Comparison in the in vitro inhibitory effects of major phytocannabinoids and polycyclic aromatic hydrocarbons contained in marijuana smoke on cytochrome P450 2C9 activity

Drug Metab Pharmacokinet. 2012;27(3):294-300. doi: 10.2133/dmpk.dmpk-11-rg-107. Epub 2011 Dec 13.


Inhibitory effects of Δ⁹-tetrahydrocannabinol (Δ⁹-THC), cannabidiol (CBD), and cannabinol (CBN), the three major constituents in marijuana, and polycyclic aromatic hydrocarbons (PAHs) contained in marijuana smoke on catalytic activity of human cytochrome P450 (CYP) 2C9 were investigated. These phytocannabinoids concentration-dependently inhibited S-warfarin 7-hydroxylase and diclofenac 4'-hydroxylase activities of human liver microsomes (HLMs) and recombinant CYP2C9 (rCYP2C9). In contrast, none of the twelve PAHs including benz[a]anthracene and benzo[a]pyrene exerted substantial inhibition (IC₅₀ > 10 µM). The inhibitory potentials of Δ⁹-THC (Ki = 0.937-1.50 µM) and CBN (Ki = 0.882-1.29 µM) were almost equivalent regardless of the enzyme sources used, whereas the inhibitory potency of CBD (Ki > = 0.954-9.88 µM) varied depending on the enzyme sources and substrates used. Δ⁹-THC inhibited both S-warfarin 7-hydroxylase and diclofenac 4'-hydroxylase activities of HLMs and rCYP2C9 in a mixed manner. CBD and CBN competitively inhibited the activities of HLMs and rCYP2C9, with the only notable difference being that CBD and CBN exhibited mixed-type inhibitions against diclofenac 4'-hydroxylation and S-warfarin 7-hydroxylation, respectively, by rCYP2C9. None of Δ⁹-THC, CBD, and CBN exerted metabolism-dependent inhibition. These results indicated that the three major phytocannabinoids but not PAHs contained in marijuana smoke potently inhibited CYP2C9 activity and that these cannabinoids can be characterized as direct inhibitors for CYP2C9.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aryl Hydrocarbon Hydroxylases / antagonists & inhibitors*
  • Aryl Hydrocarbon Hydroxylases / genetics
  • Aryl Hydrocarbon Hydroxylases / metabolism
  • Cannabidiol / pharmacology
  • Cannabinoids / pharmacology*
  • Cannabinol / pharmacology
  • Cannabis / chemistry*
  • Cytochrome P-450 CYP1A2 / genetics
  • Cytochrome P-450 CYP1A2 / metabolism
  • Cytochrome P-450 CYP1A2 Inhibitors
  • Cytochrome P-450 CYP2C9
  • Diclofenac / metabolism
  • Dronabinol / pharmacology
  • Enzyme Inhibitors / pharmacology*
  • Female
  • Humans
  • Hydroxylation / drug effects
  • Kinetics
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / enzymology
  • Microsomes, Liver / metabolism
  • Middle Aged
  • Plant Leaves / chemistry*
  • Polycyclic Aromatic Hydrocarbons / pharmacology*
  • Recombinant Proteins / antagonists & inhibitors
  • Recombinant Proteins / metabolism
  • Smoke / analysis*
  • Warfarin / metabolism


  • Cannabinoids
  • Cytochrome P-450 CYP1A2 Inhibitors
  • Enzyme Inhibitors
  • Polycyclic Aromatic Hydrocarbons
  • Recombinant Proteins
  • Smoke
  • Diclofenac
  • Cannabidiol
  • Warfarin
  • Dronabinol
  • Cannabinol
  • CYP2C9 protein, human
  • Cytochrome P-450 CYP2C9
  • Aryl Hydrocarbon Hydroxylases
  • CYP1A2 protein, human
  • Cytochrome P-450 CYP1A2