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Retrorsine, but not Monocrotaline, is A Mechanism-Based Inactivator of P450 3A4

corelboy 添加于 2009-10-16 23:49 | 1260 次阅读 | 0 个评论

作者
Dai J, Zhang F, Zheng J
摘要
Retrorsine (RTS) and monocrotaline (MCT) cause severe toxicities via P450-mediated metabolic activation. The screening of mechanism-based inhibitors showed RTS inactivated 3A4 in the presence of NADPH. Unlike RTS, MCT failed to inhibit P450 3A4 and other enzymes tested. Further studies showed the loss of P450 3A4 activity occurred in a time- and concentration-dependent way, which was not recovered after dialysis. Dextromethorphan, a P450 3A4 substrate, protected the enzyme from the inactivation. Exogenous nucleophile glutathione (GSH) and reactive oxygen species scavengers catalase and superoxide dismutase did not protect P450 3A4 from the inactivation. GSH trapping experiments showed both P450 3A4 and 2C19 converted RTS and MCT to the corresponding electrophilic metabolites which could be trapped by GSH to form 7-GSH-DHP conjugate. We conclude that RTS and MCT are metabolically activated by P450 3A4 and 2C19, and that RTS, but not MCT, is a mechanism-based inactivator of P450 3A4.
详细资料
- 文献种类: Journal Article
- 期刊名称: Chemico-Biological Interactions
- 期刊缩写: Chem Biol Interact
- 期卷页: 2009年
- 地址: Center for Developmental Therapeutics, Seattle Children's Research Institute, Division of Gastroenterology, Department of Pediatrics, University of Washington, Seattle, WA 98101, USA
- ISBN: 1872-7786
- 备注:PMID:19818743
学科领域生物医药 » 基础医学
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