No abstract

The major in vivo metabolites of S-(+)- and R-(-)-carvone in a metabolism of ingestion correlated amounts (MICA) experiment were newly identified as alpha,4-dimethyl-5-oxo-3-cyclohexene-1-acetic acid (dihydrocarvonic acid), alpha-methylene-4-methyl-5-oxo-3-cyclohexene-1-acetic acid (carvonic acid), and 5-(1,2-dihydroxy-1-methylethyl)-2-methyl-2-cyclohexen-1-one (uroterpenolone) on the basis of mass spectral analysis in combination with syntheses and NMR experiments. Minor metabolites were identified as reduction products of carvone, namely, the alcohols carveol and dihydrocarveol. The previously identified major in vivo metabolite in rabbits, 10-hydroxycarvone, could not be detected, indicating either concentration effects or interspecies differences. Metabolic pathways for carvone in humans including oxidation of the double bond in the side chain and, to a minor extent 1,2- and 1,4 + 1,2-reduction of carvone, are discussed. No differences in metabolism between S-(+)- and R-(-)-carvone were detected.

The major in vivo metabolites of (S)-(-)-pulegone in humans using a metabolism of ingestion-correlated amounts (MICA) experiment were newly identified as 2-(2-hydroxy-1-methylethyl)-5-methylcyclohexanone (8-hydroxymenthone, M1), 3-hydroxy-3-methyl-6-(1-methylethyl)cyclohexanone (1-hydroxymenthone, M2), 3-methyl-6-(1-methylethyl)cyclohexanol (menthol), and E-2-(2-hydroxy-1-methylethylidene)-5-methylcyclohexanone (10-hydroxypulegone, M4) on the basis of mass spectrometric analysis in combination with syntheses and NMR experiments. Minor metabolites were be identified as 3-methyl-6-(1-methylethyl)-2-cyclohexenone (piperitone, M5) and alpha,alpha,4-trimethyl-1-cyclohexene-1-methanol (3-p-menthen-8-ol, M6). Menthofuran was not a major metabolite of pulegone and is most probably an artifact formed during workup from known (M4) and/or unknown precursors. The differences in toxicity between (S)-(-)- and (R)-(+)-pulegone can be explained by the strongly diminished ability for enzymatic reduction of the double bond in (R)-(+)-pulegone. This might lead to further oxidative metabolism of 10-hydroxypulegone (M4) and the formation of further currently undetected metabolites that might account for the observed hepatotoxic and pneumotoxic activity in humans.

No abstract

High-resolution gas chromatography in combination with mass spectrometry and high-resolution mass spectrometry was used to determine the positions and extent of labeling in the metabolites of carvone, namely in alpha,4-dimethyl-5-oxo-3-cyclohexene-1-acetic acid (dihydrocarvonic acid), alpha-methylene-4-methyl-5-oxo-3-cyclohexene-1-acetic acid (carvonic acid), and 5-(1,2-dihydroxy-1-methylethyl)-2-methyl-2-cyclohexen-1-one (uroterpenolone), after human ingestion of 9,9-dideutero- and 9-(13)C-carvone. Carvonic acid was formed by oxidation at the methyl carbon of the isopropenyl group of carvone, whereas dihydrocarvonic acid was formed by oxidation at the methylene position, most probably via carvone epoxide. A "nonaromatic" NIH shift must occur during the subsequent reactions yielding dihydrocarvonic acid. Additionally, dehydrogenation of dihydrocarvonic acid and hydrogenation of carvonic acid were observed, resulting in minor amounts of both acids owning a carboxy group of opposite origin. Uroterpenolone was found to be exclusively formed by oxidation at the methylene carbon of the isopropenyl group of carvone, and thus, most probably by hydrolysis of carvone epoxide.