cannabidiol and cannabidiol-3-monomethyl-ether

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.

Topics: Aryl Hydrocarbon Hydroxylases; Cannabidiol; Cytochrome P-450 CYP2C19; Female; Humans; Inhibitory Concentration 50; Kinetics; Male; Microsomes, Liver; Omeprazole; Recombinant Proteins; Structure-Activity Relationship

The inhibitory effect of nordihydroguaiaretic acid (NDGA) (a nonselective lipoxygenase (LOX) inhibitor)-mediated 15-LOX inhibition has been reported to be affected by modification of its catechol ring, such as methylation of the hydroxyl group. Cannabidiol (CBD), one of the major components of marijuana, is known to inhibit LOX activity. Based on the phenomenon observed in NDGA, we investigated whether or not methylation of CBD affects its inhibitory potential against 15-LOX, because CBD contains a resorcinol ring, which is an isomer of catechol. Although CBD inhibited 15-LOX activity with an IC(50) value (50% inhibition concentration) of 2.56 microM, its monomethylated and dimethylated derivatives, CBD-2'-monomethyl ether and CBD-2',6'-dimethyl ether (CBDD), inhibited 15-LOX activity more strongly than CBD. The number of methyl groups in the resorcinol moiety of CBD (as a prototype) appears to be a key determinant for potency and selectivity in inhibition of 15-LOX. The IC(50) value of 15-LOX inhibition by CBDD is 0.28 microM, and the inhibition selectivity for 15-LOX (i.e., the 5-LOX/15-LOX ratio of IC(50) values) is more than 700. Among LOX isoforms, 15-LOX is known to be able to oxygenate cholesterol esters in the low-density lipoprotein (LDL) particle (i.e., the formation of oxidized LDL). Thus, 15-LOX is suggested to be involved in development of atherosclerosis, and CBDD may be a useful prototype for producing medicines for atherosclerosis.

Topics: Animals; Cannabidiol; Dose-Response Relationship, Drug; Humans; Lipoxygenase Inhibitors; Masoprocol; Methylation; Molecular Structure; Structure-Activity Relationship

Oxidative metabolism of cannabidiol monomethyl ether (CBDM), one of the components of marihuana, was studied in the guinea pig. Cannabielsoin monomethyl ether (CBEM) was found to be formed with hepatic microsomes by gas chromatography-mass spectrometry (GC-MS). Experiments using various modifiers of enzymatic reaction suggested that, as in the case of cannabielsoin (CBE) formation from canabidiol (CBD), CBEM was formed from CBDM by the monooxygenase system including cytochrome P450. When cannabidiol dimethyl ether (CBDD), in which phenolic hydroxyl groups of CBD are masked with methyl groups, was incubated with liver microsomes and an reduced nicotinamide adenine dinucleotide phosphate-generating system, 1S,2R-epoxy-CBDD was identified by GC-MS. The epoxy metabolite was also found in the liver of a guinea pig pretreated with CBDD (100 mg/kg, intraperitoneally) 1 h before sacrifice. Rate of 1S,2R-epoxide metabolism was slower than that of 1R,2S-epoxy-CBDD under the conditions, as in the microsomal oxidation of CBDD described above. These results indicate that 1S,2R-epoxides are formed from CBD, CBDM and CBDD and that the epoxides are quickly converted to elsoin-type metabolites in the cases of CBD and CBDM.

Topics: Animals; Biotransformation; Cannabidiol; Guinea Pigs; In Vitro Techniques; Male

Animals (rats and pigeons) trained to discriminate between the presence and absence of the effects of delta 1-tetrahydrocannabinol (delta 1-THC; 3 and 0.56 mg/kg, respectively) were tested for generalization with graded doses of delta 1-THC as well as with two 7-hydroxyhexahydrocannabinol epimers which differ in the stereochemistry at the C-1 position only, and a cannabidiol (CBD)-like compound, cannabidiol monomethyl ether (CBDM). delta 1-THC produced dose/time related effects in both rats and pigeons. Both 7-hydroxyhexahydrocannabinols generalized with delta 1-THC in both species. Greater cannabimimetic activity was observed when the substituent at the C-1 position was equatorial (as in compound NL-105) than when the substituent was axial (compound NL-106) (for chemical structures see Fig. 1, below). Thus in the absence of other substituents the planarity at the C-1 position determines cannabimimetic activity. CBDM induced only vehicle appropriate responding at the doses of 3 and 10 mg/kg in both species; 30% delta 1-THC appropriate responding occurred with 17.5 mg/kg (only tested in pigeons), a dose which also appeared to excert rate depressant effects. Thus, like CBD, CBDM has a low degree of cannabimimetic activity.

Topics: Animals; Cannabidiol; Cannabinoids; Chemical Phenomena; Chemistry; Columbidae; Cues; Discrimination Learning; Dronabinol; Male; Rats; Rats, Inbred Strains; Species Specificity; Stereoisomerism