Cannabielsoin as a new metabolite of cannabidiol in mammals.
Cannabielsoin (CBE) was identified as a novel metabolite of cannabidiol (CBD) in the guinea pig in vivo and in vitro. Its formation by liver microsomes of guinea pigs needed NADPH and molecular oxygen, and was inhibited with SKF 525-A, metyrapone and alpha-naphthoflavone, indicating participation of cytochrome P-450 (P-450). The CBE-forming activity was highest in guinea pigs, followed by mice, rabbits and rats. In the rat, sex difference was found in the CBE formation (male greater than female). CBD monomethylether (CBDM) was also biotransformed to CBE monomethylether (CBEM) in the guinea pig in vivo and in vitro. When CBD dimethylether (CBDD) was employed as substrate, 1S,2R-epoxy-CBDD was identified. The results suggest that CBD and CBDM are biotransformed by P-450 to CBE-type metabolites via 1S,2R-epoxides. In pharmacological studies using mice, CBDD and 1S,2R-epoxy-CBD-2',6'-diacetate produced hypothermia, and CBD, CBDM and CBEM prolonged pentobarbital-induced sleep. Moreover, 1S,2R-epoxy-CBD-2',6'-diacetate was examined in the Ames test, but had no mutagenicity.
Yamamoto
I
I
Department of Hygienic Chemistry, Faculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa, Japan.
Gohda
H
H
Narimatsu
S
S
Watanabe
K
K
Yoshimura
H
H
D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D002185:Cannabidiol / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology / Q000633:toxicity; D002186:Cannabinoids / Q000378:metabolism; D002375:Catalepsy / Q000139:chemically induced; D002849:Chromatography, Gas; D002851:Chromatography, High Pressure Liquid; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D009152:Mutagenicity Tests; D010424:Pentobarbital / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D012890:Sleep / Q000187:drug effects
D002186:Cannabinoids; D002185:Cannabidiol; C060665:cannabielsoin; D010424:Pentobarbital