Metabolic activation of (R)-(+)-pulegone to a reactive enonal that covalently binds to mouse liver proteins.
Pulegone, a naturally occurring hepatotoxin, is metabolically activated to chemically reactive intermediates that are capable of covalent binding to cellular protein. Studies in vivo and in vitro with inhibitors and inducers of cytochrome P-450 demonstrated an association among the hepatocellular toxicity of pulegone and its metabolic activation and covalent binding to protein. The exocyclic double bond of pulegone apparently is an important structural feature in the activation mechanism and binding to protein inasmuch as the reduced analogue, menthone, is neither hepatotoxic nor does it bind extensively to tissue proteins. Preliminary studies using semicarbazide as a trapping agent indicate that an unsaturated gamma-ketoaldehyde is the ultimate chemically reactive metabolite of pulegone.
McClanahan
R H
RH
Department of Medicinal Chemistry, University of Washington, Seattle 98195.
Thomassen
D
D
Slattery
J T
JT
Nelson
S D
SD
D000478:Alkylation; D000818:Animals; D001711:Biotransformation; D016923:Cell Death / Q000187:drug effects; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D000081005:Cyclohexane Monoterpenes; D008401:Gas Chromatography-Mass Spectrometry; D008099:Liver / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008610:Menthol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D039821:Monoterpenes; D011485:Protein Binding; D013729:Terpenes / Q000378:metabolism
D000081005:Cyclohexane Monoterpenes; D039821:Monoterpenes; D013729:Terpenes; D008610:Menthol; C039648:pulegone; C019466:menthone