Difference in epoxides formation and their further metabolism between Δ9- and Δ8-tetrahydrocannabinols by human liver microsomes

I. Yamamoto, S. Narimatsu, T. Shimonishi, K. Watanabe, H. Yoshimura

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

In vitro metabolism of Δ9- and Δ8-tetrahydrocannabinols (THCs) was studied using human liver microsomes. Δ9- or Δ8-THC was incubated with microsomes in the presence of an NADPH-generating system. The metabolites formed were extracted with ethyl acetate, separated by preparative thin-layer chromatography, and identified as trimethylsilyl derivatives by gas chromatography-mass spectrometry. 9α,10α-Epoxyhexahydrocannabinol (EHHC) together with four monohydroxylated metabolites was formed from Δ9-THC. The epoxide was found to resist the hydrolysis by epoxide hydrolase, and was further converted to several metabolites by the monooxygenase system involving cytochrome P-450. On the other hand, 8β,9α-dihydroxyhexahydrocannabinol (diOH-HHC) instead of epoxy metabolites was formed from δ8-THC under the conditions for monooxygenase. When 1,1,1-trichlorpropene-2,3-oxide was further added to the incubation mixture, both 8α,9α- and 8β,9β-EHHCs were found to be formed from Δ8-THC. These epoxides of Δ8-THC were preferentially hydrolyzed to 8β,9α-diOH-HHC by epoxide hydrolase. These results indicate that 9α,10α-EHHC formed from Δ9-THC is further metabolized nor by epoxide hydrolase but by monooxygenase system involving cytochrome P-450, and that, on the contrary, 8α,9α- and 8β,9β-EHHCs derived from Δ8-THC may be metabolized by epoxide hydrolase rather than cytochrome P-450 in the human liver, forming 8β,9α-diOH-HHC.

Original languageEnglish
Pages (from-to)254-262
Number of pages9
JournalJournal of Pharmacobio-Dynamics
Volume7
Issue number4
Publication statusPublished - 1984
Externally publishedYes

Fingerprint

Dronabinol
Epoxy Compounds
Liver Microsomes
Epoxide Hydrolases
Mixed Function Oxygenases
Cytochrome P-450 Enzyme System
Thin Layer Chromatography
Microsomes
NADP
Gas Chromatography-Mass Spectrometry
Oxides
Hydrolysis
Liver

ASJC Scopus subject areas

  • Pharmacology

Cite this

Difference in epoxides formation and their further metabolism between Δ9- and Δ8-tetrahydrocannabinols by human liver microsomes. / Yamamoto, I.; Narimatsu, S.; Shimonishi, T.; Watanabe, K.; Yoshimura, H.

In: Journal of Pharmacobio-Dynamics, Vol. 7, No. 4, 1984, p. 254-262.

Research output: Contribution to journalArticle

Yamamoto, I, Narimatsu, S, Shimonishi, T, Watanabe, K & Yoshimura, H 1984, 'Difference in epoxides formation and their further metabolism between Δ9- and Δ8-tetrahydrocannabinols by human liver microsomes', Journal of Pharmacobio-Dynamics, vol. 7, no. 4, pp. 254-262.
Yamamoto, I. ; Narimatsu, S. ; Shimonishi, T. ; Watanabe, K. ; Yoshimura, H. / Difference in epoxides formation and their further metabolism between Δ9- and Δ8-tetrahydrocannabinols by human liver microsomes. In: Journal of Pharmacobio-Dynamics. 1984 ; Vol. 7, No. 4. pp. 254-262.
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AU - Yoshimura, H.

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