Chen L-J, Lebetkin E H, Burka L T
National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
Drug Metab Dispos. 2003 Oct;31(10):1208-13. doi: 10.1124/dmd.31.10.1208.
(R)-(+)-Menthofuran is a metabolite of (R)-(+)-pulegone, the chief constituent of pennyroyal oil. Menthofuran has been shown to account for a significant percentage of pulegone toxicity through further metabolism to a reactive intermediate, an enonal (2-Z-(2'-keto-4'-methylcyclohexylidene)propanal). Hydration of the enonal followed by a 1,4-dehydration and rearrangement gives rise to diastereomeric (-)-mintlactone and (+)-isomintlactone (mintlactones). We have conducted disposition studies on pulegone as part of the National Toxicology Program initiative in herbal medicines and dietary supplements, and have reported previously unknown urinary metabolites of pulegone. Comparative metabolism studies of 14C-labeled menthofuran in Fischer-344 (F344) rats were carried out to determine urinary metabolites of pulegone that are derived from the menthofuran pathway. Three sulfonic acid metabolites, namely, hexahydro-3,6-dimethyl-1-(2-sulfoethyl)-2H-indol-2-one, hexahydro-3,6-dimethyl-7a-sulfo-2(3H)-benzofuranone, and 2-sulfomenthofuran, were identified in urine of treated rats. Formation of these metabolites may be derived from reactions of the enonal with taurine or glutathione (GSH) (or sulfite ion). Other identified urinary metabolites of menthofuran could be attributed to further metabolism of mintlactones. Further hydroxylation of mintlactones could give 7a-hydroxymintlactone and 6,7a-dihydroxymintlactone. Glucuronidation or reduction of 7a-hydroxymintlactone could give rise to the major metabolites 7a-hydroxymintlactone glucuronide and 2-[2'-keto-4'-methylcyclohexyl]propionic acids. Glucuronidation or repeated hydroxylation/dehydration of 2-[2'-keto-4'-methylcyclohexyl]propionic acids could result in formation of hexahydro-3,6-dimethyl-7a-hydroxy-2(3H)-benzofuranone glucuronide and 2-(2'-hydroxy-4'-methylphenyl)propionic acid. 2-(Glutathion-S-yl)menthofuran, a GSH conjugate of the enonal that has been partially characterized in bile of rats dosed with pulegone, is at most a minor biliary metabolite of menthofuran in rats.
(R)-(+)-薄荷呋喃是(R)-(+)-胡薄荷酮的一种代谢产物，胡薄荷酮是薄荷油的主要成分。薄荷呋喃已被证明，通过进一步代谢生成一种反应性中间体烯醛（2-Z-(2'-酮-4'-甲基环己叉基)丙醛），在胡薄荷酮的毒性中占很大比例。烯醛水合后再经过1,4-脱水和重排，生成非对映体(-)-薄荷内酯和(+)-异薄荷内酯（薄荷内酯）。作为国家毒理学计划草药和膳食补充剂倡议的一部分，我们对胡薄荷酮进行了处置研究，并报告了以前未知的胡薄荷酮尿液代谢产物。开展了14C标记薄荷呋喃在Fischer-344（F344）大鼠体内的比较代谢研究，以确定源自薄荷呋喃途径的胡薄荷酮尿液代谢产物。在受试大鼠尿液中鉴定出三种磺酸代谢产物，即六氢-3,6-二甲基-1-(2-磺乙基)-2H-吲哚-2-酮、六氢-3,6-二甲基-7a-磺基-2(3H)-苯并呋喃酮和2-磺基薄荷呋喃。这些代谢产物的形成可能源自烯醛与牛磺酸或谷胱甘肽（GSH）（或亚硫酸根离子）的反应。其他已鉴定的薄荷呋喃尿液代谢产物可能归因于薄荷内酯的进一步代谢。薄荷内酯进一步羟基化可生成7a-羟基薄荷内酯和6,7a-二羟基薄荷内酯。7a-羟基薄荷内酯的葡萄糖醛酸化或还原可生成主要代谢产物7a-羟基薄荷内酯葡萄糖醛酸苷和2-[2'-酮-4'-甲基环己基]丙酸。2-[2'-酮-4'-甲基环己基]丙酸的葡萄糖醛酸化或反复羟基化/脱水可导致生成六氢-3,6-二甲基-7a-羟基-2(3H)-苯并呋喃酮葡萄糖醛酸苷和2-(2'-羟基-4'-甲基苯基)丙酸。2-(谷胱甘肽-S-基)薄荷呋喃是烯醛的一种GSH缀合物，在给予胡薄荷酮的大鼠胆汁中已得到部分表征，在大鼠中它至多是薄荷呋喃的一种次要胆汁代谢产物。
