Characterization of major phytocannabinoids, cannabidiol and cannabinol, as isoform-selective and potent inhibitors of human CYP1 enzymes

Biochem Pharmacol. 2010 Jun 1;79(11):1691-8. doi: 10.1016/j.bcp.2010.01.028. Epub 2010 Feb 1.


Inhibitory effects of Delta(9)-tetrahydrocannabinol (Delta(9)-THC), cannabidiol (CBD), and cannabinol (CBN), the three major constituents in marijuana, on catalytic activities of human cytochrome P450 (CYP) 1 enzymes were investigated. These cannabinoids inhibited 7-ethoxyresorufin O-deethylase activity of recombinant CYP1A1, CYP1A2, and CYP1B1 in a competitive manner. CBD most potently inhibited the CYP1A1 activity; the apparent K(i) value (0.155microM) was at least one-seventeenth of the values for other CYP1 isoforms. On the other hand, CBN more effectively decreased the activity of CYP1A2 and CYP1B1 (K(i)=0.0790 and 0.148microM, respectively) compared with CYP1A1 (K(i)=0.541microM). Delta(9)-THC less potently inhibited the CYP1 activity than CBD and CBN, and showed low selectivity against the CYP1 inhibition (K(i)=2.47-7.54microM). The preincubation of CBD resulted in a time- and concentration-dependent decrease in catalytic activity of all the recombinant CYP1 enzymes and human liver microsomes. Similarly, the preincubation of Delta(9)-THC or CBN caused a time- and concentration-dependent inhibition of recombinant CYP1A1. The inactivation of CYP1A1 by CBD indicated the highest k(inact)/K(I) value (540l/mmol/min) among the CYP1 enzyme sources tested. The inactivation of recombinant CYP1A1 and human liver microsomes by CBD required NADPH, was not influenced by dialysis and by glutathione, N-acetylcysteine, and superoxide dismutase as trapping agents. These results indicated that CBD and CBN showed CYP1 isoform-selective direct inhibition and that CBD was characterized as a potent mechanism-based inhibitor of human CYP1 enzymes, especially CYP1A1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aryl Hydrocarbon Hydroxylases / antagonists & inhibitors*
  • Cannabidiol / pharmacology
  • Cannabinoids / pharmacology*
  • Cannabinol / pharmacology
  • Catalysis / drug effects
  • Cytochrome P-450 CYP1A1 / antagonists & inhibitors*
  • Cytochrome P-450 CYP1A2
  • Cytochrome P-450 CYP1A2 Inhibitors*
  • Cytochrome P-450 CYP1B1
  • Humans
  • Microsomes, Liver / enzymology
  • Protein Isoforms


  • Cannabinoids
  • Cytochrome P-450 CYP1A2 Inhibitors
  • Protein Isoforms
  • Cannabidiol
  • Cannabinol
  • Aryl Hydrocarbon Hydroxylases
  • CYP1A2 protein, human
  • CYP1B1 protein, human
  • Cytochrome P-450 CYP1A1
  • Cytochrome P-450 CYP1A2
  • Cytochrome P-450 CYP1B1