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Research ArticleArticle

CYP3A4 Is a Major Isoform Responsible for Oxidation of 7-Hydroxy-Δ8-tetrahydrocannabinol to 7-Oxo-Δ8-tetrahydrocannabinol in Human Liver Microsomes

Tamihide Matsunaga, Nobuyuki Kishi, Shinsuke Higuchi, Kazuhito Watanabe, Tohru Ohshima and Ikuo Yamamoto
Drug Metabolism and Disposition November 2000, 28 (11) 1291-1296;
Tamihide Matsunaga
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Nobuyuki Kishi
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Shinsuke Higuchi
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Kazuhito Watanabe
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Tohru Ohshima
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Ikuo Yamamoto
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Abstract

The human liver enzyme microsomal alcohol oxygenase was able to oxidize both 7α- and 7β-hydroxy-Δ8-tetrahydrocannabinol (7α- and 7β-hydroxy-Δ8-THC) to 7-oxo-Δ8-THC. The oxidative activity was determined by using a panel of 12 individual cDNA-expressed human cytochrome P450s (CYPs) (1A1, 1A2, 2A6, 2B6, 2C8, 2C9-Arg, 2C9-Cys, 2C19, 2D6-Met, 2D6-Val, 2E1 and 3A4). Among the CYP isoforms examined, CYP3A4 showed the highest activity for both of substrates. The metabolism of 7α- and 7β-hydroxy-Δ8-THC to 7-oxo-Δ8-THC was also detected for CYPs 1A1 (4.8% of CYP3A4), 1A2 (4.7%), 2A6 (2.3%), 2C8 (16.6%), and 2C9-Cys (5.4%), and CYPs 1A1 (0.4%), 2C8 (1.3%), 2C9-Arg (4.3%), and 2C9-Cys (0.9%), respectively. The 7α- and 7β-hydroxy-Δ8-THC microsomal alcohol oxygenase activities in human liver were significantly inhibited by addition of 100 μM troleandomycin, 1 μM ketoconazole, and anti-CYP3A antibody, although these activities were not inhibited by 1 μM 7,8-benzoflavone and 50 μM sulfaphenazole. When the substrates were incubated with the CYP3A4-expressed microsomes under oxygen-18 gas phase, atmospheric oxygen was incorporated into 35% of 7-oxo-Δ8-THC formed from 7α-OH-Δ8-THC, but only 12% of 7-oxo-Δ8-THC formed from 7β-OH-Δ8-THC. These results indicate that CYP3A4 is a major isoform responsible for the oxidation of 7α- and 7β-hydroxy-Δ8-THC to 7-oxo-Δ8-THC in liver microsomes of humans, although the oxidation mechanisms for 7α- and 7β-hydroxy-Δ8-THC might be different.

Footnotes

  • Send reprint requests to: Dr. Ikuo Yamamoto, Department of Hygienic Chemistry, Faculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa, 920-1181, Japan. E-mail:i-yamamoto{at}hokuriku-u.ac.jp

  • This work was partially supported by a grant-in-aid for scientific research from the Ministry of Education, Science, and Culture of Japan, and by the Special Research Fund of Hokuriku University.

  • Abbreviations used are::
    THC
    tetrahydrocannabinol
    CYP
    cytochrome P450
    MALCO
    microsomal alcohol oxygenase
    GC/MS
    gas chromatography/mass spectrometry
    • Received October 6, 1999.
    • Accepted July 24, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 28 (11)
Drug Metabolism and Disposition
Vol. 28, Issue 11
1 Nov 2000
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Research ArticleArticle

CYP3A4 Is a Major Isoform Responsible for Oxidation of 7-Hydroxy-Δ8-tetrahydrocannabinol to 7-Oxo-Δ8-tetrahydrocannabinol in Human Liver Microsomes

Tamihide Matsunaga, Nobuyuki Kishi, Shinsuke Higuchi, Kazuhito Watanabe, Tohru Ohshima and Ikuo Yamamoto
Drug Metabolism and Disposition November 1, 2000, 28 (11) 1291-1296;

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Research ArticleArticle

CYP3A4 Is a Major Isoform Responsible for Oxidation of 7-Hydroxy-Δ8-tetrahydrocannabinol to 7-Oxo-Δ8-tetrahydrocannabinol in Human Liver Microsomes

Tamihide Matsunaga, Nobuyuki Kishi, Shinsuke Higuchi, Kazuhito Watanabe, Tohru Ohshima and Ikuo Yamamoto
Drug Metabolism and Disposition November 1, 2000, 28 (11) 1291-1296;
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