Gordon W P, Huitric A C, Seth C L, McClanahan R H, Nelson S D
Department of Medicinal Chemistry, University of Washington, Seattle 98195.
Drug Metab Dispos. 1987 Sep-Oct;15(5):589-94.
(R)-(+)-Pulegone, the major monoterpene component of the abortifacient mint oil, pennyroyal oil, is metabolized by hepatic microsomal monooxygenases of the mouse to a hepatotoxin. The formation of a toxic metabolite is apparently mediated by cytochromes P-450 of the phenobarbital class inasmuch as phenobarbital pretreatment of mice increases, whereas beta-naphthoflavone pretreatment decreases, the extent of hepatic necrosis caused by pulegone. Furthermore, two inhibitors of cytochromes P-450, cobaltous chloride and piperonyl butoxide, block toxicity. An analog of (R)-(+)-pulegone that was labeled with deuterium in the allylic methyl groups was found to be significantly less hepatotoxic than the parent compound. The results indicate that oxidation of an allylic methyl group is required for generation of a hepatotoxic metabolite. Menthofuran was identified as a proximate toxic metabolite of (R)-(+)-pulegone, and investigations with (R)-(+)-pulegone-d6 and 18O2 strongly indicate that menthofuran is formed by a sequence of reactions that involve: 1) oxidation of an allylic methyl group, 2) intramolecular cyclization to form a hemiketal, and 3) dehydration to form the furan.
（R）-（+）-长叶薄荷酮是堕胎药薄荷油（胡薄荷油）的主要单萜成分，可被小鼠肝脏微粒体单加氧酶代谢为一种肝毒素。有毒代谢物的形成显然是由苯巴比妥类细胞色素P-450介导的，因为对小鼠进行苯巴比妥预处理会增加由长叶薄荷酮引起的肝坏死程度，而β-萘黄酮预处理则会降低该程度。此外，两种细胞色素P-450抑制剂，氯化钴和胡椒基丁醚，可阻断毒性。发现在烯丙基甲基上用氘标记的（R）-（+）-长叶薄荷酮类似物的肝毒性明显低于母体化合物。结果表明，烯丙基甲基的氧化是产生肝毒性代谢物所必需的。薄荷呋喃被鉴定为（R）-（+）-长叶薄荷酮的一种直接有毒代谢物，对（R）-（+）-长叶薄荷酮-d6和18O2的研究强烈表明，薄荷呋喃是由一系列反应形成的，这些反应包括：1）烯丙基甲基的氧化，2）分子内环化形成半缩酮，3）脱水形成呋喃。
