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

3 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

Fingerprint

Cannabidiol
Dronabinol
Epoxy Compounds
Pharmacology
Guinea Pigs
Microsomes
Oxides
Liver
Proadifen
Catalepsy
Metyrapone
Epoxide Hydrolases
In Vitro Techniques
Pentobarbital
Carbon Monoxide
Biotransformation
Hypothermia
NADP
Analgesia
Sleep

ASJC Scopus subject areas

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

Cite this

In vitro metabolic formation of a new metabolite, 6β-hydroxymethyl-Δ9- tetrahydrocannabinol from cannabidiol through an epoxide intermediate and its pharmacological effects on mice. / Nagai, K.; Watanabe, K.; Narimatsu, S.; Gohda, H.; Matsunaga, T.; Yamamoto, I.; Yoshimura, H.

In: Biological and Pharmaceutical Bulletin, Vol. 16, No. 10, 1993, p. 1008-1013.

Research output: Contribution to journalArticle

Nagai, K. ; Watanabe, K. ; Narimatsu, S. ; Gohda, H. ; Matsunaga, T. ; Yamamoto, I. ; Yoshimura, H. / In vitro metabolic formation of a new metabolite, 6β-hydroxymethyl-Δ9- tetrahydrocannabinol from cannabidiol through an epoxide intermediate and its pharmacological effects on mice. In: Biological and Pharmaceutical Bulletin. 1993 ; Vol. 16, No. 10. pp. 1008-1013.
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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.",
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