Mechanism of biological formation of cannabielsoin from cannabidiol in the guinea-pig, mouse, rat and rabbit.
Biological formation of cannabielsoin (CBE) from cannabidiol (CBD) was studied in the guinea pig, mouse, rat and rabbit in vitro. Emphasis was placed on the elucidation of this formation mechanism. The enzyme activity of CBE formation was localized in hepatic microsomes. The enzymatic reaction required nicotinamide adenine dinucleotide phosphate (NADPH) and molecular oxygen, and showed an optimal pH around 7.3. The microsomal CBE-forming activities decreased in the following order; guinea pig greater than mouse greater than or equal to rabbit greater than or equal to rat. The CBE formation in the guinea pig hepatic microsomes was suppressed with various inhibitors of cytochrome P-450 such as SKF 525-A, alpha-naphthoflavone and carbon monoxide, but not by disodium ethylenediamine tetraacetate. When incubated with the microsomes either in the presence or absence of NADPH, a synthetic epoxide of CBD, 1S, 2R-epoxy-CBD-2',6'-diacetate was easily and exclusively converted to CBE. On the other hand, 1R, 2S-epoxy-CBD was not changed to CBE at all, but to several oxidized metabolites. These results suggest that CBD is biotransformed to 1S,2R-epoxy-CBD with hepatic microsomal monooxygenase system including cytochrome P-450, and the epoxide is immediately converted to CBE.
Yamamoto
I
I
Department of Hygienic Chemistry, School of Pharmacy, Hokuriku University, Kanazawa, Japan.
Gohda
H
H
Narimatsu
S
S
Yoshimura
H
H
D000818:Animals; D001571:Benzoflavones / Q000494:pharmacology; D002185:Cannabidiol / Q000031:analogs & derivatives / Q000378:metabolism*; D002186:Cannabinoids / Q000378:metabolism*; D002849:Chromatography, Gas; D003035:Cobalt / Q000494:pharmacology; D004852:Epoxy Compounds / Q000378:metabolism; D008401:Gas Chromatography-Mass Spectrometry; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D008797:Metyrapone / Q000494:pharmacology; D051379:Mice; D008815:Mice, Inbred Strains; D008862:Microsomes, Liver / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D013045:Species Specificity
D001571:Benzoflavones; D002186:Cannabinoids; D004852:Epoxy Compounds; D011725:Pyridines; C013109:metapyrone; D002185:Cannabidiol; D003035:Cobalt; C060665:cannabielsoin; C011512:alpha-naphthoflavone; C018021:cobaltous chloride; D008797:Metyrapone