Major Cytochrome P450 Enzymes Responsible for Microsomal Aldehyde Oxygenation of 11-Oxo-Δ8-tetrahydrocannabinol and 9-Anthraldehyde in Human Liver

• Published in: DRUG METABOLISM AND PHARMACOKINETICS 2002, Vol.17 (6), p.516-521
• Main Authors: Watanabe, Kazuhito, Matsunaga, Tamihide, Kimura, Toshiyuki, Funahashi, Tatsuya, Funae, Yoshihiko, Ohshima, Tohru, Yamamoto, Ikuo
• Format: Article
• Language: eng ; jpn
• Subjects: 11-oxo-Δ8-tetrahydrocannabinol; 9-anthraldehyde; B-lymphoblastoid cell; CYP2C9; CYP3A4; human liver; microsomal aldehyde oxygenation
• ISSN: 1347-4367; 1880-0920
• DOI: 10.2133/dmpk.17.516

Hepatic microsomes from human liver catalyzed oxidation of the allyl aldehydes such as 11-oxo-Δ8-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 Δ8-tetrahydrocannabinol-11-oic acid and 9-anthracene carboxylic acid formed under oxygen-18 gas. The microsomal aldehyde oxygenase (named MALDO) activities of 11-oxo-Δ8-tetrahydrocannabinol and 9-anthraldehyde were significantly inhibited by the antibody against CYP2C and CYP3A, respectively. MALDO activity for 11-oxo-Δ8-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-Δ8-tetrahydrocannabinol (10.1nmol/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 (7.72nmol/min/nmol P450). These results indicate that CYP2C9 and CYP3A4 are major enzymes responsible for the MALDO activity in human liver for 11-oxo-Δ8-tetrahydrocannabinol and 9-anthraldehyde, respectively.