RT Journal Article
SR Electronic
T1 Menthofuran-dependent and independent aspects of pulegone hepatotoxicity: roles of glutathione.
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 567
OP 572
VO 253
IS 2
A1 Thomassen, D
A1 Slattery, J T
A1 Nelson, S D
YR 1990
UL http://jpet.aspetjournals.org/content/253/2/567.abstract
AB Pulegone, a monoterpene that protects source plants against predators, is a hepatotoxic constituent of the folklore abortifacient pennyroyal oil. In the rat, pulegone extensively depleted glutathione measured in both liver tissue and plasma, and its toxicity was markedly enhanced in animals treated with buthionine sulfoximine. The glutathione-depleting effect of pulegone was compromised following inhibition of cytochrome P-450 by piperonyl butoxide. In addition, we found no evidence for conjugation of glutathione to unchanged pulegone in vitro. Administration of menthofuran, a known oxidative and hepatotoxic metabolite of pulegone, only marginally affected glutathione levels in plasma and liver, and toxicity was not augmented by buthionine sulfoximine. These results provide indirect evidence for cytochrome P-450-catalyzed bioactivation of pulegone via at least two independent pathways: 1) the formation and subsequent activation of menthofuran from pulegone; and 2) the formation of reactive intermediate(s) from pulegone, but not menthofuran, which can be detoxified through a mechanism requiring reduced glutathione.