title: Major cytochrome P450 enzymes responsible for microsomal aldehyde oxygenation of 11-oxo-Delta8-tetrahydrocannabinol and 9-anthraldehyde in human liver.
abstract: Hepatic microsomes from human liver catalyzed oxidation of the allyl aldehydes such as 11-oxo-Delta(8)-tetrahydrocannabinol and 9-anthraldehyde to the corresponding carboxylic acid metabolites. The oxygenation mechanism was confirmed by GC-MS that molecular oxygen was exclusively incorporated into Delta(8)-tetrahydrocannabinol-11-oic acid and 9-anthracene carboxylic acid formed under oxygen-18 gas. The microsomal aldehyde oxygenase (named MALDO) activities of 11-oxo-Delta(8)-tetrahydrocannabinol and 9-anthraldehyde were significantly inhibited by the antibody against CYP2C and CYP3A, respectively. MALDO activity for 11-oxo-Delta(8)-tetrahydrocannabinol was significantly inhibited by sulfaphenazole whereas that for 9-anthraldehyde was markedly inhibited by troleandomycin, but not by sulfaphenazole. CYP2C9 expressed in human B-lymphoblastoid cells catalyzed efficiently the MALDO activity for 11-oxo-Delta(8)-tetrahydrocannabinol (10.1 nmol/min/nmol P450), while the catalytic activities of other human CYPs expressed in the cells were lesser extents. In MALDO activity for 9-anthraldehyde, CYP3A4 expressed in the cells had the highest catalytic activity (7.72 nmol/min/nmol P450). These results indicate that CYP2C9 and CYP3A4 are major enzymes responsible for the MALDO activity in human liver for 11-oxo-Delta(8)-tetrahydrocannabinol and 9-anthraldehyde, respectively.
authors.affiliation: Faculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa, Japan. k-watanabe@hokuriku-u.ac.jp
authors.forename: Kazuhito
authors.initials: K
authors.lastname: Watanabe
authors.forename: Tamihide
authors.initials: T
authors.lastname: Matsunaga
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Kimura
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Funahashi
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Funae
authors.forename: Tohru
authors.initials: T
authors.lastname: Ohshima
authors.forename: Ikuo
authors.initials: I
authors.lastname: Yamamoto