Cannabis (Cannabis sativa)
Cannabidiol is a potent inhibitor of the catalytic activity of cytochrome P450 2C19. CSV JSON

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.

Cannabis (Cannabis sativa)

23318708

1 . Inhibition of CYP2C19 enzyme with Cannabidiol (id=NPDI-Z_m2jA)

In Vitro Enzyme Inhibition Experiment

Inhibition was detected.  Cutoff used —

N/A

mephenytoin, (s)-

cannabidiol

4-hydroxymephenytoin, (s)-

  • CYP2C19 4311137

Cell fraction Pooled human liver microsomes -7999662

Results

Sample Compound measured Value Measurement Study sequence Additional information N replicates

Experimental Conditions

2 pmol

250 µL

20 min

NADH

60 µM

2 . Inhibition of CYP2C19 by Cannabidiol (id=NPDI-GEE68Q)

In Vitro Enzyme Inhibition Experiment

Inhibition was detected.  Cutoff used —

N/A

mephenytoin, (s)-

cannabidiol

4-hydroxymephenytoin, (s)-

  • CYP2C19 4311137

Recombinant expression system Baculovirus-insect cells
Cytochrome B5 Not available

Results

Sample Compound measured Value Measurement Study sequence Additional information N replicates

Experimental Conditions

2 pmol

250 µL

40 min

MgCl2

60 µM

3 . Inhibition of CYP2C19 by Cannabidiol (id=NPDI-9kN5_g)

In Vitro Enzyme Inhibition Experiment

Inhibition was detected.  Cutoff used —

N/A

mephenytoin, (s)-

cannabidiol

4-hydroxymephenytoin, (s)-

  • CYP2C19 4311137

Cell fraction Pooled human liver microsomes -7999662

Results

Sample Compound measured Value Measurement Study sequence Additional information N replicates

Experimental Conditions

50 µg

250 µL

20 min

NADH

60 µM

4 . Inhibition of CYP2C19 by Cannabidiol (id=NPDI-fw_WMw)

In Vitro Enzyme Inhibition Experiment

Inhibition was detected.  Cutoff used —

N/A

omeprazole

cannabidiol

5-hydroxyomeprazole

  • CYP2C19 4311137

Recombinant expression system Baculovirus-insect cells
Cytochrome B5 Not available

Results

Sample Compound measured Value Measurement Study sequence Additional information N replicates

Experimental Conditions

2 pmol

250 µL

20 min

NADH

2 µM