Δ9-Tetrahydrocannabinol, cannabidiol (CBD), and cannabinol are the three major cannabinoids contained in marijuana, which are devoid of nitrogen atoms in their structures. In this study, we investigated the inhibitory effects of the major phytocannabinoids on the catalytic activity of human CYP2D6. These major cannabinoids inhibited the 3-[2-(N,N-diethyl-N-methylammonium)ethyl]-7-methoxy-4-methylcoumarin (AMMC) and dextromethorphan O-demethylase activities of recombinant CYP2D6 and pooled human liver microsomes in a concentration-dependent manner (IC50 = 4.01–24.9 μM), indicating the strongest inhibitory potency of CBD. However, these cannabinoids showed no or weak metabolism-dependent inhibition. CBD competitively inhibited the CYP2D6 activities with the apparent Ki values of 1.16 to 2.69 μM. To clarify the structural requirement for CBD-mediated CYP2D6 inhibition, effects of CBD-related compounds on the AMMC O-demethylase activity of recombinant CYP2D6 were examined. Olivetol (IC50 = 7.21 μM) inhibited CYP2D6 activity as potently as CBD did (IC50 = 6.52 μM), whereas d-limonene did not show any inhibitory effect. Pentylbenzene failed to inhibit CYP2D6 activity. Furthermore, neither monomethyl nor dimethyl ethers of CBD inhibited the activity. Cannabidivarin having a propyl side chain inhibited CYP2D6 activity; its inhibitory effect (IC50 = 10.2 μM) was less potent than that of CBD. On the other hand, orcinol and resorcinol showed lack of inhibition. The inhibitory effect of CBD on CYP2D6 activity was more potent than those of 16 compounds without nitrogen atoms tested, such as progesterone. These results indicated that CBD caused potent direct CYP2D6 inhibition, in which two phenolic hydroxyl groups and the pentyl side chain of CBD may play important roles.
This work was supported in part by the Ministry of Education, Culture, Sports, Science, and Technology of Japan [Grant-in-Aid for Scientific Research (C) 20590127 and Grant-in-Aid for Young Scientists (B) 23790159]; and the Academic Frontier Project for Private Universities from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (2005–2009).
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
- cytochrome P450
- CBD-2′-monomethyl ether
- CBD-2′,6′-dimethyl ether
- dimethyl sulfoxide
- human liver microsomes
- polycyclic aromatic hydrocarbon
- area under the curve.
- Received June 26, 2011.
- Accepted August 5, 2011.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics