Stereospecific hydrolysis of 8α,9α- and 8β,9β-epoxyhexahydrocannabinols in the mouse in vivo and in vitro

Abstract

1. After i.v. injections to the mouse, both 8α,9β- and 8β,9β-epoxyhexahydro-cannabinols (EHHCs) were easily hydrolysed to 8$b,9α-dihydroxyhexahydrocannabinol (dihydroxy-HHC) rather than 8α,9β-dihydroxy-HHC in the liver.

2. 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.

3. 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.

4. 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.

5. The magnitude of the binding affinities of cannabinoids to cytochrome P-450 was ranked in the following order: δ⁸-tetrahydrocannabinol (spectral dissociation constant K^s = 9.4 μM) > 8β,9β-EHHC (13.3 μM) > 8α,9α-EHHC (34.5 μM).