In vitro metabolic formation of a new metabolite, 6 beta-hydroxymethyl-delta 9-tetrahydrocannabinol from cannabidiol through an epoxide intermediate and its pharmacological effects on mice.
The oxidative metabolism of cannabidiol (CBD) at the 8,9-double bond was examined. 8R,9-Epoxy-CBD was identified by GC-MS as a new metabolite of CBD produced by hepatic microsomal fractions of guinea pigs, rats and mice. The reaction required NADPH as a cofactor and molecular oxygen. The optimal pH for the reaction was 7.4-8.0. The 8R,9-epoxy-CBD forming activity was highest in guinea pigs, followed by mice and rats in the presence of 3,3,3-trichloropropene-1,2-oxide (TCPO), an inhibitor of epoxide hydrolase. The activity was significantly suppressed by SKF 525-A, alpha-naphthoflavone, metyrapone and carbon monoxide. 8R,9-Epoxy-CBD was further converted to 6 beta-hydroxymethyl-delta 9-tetrahydrocannabinol (6 beta-CH2OH-delta 9-TCH) and 8,9-dihydro-8,9-dihydroxy-CBD by hepatic microsomes of guinea pigs, rats and mice. Microsomal formation of 6 beta-CH2OH-delta 9-THC was markedly increased in the presence of TCPO with a concomitant decrease in the formation of 8,9-dihydro-8,9-dihydroxy-CBD in all animal species examined. Furthermore, 6 beta-CH2OH-delta 9-THC was also identified as a new metabolite of CBD produced by hepatic microsomes of guinea pigs. 6 beta-CH2OH-delta 9-THC exhibited THC-like pharmacological effects, catalepsy, analgesia, pentobarbital-induced sleep prolongation and hypothermia in mice, although these effects were less marked than those of delta 9-THC. This study presents the first example of the biotransformation of CBD to a delta 9-THC derivative which exhibits some pharmacological effects.
Nagai
K
K
Department of Hygienic Chemistry, Faculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa, Japan.
Watanabe
K
K
Narimatsu
S
S
Gohda
H
H
Matsunaga
T
T
Yamamoto
I
I
Yoshimura
H
H
D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D001711:Biotransformation; D001831:Body Temperature / Q000187:drug effects; D002185:Cannabidiol / Q000378:metabolism*; D002375:Catalepsy / Q000139:chemically induced; D013759:Dronabinol / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D004852:Epoxy Compounds / Q000378:metabolism; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012890:Sleep / Q000187:drug effects
D000700:Analgesics; D004852:Epoxy Compounds; D002185:Cannabidiol; D013759:Dronabinol; C012366:8 beta-hydroxymethyl-delta(1)-tetrahydrocannabinol