title: In vitro inhibition of liver monooxygenases by beta-ionone, 1,8-cineole, (-)-menthol and terpineol.
abstract: The present study was undertaken to investigate the inhibitory effects of beta-ionone, (-)-menthol, 1,8-cineole and alpha-terpineol on liver microsomal enzymes involved in the biotransformation of xenobiotic substances. The effects of beta-ionone and the foregoing monoterpenoid compounds on the activity of pentoxyresorufin-O-depentilase (PROD), a selective marker for CYP2B1, were determined in a pool of liver microsomes prepared from phenobarbital-treated rats. On the other hand, the inhibitory effects of these substances on the activities of ethoxyresorufin-O-deethylase (EROD), a marker for CYP1A1, and methoxyresorufin-O-demethylase (MROD), a marker for CYP1A2, were investigated in a pool of hepatic microsomes from beta-naphthoflavone-treated rats. Beta-ionone caused a concentration-related reduction of PROD activity with an IC50 value as low as 0.03 microM. The analysis of alterations produced by beta-ionone on PROD kinetic parameters (Lineweaver-Burk double-reciprocal plot) suggested that inhibition is non-competitive (Ki = 89.9 nM). Although being less potent than beta-ionone, 1,8-cineole (IC50 = 4.7 microM), (-)-menthol (IC50 = 10.6 microM) and terpineol (IC50 = 14.8 microM) also proved to be in vitro inhibitors of PROD reaction. Results also revealed that beta-ionone was a weak inhibitor of EROD (IC50 >100 microM) and MROD (IC50 >200 microM). Neither 1,8-cineole nor terpineol--tested in concentrations up to 150 microM--caused any decrease of EROD activity while (-)-menthol, at a concentration as high as 160 microM, produced only a slight reduction of the reaction rate. Terpineol (up to 150 microM) did not induce any reduction of MROD activity while 1,8-cineole (IC50 >300 microM) and (-)-menthol (IC50 >300 microM) caused only slight decreases of the reaction rate. The potent inhibitory effects on CYP2B1 suggest that beta-ionone, and the other monoterpenoids tested, may interfere with the metabolism of xenobiotics which are substrates for this isoenzyme.
authors.affiliation: Laboratory of Environmental Toxicology, The National School of Public Health, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil.
authors.forename: A C
authors.initials: AC
authors.lastname: De-Oliveira
authors.forename: A A
authors.initials: AA
authors.lastname: Fidalgo-Neto
authors.forename: F J
authors.initials: FJ
authors.lastname: Paumgartten
mesh_terms: D000818:Animals; D000081005:Cyclohexane Monoterpenes; D003511:Cyclohexanols; D053138:Cyclohexenes; D019363:Cytochrome P-450 CYP1A1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D019362:Cytochrome P-450 CYP2B1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D000077591:Eucalyptol; D005260:Female; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008610:Menthol / Q000031:analogs & derivatives / Q000494:pharmacology; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D039821:Monoterpenes; D045792:Norisoprenoids; D010088:Oxidoreductases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013729:Terpenes / Q000494:pharmacology*
chemical_list: D000081005:Cyclohexane Monoterpenes; D003511:Cyclohexanols; D053138:Cyclohexenes; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D039821:Monoterpenes; D045792:Norisoprenoids; D013729:Terpenes; D008610:Menthol; C016775:alpha-terpineol; D003577:Cytochrome P-450 Enzyme System; C008157:beta-ionone; D010088:Oxidoreductases; C076307:methoxyresorufin-O-demethylase; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D019362:Cytochrome P-450 CYP2B1; D000077591:Eucalyptol