A cytochrome P450 (designated P450 MUT-2) which catalyses the oxidation of 11-oxo-Δ8-tetrahydrocannabinol (11-oxo- Δ8-THC) to Δ8-THC-11-oic acid has been purified from hepatic microsomes of untreated male mice. Analysis of NH2-terminal sequence suggests that the isozyme is a member of the P450 2C gene subfamily. P450 MUT-2 exhibited aldehyde oxygenase activity for 11-oxo-Δ8-TH, 11-oxo-Δ9-THC, 11-oxo-cannabinol (11-oxo-CBN) and 9-anthraldehyde together with high activity for the hydroxylation of cannabinoids at the 11-position. Antibody against P450 MUT-2 significantly inhibited the microsomal formation of Δ8-THC-11-oic acid from 11-oxo-Δ8-THC, but not that of 9-anthracene carboxylic acid from 9-anthraldehyde. Major metabolic reactions of Δ8-THC, Δ9-THC and CBN with mouse hepatic microsomes were the 11-hydroxylation (all cannabinoids), 7α-(Δ8-THC) or 8 α-hydroxylation (Δ9-THC) and epoxide formation (Δ8- and Δ9-THC). All these reactions except for 7 α-hydroxylation of Δ8-THC and α-epoxide formation from Δ9-THC were also markedly inhibited by the antibody. These results indicate that P450 MUT-2 is a major enzyme for metabolizing cannabinoids by mouse hepatic microsomes.
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