Metabolic disposition of a monoterpene ketone, piperitenone, in rats: Evidence for the formation of a known toxin, p-cresol

It was shown earlier that the monoterpene ketone, piperitenone (I) is one o f the major metabolites of R-(+)-pulegone, a potent hepatotoxin, In the pre sent studies, the metabolic disposition of piperitenone (I) was examined in rats. Piperitenone (I) was administered orally (400 mg/kg of the b. wt./da y) to rats for 5 days, The following urinary metabolites were isolated and identified by various spectral analyses: p-cresol (VI), 6,7-dehydromenthofu ran (III), p-mentha-1,3,5,8-tetraen-3-ol (IX), p-mentha-1,3, 5-friene-3, 8- diol (X), 5-hydroxypiperitenone (VIII), 7-hydroxypiperitenone (XI), 10-hydr oxypiperitenone (XII), and 4-hydroxypiperitenone (VII). Incubation of piper itenone (I) with phenobarbital-induced rat liver microsomes in the presence of NADPH resulted in the formation of five metabolites which have been ten tatively identified as metabolites III, VII, VIII, XI, XII, on the basis of gas chromatography retention time and gas chromatography-mass spectrometry analysis. Based on these results, a probable mechanism for the formation o f p-cresol from piperitenone (I) via the intermediacy of metabolite III has been proposed.