title: Potent inhibition of human cytochrome P450 3A isoforms by cannabidiol: role of phenolic hydroxyl groups in the resorcinol moiety.
abstract: OBJECTIVE
  In this study, we examined the inhibitory effects of Δ(9)-tetrahydrocannabinol (Δ(9)-THC), cannabidiol (CBD), and cannabinol (CBN), the three major cannabinoids, on the activity of human cytochrome P450 (CYP) 3A enzymes. Furthermore, we investigated the kinetics and structural requirement for the inhibitory effect of CBD on the CYP3A activity.
  
  
  METHODS
  Diltiazem N-demethylase activity of recombinant CYP3A4, CYP3A5, CYP3A7, and human liver microsomes (HLMs) in the presence of cannabinoids was determined.
  
  
  RESULTS
  Among the three major cannabinoids, CBD most potently inhibited CYP3A4 and CYP3A5 (IC(50)=11.7 and 1.65 μM, respectively). The IC(50) values of Δ(9)-THC and CBN for CYP3A4 and CYP3A5 were higher than 35 μM. For CYP3A7, Δ(9)-THC, CBD, and CBN inhibited the activity to a similar extent (IC(50)=23-31 μM). CBD competitively inhibited the activity of CYP3A4, CYP3A5, and HLMs (K(i)=1.00, 0.195, and 6.14 μM, respectively). On the other hand, CBD inhibited the CYP3A7 activity in a mixed manner (K(i)=12.3 μM). Olivetol partially inhibited all the CYP3A isoforms tested, whereas d-limonene showed lack of inhibition. The lesser inhibitory effects of monomethyl and dimethyl ethers of CBD indicated that the ability of CYP3A inhibition by the cannabinoid attenuated with the number of methylation on the phenolic hydroxyl groups in the resorcinol moiety.
  
  
  CONCLUSIONS
  This study indicated that CBD most potently inhibited catalytic activity of human CYP3A enzymes, especially CYP3A4 and CYP3A5. These results suggest that two phenolic hydroxyl groups in the resorcinol moiety of CBD may play an important role in the CYP3A inhibition.
authors.affiliation: Department of Hygienic Chemistry, Faculty of Pharmaceutical Sciences, Hokuriku University, Ho-3, Kanagawa-machi, Kanazawa 920-1181, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yamaori
authors.forename: Juri
authors.initials: J
authors.lastname: Ebisawa
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Okushima
authors.forename: Ikuo
authors.initials: I
authors.lastname: Yamamoto
authors.forename: Kazuhito
authors.initials: K
authors.lastname: Watanabe
mesh_terms: D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors / Q000378:metabolism; D002185:Cannabidiol / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D002187:Cannabinol / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D004110:Diltiazem / Q000378:metabolism; D013759:Dronabinol / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D008875:Middle Aged; D012118:Resorcinols / Q000737:chemistry
chemical_list: D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors; D012118:Resorcinols; D002185:Cannabidiol; D013759:Dronabinol; D002187:Cannabinol; D001189:Aryl Hydrocarbon Hydroxylases; C510164:CYP3A5 protein, human; C103123:CYP3A7 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D004110:Diltiazem; C031389:resorcinol