In Vitro Metabolic Formation of a New Metabolite, 6β-Hydroxymethyl-Δ^9-tetrahydrocannabinol from Cannabidiol through an Epoxide Intermediate and Its Pharmacological Effects on Mice
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概要
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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, α-naphthoflavone, metyrapone and carbon monoxide. 8R, 9-Epoxy-CBD was further converted to 6β-hydroxymethyl-Δ^9-tetrahydrocannabinol (6β-CH_2OH-Δ^9-THC) and 8,9-dihydro-8,9-dihydroxy-CBD by hepatic microsomes of guinea pigs, rats and mice. Microsomal formation of 6β-CH_2OH-Δ^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, 6β-CH_2OH-Δ^9-THC was also identified as a new metabolite of CBD produced by hapatic microsomes of guinea pigs. 6β-CH_2OH-Δ^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 Δ^9-THC. This study presents the first example of the biotransformation of CBD to a Δ^9-THC derivative which exhibits some pharmacological effects.
- 社団法人日本薬学会の論文
- 1993-10-15
著者
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吉村 英敏
中村学園大学
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成松 鎮雄
千葉大・薬
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渡辺 和人
Department of Hygienic Chemistry, Faculty of Pharmaceutical Sciences, Hokuriku University
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松永 民秀
Department of Hygienic Chemistry, Faculty of Pharmaceutical Sciences, Hokuriku University
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山本 郁男
Department of Hygienic Chemistry, Faculty of Pharmaceutical Sciences, Hokuriku University
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吉村 英敏
Department of Food and Nutrition, Nakamura Gakuen University
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成松 鎮雄
岡山大・薬・衛生化学
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成松 鎭雄
Laboratory Of Biopharmaceutics Faculty Of Pharmaceutical Sciences Chiba University
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松永 民秀
北陸大学薬学部衛生化学教室
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永井 克典
Department of Hygienic Chemistry, Faculty of Pharmaceutical Sciences, Hokuriku University
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成松 鎮雄
Department of Hygienic Chemistry, Faculty of Pharmaceutical Sciences, Hokuriku University
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郷田 浩志
Department of Hygienic Chemistry, Faculty of Pharmaceutical Sciences, Hokuriku University
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郷田 浩志
Department Of Hygienic Chemistry Faculty Of Pharmaceutical Sciences Hokuriku University
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Yoshida H
Lab. Of Food & Nutritional Sciences Dep. Of Nutritional Sci. Kobe-gakuin Univ.
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永井 克典
Department Of Hygienic Chemistry Faculty Of Pharmaceutical Sciences Hokuriku University
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Yoshimura H
Department Of Food And Nutrition Nakamura Gakuen University
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Narimatsu S
Laboratory Of Biopharmaceutics Faculty Of Pharmaceutical Sciences Chiba University
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成松 鎮雄
Department Of Hygienic Chemistry Faculty Of Pharmaceutical Sciences Hokuriku University
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吉村 英敏
Department Of Food And Nutrition Nakamura Gakuen University
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