using (18)O water in both enzyme reaction systems followed by liquid chromatography/tandem mass spectometry analysis of the TGZ quinone product. The resultant TGZ quinone formed by either liver microsomes or MPO contained a single atom of (18)O. The (18)O atom was determined to be the quinone carbonyl oxygen by collision-induced dissociation fragmentation of the (18)O-labeled TGZ quinone. The formation of TGZ quinone was inhibited approximately 90% by coincubation with ascorbic acid or cysteine in the MPO reaction system but only 10 to 20% in liver microsomes, which might reflect the difference in the mechanism by which TGZ quinone is formed by P450 and peroxidase. These results suggest that P450 catalyze an atypical reaction to form TGZ quinone, involving the incorporation of an oxygen from water into the quinone carbonyl position.
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عنوان ژورنال:
- Drug metabolism and disposition: the biological fate of chemicals
دوره 32 4 شماره
صفحات -
تاریخ انتشار 2004