(R)-(+)-胡薄荷酮活性代谢产物形成机制的研究。

Investigations of mechanisms of reactive metabolite formation from (R)-(+)-pulegone.

Nelson S D, McClanahan R H, Thomassen D, Gordon W P, Knebel N

Department of Medicinal Chemistry, University of Washington, Seattle 98195.

Xenobiotica. 1992 Sep-Oct;22(9-10):1157-64. doi: 10.3109/00498259209051869.

Abstract

(R)-(+)-Pulegone is a monoterpene that is oxidized by cytochromes P-450 to reactive metabolites that initiate events in the pathogenesis of hepatotoxicity in mice, rats and humans. 2. Selective labelling of (R)-(+)-pulegone with deuterium revealed that menthofuran was a proximate hepatotoxic metabolite formed by oxidation of the allylic methyl groups of pulegone. Incubations of pulegone with mouse liver microsomes in an atmosphere of 18O2 resulted in the formation of menthofuran that contained only oxygen-18 in the furan moiety. These results are consistent with oxidation of pulegone to an allylic alcohol that reacts intramolecularly with the ketone moiety to form a hemiketal that subsequently dehydrates to generate menthofuran. 3. Studies on the metabolism of menthofuran revealed that it is oxidized by cytochromes P-450 to an electrophilic gamma-ketoenal that reacts with nucleophilic groups on proteins to form covalent adducts. In addition, diastereomeric mintlactones are formed. Investigations with H2(18)O and 18O2 are indicative of a furan epoxide intermediate, or a precursor, in the formation of the gamma-ketoenal and mintlactones.

摘要

（R）-（+）-胡薄荷酮是一种单萜，可被细胞色素P-450氧化为活性代谢物，这些代谢物会引发小鼠、大鼠和人类肝毒性发病机制中的一系列事件。2. 用氘对（R）-（+）-胡薄荷酮进行选择性标记表明，薄荷呋喃是由胡薄荷酮的烯丙基甲基氧化形成的一种直接肝毒性代谢物。在18O2气氛中，将胡薄荷酮与小鼠肝微粒体一起孵育，结果形成了仅在呋喃部分含有氧-18的薄荷呋喃。这些结果与胡薄荷酮氧化为烯丙醇一致，烯丙醇与酮部分发生分子内反应形成半缩酮，随后脱水生成薄荷呋喃。3. 对薄荷呋喃代谢的研究表明，它被细胞色素P-450氧化为亲电的γ-酮烯醛，该醛与蛋白质上的亲核基团反应形成共价加合物。此外，还形成了非对映体薄荷内酯。用H2（18）O和18O2进行的研究表明，在γ-酮烯醛和薄荷内酯的形成过程中存在呋喃环氧化物中间体或前体。