Objective: This review consists of three parts, representing three different possibilities of interactions
between cannabinoid receptor ligands of both exogenous and endogenous origin and cytochrome P450 enzymes
(CYPs). The first part deals with cannabinoids as CYP substrates, the second summarizes current knowledge on the
influence of various cannabinoids on the metabolic activity of CYP, and the third outline a possible involvement of
the endocannabinoid system and cannabinoid ligands in the regulation of CYP liver activity.
Methods: We performed a structured search of bibliographic and drug databases for peer-reviewed literature using
focused review questions.
Results: 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. In vitro experiments
document the mostly CYP inhibitory activity of the major phytocannabinoids, with cannabidiol as the most potent inhibitor of
many CYPs. The drug-drug interactions between cannabinoids and various drugs at the CYP level are reported, but their clinical relevance
remains unclear. The direct activation/inhibition of nuclear receptors in the liver cells by cannabinoids may result in a change of
CYP expression and activity. Finally, we hypothesize the interplay of central cannabinoid receptors with numerous nervous systems, resulting
in a hormone-mediated signal towards nuclear receptors in hepatocytes.