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

Toxicology. 1999 Jul 1;135(1):33-41. doi: 10.1016/s0300-483x(99)00043-8.


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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cyclohexane Monoterpenes
  • Cyclohexanols*
  • Cyclohexenes
  • Cytochrome P-450 CYP1A1 / antagonists & inhibitors
  • Cytochrome P-450 CYP1A1 / metabolism
  • Cytochrome P-450 CYP1A2 / metabolism
  • Cytochrome P-450 CYP1A2 Inhibitors
  • Cytochrome P-450 CYP2B1 / antagonists & inhibitors
  • Cytochrome P-450 CYP2B1 / metabolism
  • Cytochrome P-450 Enzyme Inhibitors*
  • Cytochrome P-450 Enzyme System / metabolism
  • Eucalyptol
  • Female
  • Liver / drug effects*
  • Liver / enzymology
  • Menthol / analogs & derivatives
  • Menthol / pharmacology
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / enzymology
  • Monoterpenes*
  • Norisoprenoids*
  • Oxidoreductases / antagonists & inhibitors
  • Oxidoreductases / metabolism
  • Rats
  • Rats, Wistar
  • Terpenes / pharmacology*


  • Cyclohexane Monoterpenes
  • Cyclohexanols
  • Cyclohexenes
  • Cytochrome P-450 CYP1A2 Inhibitors
  • Cytochrome P-450 Enzyme Inhibitors
  • Monoterpenes
  • Norisoprenoids
  • Terpenes
  • Menthol
  • alpha-terpineol
  • Cytochrome P-450 Enzyme System
  • beta-ionone
  • Oxidoreductases
  • methoxyresorufin-O-demethylase
  • Cytochrome P-450 CYP1A1
  • Cytochrome P-450 CYP1A2
  • Cytochrome P-450 CYP2B1
  • Eucalyptol