RT Journal Article
SR Electronic
T1 CYP3A4 Is a Major Isoform Responsible for Oxidation of 7-Hydroxy-Δ8-tetrahydrocannabinol to 7-Oxo-Δ8-tetrahydrocannabinol in Human Liver Microsomes
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1291
OP 1296
VO 28
IS 11
A1 Tamihide Matsunaga
A1 Nobuyuki Kishi
A1 Shinsuke Higuchi
A1 Kazuhito Watanabe
A1 Tohru Ohshima
A1 Ikuo Yamamoto
YR 2000
UL http://dmd.aspetjournals.org/content/28/11/1291.abstract
AB The human liver enzyme microsomal alcohol oxygenase was able to oxidize both 7α- and 7β-hydroxy-Δ8-tetrahydrocannabinol (7α- and 7β-hydroxy-Δ8-THC) to 7-oxo-Δ8-THC. The oxidative activity was determined by using a panel of 12 individual cDNA-expressed human cytochrome P450s (CYPs) (1A1, 1A2, 2A6, 2B6, 2C8, 2C9-Arg, 2C9-Cys, 2C19, 2D6-Met, 2D6-Val, 2E1 and 3A4). Among the CYP isoforms examined, CYP3A4 showed the highest activity for both of substrates. The metabolism of 7α- and 7β-hydroxy-Δ8-THC to 7-oxo-Δ8-THC was also detected for CYPs 1A1 (4.8% of CYP3A4), 1A2 (4.7%), 2A6 (2.3%), 2C8 (16.6%), and 2C9-Cys (5.4%), and CYPs 1A1 (0.4%), 2C8 (1.3%), 2C9-Arg (4.3%), and 2C9-Cys (0.9%), respectively. The 7α- and 7β-hydroxy-Δ8-THC microsomal alcohol oxygenase activities in human liver were significantly inhibited by addition of 100 μM troleandomycin, 1 μM ketoconazole, and anti-CYP3A antibody, although these activities were not inhibited by 1 μM 7,8-benzoflavone and 50 μM sulfaphenazole. When the substrates were incubated with the CYP3A4-expressed microsomes under oxygen-18 gas phase, atmospheric oxygen was incorporated into 35% of 7-oxo-Δ8-THC formed from 7α-OH-Δ8-THC, but only 12% of 7-oxo-Δ8-THC formed from 7β-OH-Δ8-THC. These results indicate that CYP3A4 is a major isoform responsible for the oxidation of 7α- and 7β-hydroxy-Δ8-THC to 7-oxo-Δ8-THC in liver microsomes of humans, although the oxidation mechanisms for 7α- and 7β-hydroxy-Δ8-THC might be different. The American Society for Pharmacology and Experimental Therapeutics