Difference in epoxides formation and their further metabolism between delta 9- and delta 8-tetrahydrocannabinols by human liver microsomes.
In vitro metabolism of delta 9- and delta 8-tetrahydrocannabinols (THCs) was studied using human liver microsomes. Delta 9- or delta 8-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. 9 alpha, 10 alpha-Epoxyhexahydrocannabinol (EHHC) together with four monohydroxylated metabolites was formed from delta 9-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, 8 beta, 9 alpha-dihydroxyhexahydrocannabinol (diOH-HHC) instead of epoxy metabolites was formed from delta 8-THC under the conditions for monooxygenase. When 1,1,1-trichloropropene-2,3-oxide was further added to the incubation mixture, both of 8 alpha, 9 alpha-EHHCs were found to be formed from delta 8-THC. These epoxides of delta 8-THC were preferentially hydrolyzed to 8 beta, 9 alpha-diOH-HHC by epoxide hydrolase. These results indicate that 9 alpha, 10 alpha-EHHC formed from delta 9-THC is further metabolized not by epoxide hydrolase but by monooxygenase system involving cytochrome P-450, and that, on the contrary, 8 alpha, 9 alpha- and 8 beta, 9 beta-EHHCs derived from delta 8-THC may be metabolized by epoxide hydrolase rather than cytochrome P-450 in the human liver, forming 8 beta, 9 alpha-diOH-HHC.
D003577:Cytochrome P-450 Enzyme System / Q000032:analysis; D013759:Dronabinol / Q000031:analogs & derivatives* / Q000378:metabolism*; D004852:Epoxy Compounds / Q000378:metabolism*; D004988:Ethers, Cyclic / Q000378:metabolism*; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D008875:Middle Aged
D004852:Epoxy Compounds; D004988:Ethers, Cyclic; C035731:delta-8-tetrahydrocannabinol; C019370:1 alpha,2 alpha-epoxyhexahydrocannabinol; D013759:Dronabinol; D003577:Cytochrome P-450 Enzyme System