In vitro metabolic formation of a new metabolite, 6β-hydroxymethyl-Δ9- tetrahydrocannabinol from cannabidiol through an epoxide intermediate and its pharmacological effects on mice

K. Nagai, K. Watanabe, S. Narimatsu, H. Gohda, T. Matsunaga, I. Yamamoto, H. Yoshimura

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

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, σ-naphthoflavone, metyrapone and carbon monoxide. 8R,9-Epoxy-CBD was further converted to 6β- hydroxymethyl-Δ9-tetrahydrocannabinol (6β-CH2OH-Δ9-THC) and 8,9- dihydro-8,9-dihydroxy-CBD by hepatic microsomes of guinea pigs, rats and mice. Microsomal formation of 6β-CH2OH-Δ9-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, 6β- CH2OH-Δ9-THC was also identified as a new metabolite of CBD produced by hepatic microsomes of guinea pigs. 6β-CH2OH-Δ9-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 Δ9-THC. This study presents the first example of the biotransformation of CBD to a Δ9-THC derivative which exhibits some pharmacological effects.

Original languageEnglish
Pages (from-to)1008-1013
Number of pages6
JournalBiological and Pharmaceutical Bulletin
Volume16
Issue number10
Publication statusPublished - 1993
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology, Toxicology and Pharmaceutics(all)

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