CYP3A4 is a major isoform responsible for oxidation of 7-hydroxy-Delta(8)-tetrahydrocannabinol to 7-oxo-delta(8)-tetrahydrocannabinol in human liver microsomes.
The human liver enzyme microsomal alcohol oxygenase was able to oxidize both 7alpha- and 7beta-hydroxy-Delta(8)-tetrahydrocannabinol (7alpha- and 7beta-hydroxy-Delta(8)-THC) to 7-oxo-Delta(8)-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 7alpha- and 7beta-hydroxy-Delta(8)-THC to 7-oxo-Delta(8)-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 7alpha- and 7beta-hydroxy-Delta(8)-THC microsomal alcohol oxygenase activities in human liver were significantly inhibited by addition of 100 microM troleandomycin, 1 microM ketoconazole, and anti-CYP3A antibody, although these activities were not inhibited by 1 microM 7, 8-benzoflavone and 50 microM 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-Delta(8)-THC formed from 7alpha-OH-Delta(8)-THC, but only 12% of 7-oxo-Delta(8)-THC formed from 7beta-OH-Delta(8)-THC. These results indicate that CYP3A4 is a major isoform responsible for the oxidation of 7alpha- and 7beta-hydroxy-Delta(8)-THC to 7-oxo-Delta(8)-THC in liver microsomes of humans, although the oxidation mechanisms for 7alpha- and 7beta-hydroxy-Delta(8)-THC might be different.
Matsunaga
T
T
Department of Hygienic Chemistry, Faculty of Pharmaceutical Sciences, Hokuriku University, Hokuriku, Japan.
Kishi
N
N
Higuchi
S
S
Watanabe
K
K
Ohshima
T
T
Yamamoto
I
I
D000293:Adolescent; D001402:B-Lymphocytes / Q000201:enzymology / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D013759:Dronabinol / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism*; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism
C109363:7-hydroxy-delta(8)-tetrahydrocannabinol; C109364:7-oxo-delta(8)-tetrahydrocannabinol; D013759:Dronabinol; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D010100:Oxygen