In vitro inhibition of liver monooxygenases by β-ionone, 1,8-cineole, (-)-menthol and terpineol

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 mu M. The analysis of alterations produced by beta-ionone on PROD kinetic parameters (Lineweaver-Burk double-reciprocal plot) suggested that inhibition is non-competitive (K-i = 89.9 nM). Although being less potent than beta-ionone, 1,8-cineole (IC50 = 4.7 mu M), (-)-menthol (IC50 = 10.6 mu M) and terpineol (IC50 = 14.8 mu M) also proved to be in vitro inhibitors of PROD reaction. Results also revealed that beta-ionone was a weak inhibitor of EROD (IC50 > 100 mu M) and MROD (IC,, > 200 mu M). Neither 1,8-cineole nor terpineol-tested in concentrations up to 150 mu M-caused any decrease of EROD activity while (-)-menthol, at a concentration as high as 160 mu M, produced only a slight reduction of the reaction rate. Terpineol (up to 150 mu M) did not induce any reduction of MROD activity while 1,8-cineole (IC50 > 300 mu M) and (-)-menthol (IC50 > 300 mu M) 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. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved.