Bioactivation of antituberculosis thioamide and thiourea prodrugs by bacterial and mammalian flavin monooxygenases

被引：63
作者：
Nishida, Clinton R. [1 ]
de Montellano, Paul R. Ortiz [1 ]
机构：
[1] Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA 94158 USA
来源：
CHEMICO-BIOLOGICAL INTERACTIONS | 2011年 / 192卷 / 1-2期
关键词：
Antituberculosis drugs; Drug metabolism; Flavin monooxygenases; Thiacetazone; Ethionamide; lsoxyl; MYCOBACTERIUM-TUBERCULOSIS; DRUG ETHIONAMIDE; ACTIVATION; TARGET; INHA; THIACETAZONE; OXYGENATION; MECHANISM; ISOXYL; GENE;
D O I：
10.1016/j.cbi.2010.09.015
中图分类号：
Q5 [生物化学]; Q7 [分子生物学];
学科分类号：
071010 ; 081704 ;
摘要：
The thioamide and thiourea class of antituberculosis agents encompasses prodrugs that are oxidatively converted to their active forms by the Flavin monooxygenase EtaA of Mycobacterium tuberculosis. Reactive intermediates produced in the EtaA-catalyzed transformations of ethionamide and prothionamide result in NAD(+)/NADH adducts that inhibit the enoyl CoA reductase InhA, the ultimate target of these drugs. In the case of thiacetazone and isoxyl. EtaA produces electrophilic metabolites that mediate the antibacterial activity of these agents. The oxidation of the thioamide/thiourea drugs by the human flavin monooxygenases yields similar reactive metabolites that contribute to the toxicities associated with these second line antituberculosis drugs. (C) 2010 Elsevier Ireland Ltd. All rights reserved.
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收藏
页码：21 / 25
页数：5
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