Effect of repeated administration of 11-hydroxy-Δ8-tetrahydrocannabinol, an active metabolite of Δ8tetrahydrocannabinol, on the hepatic microsomal drug-metabolizing enzyme system of mice

Watanabe Kazuhito, Aarai Mayumi, Narimatsu Shizuo, Yamamoto Ikuo, Yoshimura Hidetoshi

Research output: Contribution to journalArticle

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Abstract

The effects of Δ8-tetrahydrocannabinol (Δ8-THC) and its major and active metabolite, 11-hydroxy-Δ8-tetrahydrocannabinol (11-OH-Δ8-THC), on the hepatic microsomal drug-metabolizing enzyme system were studied in mice. The repeated administration of 11-OH-Δ8-THC (5 mg/kg/day, i.v.) for 3 or 7 days increased significantly the activities of aniline hydroxylase and p-nitroanisole O-demethylase. By the same treatment, cytochrome P-450 content (3 days) or NADPH-cytochrome c reductase activity (7 days) was also increased significantly. The treatment with Δ8-THC for 7 days (5 mg/kg/day, i.v.) significantly increased aniline hydroxylase only. 11-OH-Δ8-THC increased the Vmax, but not the Km, values for both drug-metabolizing enzymes, whereas Δ8-THC decreased significantly the Km, value (270 μM) for p-nitroanisole O-demethylase as compared with the control (398 μM). Repeated administration of these cannabinoids for 7 days also increased the metabolism of Δ8-THC by hepatic microsomes; this was attributed to an enhanced formation of 11-OH-Δ8-THC. In contrast, microsomal formation of 7α-OH-Δ8-THC was decreased significantly by treatment with Δ8-THC. 11-OH-Δ8-THC, but not Δ8-THC, treatment increased the metabolism of 11-OH-Δ8-THC by hepatic microsomes. These findings indicate that Δ8-THC and 11-OH-Δ8-THC treatment can induce hepatic microsomal drug-metabolizing enzymes and affect differently the catalytic properties of the enzymes.

Original languageEnglish
Pages (from-to)1861-1865
Number of pages5
JournalBiochemical Pharmacology
Volume35
Issue number11
DOIs
Publication statusPublished - Jun 1 1986
Externally publishedYes

Fingerprint

Dronabinol
Metabolites
Liver
Enzymes
Pharmaceutical Preparations
Aniline Hydroxylase
Microsomes
Metabolism
NADPH-Ferrihemoprotein Reductase
Cannabinoids
hydroxide ion

ASJC Scopus subject areas

  • Pharmacology

Cite this

Effect of repeated administration of 11-hydroxy-Δ8-tetrahydrocannabinol, an active metabolite of Δ8tetrahydrocannabinol, on the hepatic microsomal drug-metabolizing enzyme system of mice. / Kazuhito, Watanabe; Mayumi, Aarai; Shizuo, Narimatsu; Ikuo, Yamamoto; Hidetoshi, Yoshimura.

In: Biochemical Pharmacology, Vol. 35, No. 11, 01.06.1986, p. 1861-1865.

Research output: Contribution to journalArticle

Kazuhito, Watanabe ; Mayumi, Aarai ; Shizuo, Narimatsu ; Ikuo, Yamamoto ; Hidetoshi, Yoshimura. / Effect of repeated administration of 11-hydroxy-Δ8-tetrahydrocannabinol, an active metabolite of Δ8tetrahydrocannabinol, on the hepatic microsomal drug-metabolizing enzyme system of mice. In: Biochemical Pharmacology. 1986 ; Vol. 35, No. 11. pp. 1861-1865.
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abstract = "The effects of Δ8-tetrahydrocannabinol (Δ8-THC) and its major and active metabolite, 11-hydroxy-Δ8-tetrahydrocannabinol (11-OH-Δ8-THC), on the hepatic microsomal drug-metabolizing enzyme system were studied in mice. The repeated administration of 11-OH-Δ8-THC (5 mg/kg/day, i.v.) for 3 or 7 days increased significantly the activities of aniline hydroxylase and p-nitroanisole O-demethylase. By the same treatment, cytochrome P-450 content (3 days) or NADPH-cytochrome c reductase activity (7 days) was also increased significantly. The treatment with Δ8-THC for 7 days (5 mg/kg/day, i.v.) significantly increased aniline hydroxylase only. 11-OH-Δ8-THC increased the Vmax, but not the Km, values for both drug-metabolizing enzymes, whereas Δ8-THC decreased significantly the Km, value (270 μM) for p-nitroanisole O-demethylase as compared with the control (398 μM). Repeated administration of these cannabinoids for 7 days also increased the metabolism of Δ8-THC by hepatic microsomes; this was attributed to an enhanced formation of 11-OH-Δ8-THC. In contrast, microsomal formation of 7α-OH-Δ8-THC was decreased significantly by treatment with Δ8-THC. 11-OH-Δ8-THC, but not Δ8-THC, treatment increased the metabolism of 11-OH-Δ8-THC by hepatic microsomes. These findings indicate that Δ8-THC and 11-OH-Δ8-THC treatment can induce hepatic microsomal drug-metabolizing enzymes and affect differently the catalytic properties of the enzymes.",
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