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 6beta-hydroxymethyl-DELTA9-tetrahydrocannabinol (6beta-CH2OH-DELTA9-THC) and 8,9-dihydro-8,9-dihydroxy-CBD by hepatic microsomes of guinea pigs, rats and mice. Microsomal formation of 6beta-CH2OH-DELTA9-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, 6beta-CH,OH-DELTA9-THC was also identified as a new metabolite of CBD produced by hepatic microsomes of guinea pigs. 6beta-CH2OH-DELTA9-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 DELTA9-THC. This study presents the first example of the biotransformation of CBD to a DELTA9-THC derivative which exhibits some pharmacological effects.
