Metabolism of (+)-terpinen-4-ol by cytochrome P450 enzymes in human liver microsomes

J Oleo Sci. 2012;61(1):35-43. doi: 10.5650/jos.61.35.

Abstract

We examined the in vitro metabolism of (+)-terpinen-4-ol by human liver microsomes and recombinant enzymes. The biotransformation of (+)-terpinen-4-ol was investigated by gas chromatography-mass spectrometry (GC-MS). (+)-Terpinen-4-ol was found to be oxidized to (+)-(1R,2S,4S)-1,2-epoxy-p-menthan-4-ol, (+)-(1S,2R,4S)-1,2-epoxy-p-menthan-4-ol, and (4S)-p-menth-1-en-4,8-diol by human liver microsomal P450 enzymes. The identities of (+)-terpinen-4-ol metabolites were determined through the relative abundance of mass fragments and retention times on GC-MS. Of 11 recombinant human P450 enzymes tested, CYP1A2, CYP2A6, and CYP3A4 were found to catalyze the oxidation of (+)-terpinen-4-ol. Based on several lines of evidence, CYP2A6 and CYP3A4 were determined to be major enzymes involved in the oxidation of (+)-terpinen-4-ol by human liver microsomes. First, of the 11 recombinant human P450 enzymes tested, CYP1A2, CYP2A6 and CYP3A4 catalyzed oxidation of (+)-terpinen-4-ol. Second, oxidation of (+)-terpinen-4-ol was inhibited by (+)-menthofuran and ketoconazole, inhibitors known to be specific for these enzymes. Finally, there was a good correlation between CYP2A6 and CYP3A4 activities and (+)-terpinen-4-ol oxidation activities in the 10 human liver microsomes.

MeSH terms

  • Aryl Hydrocarbon Hydroxylases / physiology
  • Biotransformation
  • Catalysis
  • Cytochrome P-450 CYP2A6
  • Cytochrome P-450 CYP3A / physiology
  • Cytochrome P-450 Enzyme System / physiology*
  • Gas Chromatography-Mass Spectrometry
  • Humans
  • In Vitro Techniques
  • Microsomes, Liver / enzymology*
  • Microsomes, Liver / metabolism*
  • Oxidation-Reduction
  • Terpenes / metabolism*

Substances

  • Terpenes
  • terpinenol-4
  • Cytochrome P-450 Enzyme System
  • Aryl Hydrocarbon Hydroxylases
  • CYP2A6 protein, human
  • Cytochrome P-450 CYP2A6
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human