Stereospecific hydrolysis of 8 alpha,9 alpha- and 8 beta,9 beta-epoxyhexahydrocannabinols in the mouse in vivo and in vitro.
After i.v. injections to the mouse, both 8 alpha,9 alpha- and 8 beta,9 beta-epoxyhexahydrocannabinols (EHHCs) were easily hydrolysed to 8 beta,9 alpha-dihydroxyhexahydrocannabinol (dihydroxy-HHC) rather than 8 alpha,9 beta-dihydroxy-HHC in the liver. 8,9-Dihydroxy-HHCs hydroxylated at the 2' or 3' position of a pentyl side-chain were identified in vivo as liver metabolites of the epoxides. The same stereospecific hydrolysis of 8,9-EHHCs were observed in vitro using liver-microsomal fractions of mice, though both epoxides were resistant to enzymic hydrolysis. Several monohydroxylated 8,9-EHHCs, together with small amounts of 8,9-dihydroxy-HHCs were identified as in vitro liver metabolites of the epoxides. These metabolites could be formed not only by epoxide hydrolase but also by a mono-oxygenase system involving cytochrome P-450. The magnitude of the binding affinities of cannabinoids to cytochrome P-450 was ranked in the following order: delta 8-tetrahydrocannabinol (spectral dissociation constant Ks = 9.4 microM) greater than 8 beta,9 beta-EHHC (13.3 microM) greater than 8 alpha,9 alpha-EHHC (34.5 microM).
Narimatsu
S
S
Yamamoto
I
I
Yoshimura
H
H
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D013759:Dronabinol / Q000031:analogs & derivatives* / Q000378:metabolism; D004851:Epoxide Hydrolases / Q000378:metabolism; D006868:Hydrolysis; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D008862:Microsomes, Liver / Q000201:enzymology*; D013237:Stereoisomerism
C019370:1 alpha,2 alpha-epoxyhexahydrocannabinol; D013759:Dronabinol; D003577:Cytochrome P-450 Enzyme System; D004851:Epoxide Hydrolases