Difference in epoxides formation and their further metabolism between D9- and D8-tetrahydrocannabinols by human liver microsomes

Abstract

In vitro metabolism of D9- and D8-tetrahydrocannabinols (THCs) was studied using human liver microsomes. D9- or D8-THC was incubated with microsomes in the presence of an 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-Epoxyhexa-hydrocannabinol (EHHC) together with four monohydroxylated metabolites was formed from D9-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 D8-THC under the conditions for monooxygenase. When l,l,l-trichloropropene-2,3-oxide was further added to the incubation mixture, both of 8α, 9α- and 8 ft, 9β-EHHCs were found to be formed from D8-THC. These epoxides of D8-THC were preferentially hydrolyzed to 8β,9α-diOH-HHC by epoxide hydrolase. These results indicate that 9α,10α-EHHC formed from D9-THC is further metabolized not by epoxide hydrolase but by monooxygenase system involving cytochrome P-450, and that, on the contrary, 8α, 9α- and 8 ft, 9β-EHHCs derived from D8-THC may be metabolized by epoxide hydrolase rather than cytochrome P-450 in the human liver, forming 8 ft, 9α-diOH-HHC. © 1984, The Pharmaceutical Society of Japan. All rights reserved.