Troglitazone quinone formation catalyzed by human and rat CYP3A: an atypical CYP oxidation reaction

被引:35
作者
He, K [1 ]
Woolf, TF [1 ]
Kindt, EK [1 ]
Fielder, AE [1 ]
Talaat, RE [1 ]
机构
[1] Warner Lambert Co, Parke Davis Pharmaceut Res, Dept Pharmacokinet Dynam & Drug Metab, Ann Arbor, MI 48105 USA
关键词
troglitazone; quinone; metabolism; CYP3A4; one-electron oxidation;
D O I
10.1016/S0006-2952(01)00653-0
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Oxidative ring opening of troglitazone (TGZ), a thiazolidine 2,4-dione derivative used for the treatment of type II diabetes mellitus, leads to the formation of a quinone metabolite. The formation of TGZ quinone was shown to be NADPH dependent and to require active microsomal enzymes. Quinone formation was not affected by co-incubation with catalase or sodium azide and was partially inhibited (25%) by superoxide dismutase (SOD). Kinetic analysis of TGZ quinone formation in human liver microsomes implied single enzyme involvement. CYP3A isoforms were characterized as the primary enzymes involved in quinone formation by several lines of evidence including: (a) troleandomycin and ketoconazole almost completely inhibited microsomal quinone formation when SOD was present, whereas other CYP inhibitors had minimal effects (<20%); (b) TGZ quinone formation was highly correlated with regard to both contents (r(2): 0.9374) and activities (r(2): 0.7951) of CYP3A4 in human liver microsomes (HLM); (c) baculovirus insect cell-expressed human CYP3A4 was able to catalyze TGZ quinone formation at a higher capacity (V-max/K-m) than other human CYPs with the relative contribution of CYP3A4 in HLM estimated to be 20-fold higher than that of other CYPs; (d) TGZ quinone formation was increased by 350% in liver microsomes from rats pretreated with dexamethasone (DEX); and (e) plasma concentrations of TGZ quinone were increased by 260-680% in rats pretreated with DEX. The chemical nature of the quinone metabolite suggests an atypical CYP reaction consistent with a one-electron oxidation mechanism where an intermediate phenoxy radical combines with ferryl oxygen to subsequently form the quinone metabolite. (C) 2001 Elsevier Science Inc. All rights reserved.
引用
收藏
页码:191 / 198
页数:8
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