Reactive intermediates in the oxidation of menthofuran by cytochromes P-450.
Menthofuran, a naturally occurring hepatotoxin, is metabolically activated to chemically reactive intermediates that are capable of covalent binding to cellular proteins. Studies in vivo and in vitro with inhibitors and inducers of hepatic cytochromes P-450 demonstrated an association between hepatocellular damage caused by menthofuran and its metabolic activation and covalent binding to target organ proteins. The same gamma-ketoenal formed from the metabolic precursor of menthofuran, pulegone, is the major electrophilic metabolite of menthofuran as well. Diastereomeric mintlactones also are formed, and studies with H218O and 18O2 indicate that the gamma-ketoenal is a precursor to the mintlactones, as well as other reactive intermediates in the cytochrome P-450 mediated oxidation of menthofuran.
Thomassen
D
D
Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle 98195.
Knebel
N
N
Slattery
J T
JT
McClanahan
R H
RH
Nelson
S D
SD
D000082:Acetaminophen / Q000032:analysis / Q000378:metabolism; D000328:Adult; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000378:metabolism; D003500:Cyclization; D000081005:Cyclohexane Monoterpenes; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004852:Epoxy Compounds / Q000737:chemistry / Q000633:toxicity; D006801:Humans; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008610:Menthol / Q000031:analogs & derivatives / Q000737:chemistry / Q000633:toxicity; D051379:Mice; D008807:Mice, Inbred BALB C; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D008875:Middle Aged; D039821:Monoterpenes; D010084:Oxidation-Reduction; D051381:Rats; D011919:Rats, Inbred Strains; D013729:Terpenes / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity
D000081005:Cyclohexane Monoterpenes; D004852:Epoxy Compounds; D039821:Monoterpenes; D013729:Terpenes; D008610:Menthol; D000082:Acetaminophen; C054487:menthofuran; C039648:pulegone; D003577:Cytochrome P-450 Enzyme System