Involvement of CYP2C in the Metabolism of Cannabinoids by Human Hepatic Microsomes from an Old Woman

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The hepatic microsomal metabolism of cannabinoids was studied using the liver from an old woman. Δ⁸-Tetrahydrocannabinol, Δ⁹-tetrahydrocannabinol and cannabinol were biotransformed to their respective 11-hydroxy metabolites by a microsomal fraction with specific activities (pmol/min/mg protein) of 29.1, 47.1 and 27.9, respectively. In addition, both 11-oxo-Δ⁸-tetrahydrocannabinol and 11-oxo-Δ⁹-tetrahydrocannabinol were metabolized to the corresponding carboxylic acids with the microsomes. An antibody against mouse CYP2C29 almost completely inhibited 11-hydroxylation of the cannabinoids and microsomal aldehyde oxygenase (MALDO) activity for 11-oxo-Δ⁸-tetrahydrocannabinol and 11-oxo-Δ⁹-tetrahydrocannabinol, used as substrates, whereas an antibody against rat CYP3A2 conversely stimulated the 11-hydroxylation of Δ⁸-tetrahydrocannabinol and MALDO activity for 11-oxo-Δ⁸-tetrahydrocannabinol. The results indicate that a member of CYP2C is primarily responsible for the metabolism of the above cannabinoids in the human hepatic microsomes.