In vivo studies on the metabolism of the monoterpene pulegone in humans using the metabolism of ingestion-correlated amounts (MICA) approach: explanation for the toxicity differences between (S)-(-)- and (R)-(+)-pulegone.
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.
Engel
Wolfgang
W
Deutsche Forschungsanstalt für Lebensmittelchemie, Lichtenbergstrasse 4, D-85748 Garching, Germany. wolfgang.engel@lrz.tum.de
D003408:Cresols / Q000378:metabolism / Q000652:urine; D000081005:Cyclohexane Monoterpenes; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D006868:Hydrolysis; D008297:Male; D039821:Monoterpenes / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity* / Q000652:urine
D003408:Cresols; D000081005:Cyclohexane Monoterpenes; D039821:Monoterpenes; C032538:4-cresol; C054487:menthofuran; C039648:pulegone