anandamide and cannabichromene

Phytocannabinoids have well-known cardiovascular implications. For instance, Δ9-tetrahydrocannabinol (Δ9-THC), the principal component of cannabis, induces tachycardia in humans. In order to understand the impact of phytocannabinoids on human cardiovascular health, there is a need to study the metabolism of phytocannabinoids by cardiac cytochromes p450 (CYPs). CYP2J2, the primary CYP of cardiomyocytes, is responsible for the metabolism of the endocannabinoid, anandamide (AEA), into cardioprotective epoxides (EET-EAs). Herein, we have investigated the kinetics of the direct metabolism of six phytocannabinoids (Δ9-THC, Δ8-tetrahydrocannabinol, cannabinol, cannabidiol, cannabigerol, and cannabichromene) by CYP2J2. CYP2J2 mainly produces 1'/1″-OH metabolites of these phytocannabinoids. These phytocannabinoids are metabolized with greater catalytic efficiency compared to the metabolism of AEA by CYP2J2. We have also determined that the phytocannabinoids are potent inhibitors of CYP2J2-mediated AEA metabolism, with Δ9-THC being the strongest inhibitor. Most of the inhibition of CYP2J2 by the phytocannabinoids follow a noncompetitive inhibition model, and therefore dramatically reduce the formation of EET-EAs by CYP2J2. Taken together, these data demonstrate that phytocannabinoids are directly metabolized by CYP2J2 and inhibit human cardiac CYP2J2, leading to a reduction in the formation of cardioprotective EET-EAs.

Topics: Arachidonic Acids; Cannabinoids; Cells, Cultured; Cytochrome P-450 CYP2J2; Cytochrome P-450 Enzyme System; Dronabinol; Endocannabinoids; Epoxy Compounds; Humans; Polyunsaturated Alkamides

Cannabichromene (CBC) is a major non-psychotropic phytocannabinoid that inhibits endocannabinoid inactivation and activates the transient receptor potential ankyrin-1 (TRPA1). Both endocannabinoids and TRPA1 may modulate gastrointestinal motility. Here, we investigated the effect of CBC on mouse intestinal motility in physiological and pathological states.. Inflammation was induced in the mouse small intestine by croton oil. Endocannabinoid (anandamide and 2-arachidonoyl glycerol), palmitoylethanolamide and oleoylethanolamide levels were measured by liquid chromatography-mass spectrometry; TRPA1 and cannabinoid receptors were analysed by quantitative RT-PCR; upper gastrointestinal transit, colonic propulsion and whole gut transit were evaluated in vivo; contractility was evaluated in vitro by stimulating the isolated ileum, in an organ bath, with ACh or electrical field stimulation (EFS).. Croton oil administration was associated with decreased levels of anandamide (but not 2-arachidonoyl glycerol) and palmitoylethanolamide, up-regulation of TRPA1 and CB₁ receptors and down-regulation of CB₂ receptors. Ex vivo CBC did not change endocannabinoid levels, but it altered the mRNA expression of TRPA1 and cannabinoid receptors. In vivo, CBC did not affect motility in control mice, but normalized croton oil-induced hypermotility. In vitro, CBC reduced preferentially EFS- versus ACh-induced contractions. Both in vitro and in vivo, the inhibitory effect of CBC was not modified by cannabinoid or TRPA1 receptor antagonists.. CBC selectively reduces inflammation-induced hypermotility in vivo in a manner that is not dependent on cannabinoid receptors or TRPA1.

Topics: Amides; Animals; Arachidonic Acids; Cannabinoids; Cannabis; Duodenum; Endocannabinoids; Ethanolamines; Gastrointestinal Agents; Gastrointestinal Motility; Gene Expression Regulation; Ileitis; Ileum; In Vitro Techniques; Jejunum; Male; Mice; Mice, Inbred ICR; Muscle Contraction; Palmitic Acids; Polyunsaturated Alkamides; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; RNA, Messenger; Transient Receptor Potential Channels; TRPA1 Cation Channel