代谢
( R )-(+)-薄荷酮，是一种单萜烯酮，是薄荷油的主要成分。过量摄入薄荷油会导致严重毒性，偶尔甚至死亡。研究表明，薄荷酮的代谢物是导致毒性的原因。以前的代谢研究使用了高剂量，接近致死剂量，以及可能导致某些代谢物降解的分离和分析技术。为了澄清这些问题并进一步探索代谢途径，进行了一项关于 F344 大鼠中 (14)C-标记薄荷酮的研究，剂量从 0.8 到 80 mg/kg。对收集的尿液进行高效液相色谱 (HPLC) 分析显示薄荷酮的代谢广泛且复杂。通过 HPLC 分离出 14 种代谢物，并通过 NMR、UV 和质谱进行了鉴定。结果表明薄荷酮通过三个主要途径进行代谢：1) 羟基化生成单羟基薄荷酮，然后进行葡萄糖苷酸化或进一步代谢；2) 碳碳双键还原生成对映异构的孟酮/异孟酮，然后进行羟基化和葡萄糖苷酸化；3) 谷胱甘肽与薄荷酮发生迈克尔加成，然后进一步代谢生成对映异构的 8-(N-乙酰半胱氨-S-基)孟酮/异孟酮。这种 1,4-加成不仅在体内发生，而且在体外在谷胱甘肽 S-转移酶或温和碱的催化下也能发生。还观察到了两种巯基尿酸的几种羟基化产物。与以前的研究相反，本次研究鉴定出的主要代谢物中，除了一个之外都是二期代谢物，而且大多数自由形式的代谢物在结构上与以前鉴定的一期代谢物不同。
(R)-(+)-Pulegone, a monoterpene ketone, is a major component of pennyroyal oil. Ingestion of high doses of pennyroyal oil has caused severe toxicity and occasionally death. Studies have shown that metabolites of pulegone were responsible for the toxicity. Previous metabolism studies have used high, near lethal doses and isolation and analysis techniques that may cause degradation of some metabolites. To clarify these issues and further explore the metabolic pathways, a study of (14)C-labeled pulegone in F344 rats at doses from 0.8 to 80 mg/kg has been conducted. High-pressure liquid chromatography (HPLC) analysis of the collected urine showed the metabolism of pulegone to be extensive and complex. Fourteen metabolites were isolated by HPLC and characterized by NMR, UV, and mass spectroscopy. The results demonstrated that pulegone was metabolized by three major pathways: 1) hydroxylation to give monohydroxylated pulegones, followed by glucuronidation or further metabolism; 2) reduction of the carbon-carbon double bond to give diastereomeric menthone/isomenthone, followed by hydroxylation and glucuronidation; and 3) Michael addition of glutathione to pulegone, followed by further metabolism to give diastereomeric 8-(N-acetylcystein-S-yl)menthone/isomenthone. This 1,4-addition not only took place in vivo but also in vitro under catalysis of glutathione S-transferase or mild base. Several hydroxylated products of the two mercapturic acids were also observed. Contrary to the previous study, all but one of the major metabolites characterized in the present study are phase II metabolites, and most of the metabolites in free forms are structurally different from those previously identified phase I metabolites.
来源:Hazardous Substances Data Bank (HSDB)
