Abstract
In vitro metabolism of Δ9-and Δ8-tettahydrocannabinols (THCs) was studied using human liver microsomes. Δ9-orΔ8-THC was incubated with microsomes in the presence of NADPH-generating system. The metabolites formed were extracted with ethyl acetate, separated by preparative thin-layer chromatography, and identified as trimethylsilyl derivatives by gas chromatography-mass spectrometry. 9α, 10α-Epoxyhexahydrocannabinol (EHHC) together with four monohydroxylated metabolites was formed from Δ9-THC. The epoxide was found to resist the hydrolysis by epoxide hydrolase, and was further converted to several metabolites by monooxygenase system involving cytochrome P-450. On the other hand, 8β, 9α-dihydroxyhexahydrocannabinol (diOH-HHC) instead of epoxy metabolites was formed from Δ8-THC under the conditions for monooxygenase. When 1, 1, 1-trichloropropene-2, 3-oxide was further added to the incubation mixture, both of 8α, 9α- and 8β, 9β-EHHCs were found to be formed from Δ8-THC. These epoxides of Δ8-THC were preferentially hydrolyzed to 8β, 9α-diOH-HHC by epoxide hydrolase. These results indicate that 9α, 10α-EHHC formed from Δ9-THC is further metabolized not by epoxide hydrolase but by monooxygenase system involving cytochrome P-450, and that, on the contrary, 8α, 9α-and 8β, 9β-EHHCs derived from Δ8-THC may be metabolized by epoxide hydrolase rather than cytochrome P-450 in the human liver, forming 8β, 9α-diOH-HHC.
