title: Cannabidiol is a potent inhibitor of the catalytic activity of cytochrome P450 2C19.
abstract: The present study investigated the inhibitory effect of cannabidiol (CBD), a major constituent of marijuana, on the catalytic activity of cytochrome P450 2C19 (CYP2C19). (S)-Mephenytoin 4'-hydroxylase activities of human liver microsomes (HLMs) and recombinant CYP2C19 were inhibited by CBD in a concentration-dependent manner (IC₅₀ = 8.70 and 2.51 µM, respectively). Omeprazole 5-hydroxylase and 3-O-methylfluorescein O-demethylase activities in recombinant CYP2C19 were also strongly inhibited by CBD (IC₅₀ = 1.55 and 1.79 µM, respectively). Kinetic analysis for inhibition revealed that CBD showed a mixed-type inhibition against (S)-mephenytoin 4'-hydroxylation by recombinant CYP2C19. To clarify the structural requirements for CBD-mediated CYP2C19 inhibition, the effects of CBD-related compounds on CYP2C19 activity were examined. Olivetol inhibited the (S)-mephenytoin 4'-hydroxylase activity of recombinant CYP2C19 with the IC₅₀ value of 15.3 µM, whereas d-limonene slightly inhibited the activity (IC₅₀ > 50 µM). The inhibitory effect of CBD-2'-monomethyl ether (IC₅₀ = 1.88 µM) on CYP2C19 was comparable to that of CBD, although the inhibitory potency of CBD-2',6'-dimethyl ether (IC₅₀ = 14.8 µM) was lower than that of CBD. Cannabidivarin, possessing a propyl side chain, showed slightly less potent inhibition (IC₅₀ = 3.45 µM) as compared with CBD, whereas orcinol and resorcinol did not inhibit CYP2C19 activity at all. These results indicate that CBD caused potent CYP2C19 inhibition, in which one free phenolic hydroxyl group and the pentyl side chain of CBD may play important roles.
authors: Department of Hygienic Chemistry, Faculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa, Japan.
authors: Rongrong
authors: R
authors: Jiang
authors: Satoshi
authors: S
authors: Yamaori
authors: Yasuka
authors: Y
authors: Okamoto
authors: Ikuo
authors: I
authors: Yamamoto
authors: Kazuhito
authors: K
authors: Watanabe
mesh_terms: D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors*; D002185:Cannabidiol / Q000031:analogs & derivatives / Q000494:pharmacology*; D065731:Cytochrome P-450 CYP2C19; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects; D009853:Omeprazole / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D011994:Recombinant Proteins; C050352:cannabidiol-3-monomethyl ether; D002185:Cannabidiol; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D009853:Omeprazole