Cannabinoids and Cytochrome P450 Interactions.

The article describes various kinds of interactions between cannabinoid receptor ligands of both exogenous and endogenous origin and cytochrome P450 enzymes (CYPs). This review consists of three parts, representing three different interaction possibilities. The first part deals with cannabinoids as CYP substrates. Biotransformation via a hydrolytic pathway is the major route of endocannabinoid metabolism and the deactivation of substrates is characteristic, in contrast to the minor oxidative pathway via CYP involved in the bioactivation reactions. Phytocannabinoids are extensively metabolized by CYPs. The enzymes CYP2C9, CYP2C19, and CYP3A4 catalyze most of their hydroxylations. Similarly, CYP represents a major metabolic pathway for both synthetic cannabinoids used therapeutically and drugs that are abused. The second part summarizes current knowledge on the influence of various cannabinoids on the metabolic activity of CYP. In vitro experiments document the mostly CYP inhibitory activity of the major phytocannabinoids, with cannabidiol as the most potent one in many CYPs. The drug-drug interactions between cannabinoids and various drugs at the CYP level are reported, but their clinical relevance remains unclear. Finally, we outline a possible involvement of the endocannabinoid system and cannabinoid ligands in the regulation of CYP liver activity. Firstly, the direct activation/inhibition of nuclear receptors in the liver cells by cannabinoids results in a change of CYP expression and activity. Secondly, we hypothesize the interplay of central cannabinoid receptors with numerous nervous systems, resulting in a hormone-mediated signal towards nuclear receptors in hepatocytes.