title: Metabolism of (+)-terpinen-4-ol by cytochrome P450 enzymes in human liver microsomes.
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.
authors.affiliation: Department of Applied Chemistry, Faculty of Science and Engineering, Kinki University.
authors.forename: Risa
authors.initials: R
authors.lastname: Haigou
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Miyazawa
mesh_terms: D001189:Aryl Hydrocarbon Hydroxylases / Q000502:physiology; D001711:Biotransformation; D002384:Catalysis; D065637:Cytochrome P-450 CYP2A6; D051544:Cytochrome P-450 CYP3A / Q000502:physiology; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology*; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D066298:In Vitro Techniques; D008862:Microsomes, Liver / Q000201:enzymology* / Q000378:metabolism*; D010084:Oxidation-Reduction; D013729:Terpenes / Q000378:metabolism*
chemical_list: D013729:Terpenes; C034019:terpinenol-4; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; D065637:Cytochrome P-450 CYP2A6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human