Further studies on the oxidative cleavage of the pentyl side-chain of cannabinoids: Identification of new biotransformation pathways in the metabolism of 3′-hydroxy-delta-9-tetrahydrocannabinnol by the mouse

Abstract

1. Oxidative degradation of the pentyl side-chain of cannabinoids leading to compounds containing even numbers of carbon atoms was studied by investigating the in vivo metabolism of 2′- and 3′-hydroxy-delta-9-tetrahydrocannabinol (THC).

2. The hydroxy cannabinoids were administered i.p. to mice, the livers were removed after 1 h and extracted metabolites were identified by g.l.c.-mass spectrometry.

3. The major metabolic route for both compounds was hydroxylation at the allylic 11-position followed by oxidation to a carboxylic acid. Additional hydroxylation occurred at C-8.

4. Little oxidative degradation of the side-chain was found for 2′-hydroxy-delta-9-THC but abundant metabolites were formed by this route from the 3′-hydroxy compound.

5. The major metabolies of this type were acids containing three carbon atoms in the chain. These are the normal products of β-oxidation but their formation from an (ω-2)-hydroxy intermediate appears novel.

6. Other metabilites contained two carbon atoms in the side-chain but were alcohols rather than acids and were again apparently formed by novel mechanisms.

7. The results indicate that the major route leading to cannabinoid metabolites with two-carbon side-chains (loss of three carbon atoms) is initiated by ω-2 hydroxylation.