Metabolism of (+)-fenchone by CYP2A6 and CYP2B6 in human liver microsomes.
The in vitro metabolism of (+)-fenchone was examined in human liver microsomes and recombinant enzymes. Biotransformation of (+)-fenchone was investigated by gas chromatography-mass spectrometry. (+)-Fenchone was found to be oxidized to 6-exo-hydroxyfenchone, 6-endo-hydroxyfenchone and 10-hydroxyfenchone by human liver microsomal P450 enzymes. The formation of metabolite of (+)-fenchone was determined by relative abundance of mass fragments and retention time with GC. CYP2A6 and CYP2B6 in human liver microsomes were major enzymes involved in the hydroxylation of (+)-fenchone, based on the following lines of evidence. First, of eleven recombinant human P450 enzymes tested, CYP2A6 and CYP2B6 catalyzed oxidation of (+)-fenchone. Second, oxidation of (+)-fenchone was inhibited by thioTEPA, (+)-menthofuran anti-CYP2A6 and anti-CYP2B6 antibodies. Finally, there was a good correlation between CYP2A6, CYP2B6 contents and (+)-fenchone hydroxylation activities in liver microsomes of 8 human samples.
Miyazawa
Mitsuo
M
Department of Applied Chemistry, Faculty of Science and Engineering, Kinki University, Osaka, Japan. miyazawa@apch.kindai.ac.jp
Gyoubu
Kunihiko
K
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism*; D001892:Camphanes; D002849:Chromatography, Gas; D065637:Cytochrome P-450 CYP2A6; D065702:Cytochrome P-450 CYP2B6; D006801:Humans; D006900:Hydroxylation; D009682:Magnetic Resonance Spectroscopy; D008862:Microsomes, Liver / Q000201:enzymology*; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D009036:Moths; D009636:Norbornanes / Q000378:metabolism* / Q000493:pharmacokinetics; D010084:Oxidation-Reduction; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism*; D021241:Spectrometry, Mass, Electrospray Ionization
D001892:Camphanes; D009636:Norbornanes; C027327:fenchone; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; C585599:CYP2B6 protein, human; D065637:Cytochrome P-450 CYP2A6; D065702:Cytochrome P-450 CYP2B6; D010089:Oxidoreductases, N-Demethylating