Monkey Hepatic Microsomal Alcohol Oxygenase: Purification and Characterization of a Cytochrome P450 Enzyme Catalyzing the Stereoselective Oxidation of 7α-and 7β-Hydroxy-Δ^8-tetrahydrocannabinol to 7-Oxo-Δ^8-tetrahydrocannabinol

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概要

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• The formation of 7-oxo-Δ^8-tetrahydrocannabinol(7-Oxo-Δ^8-THC)from 7 α-or 7β-hydroxy-Δ^8-THC(7α-or 7β-OH-Δ^8-THC)was found in hepatic microsomes of monkeys. The activity in 7β-OH-Δ^8-THC was stereoselectively 2.5-to 4.6-fold higher than that from 7α-OH-Δ^8-THC. The oxidative activities of 7α-and 7β-OH-Δ^8-THC to 7-Oxo-Δ^8-THC were inhibited to 35% and 10%, respectively, of the control value by the antibody against P450GPF-B(CYP3A), a major enzyme responsible for the formation of 7-Oxo-Δ^8-THC in guinea pigs. In the Lineweaver-Burk double-reciprocal plot analysis, testosterone 6β-hydroxylase activity was competitively inhibited by 7β-OH-Δ^8-THC. Two cytochrome P450 enzymes, called P450JM-D and P450JM-E, were purified from hepatic microsomes of Japanese monkeys. P450JM-E, assumed to be CYP3A8, immunologically reacted with the antibody against P450GPF-B and showed high forming activity of 7-Oxo-Δ^8-THC from 7-OH-Δ^8-THC. On the other hand, 7-Oxo-Δ^8-THC forming activity of P450JM-D, assumed to be CYP2C, was less than 10% of that of P450JM-E(CYP3A8). Oxygen-18(^<18>O)derived from atmospheric oxygen was incorporated into about 40% of the corresponding ketone formed from 7α-OH-Δ^8-THC or 8β-OH-Δ^9-THC by P450JM-E(CYP3A8), although the incorporation of the stable isotope into the oxidized metabolite from 7β-OH-Δ^9-THC or 8α-OH-Δ^9-THC was negligible. These results indicate that P450JM-E(CYP3A8)is a major enzyme of the oxidation of 7-OH-Δ^8-THC in monkey hepatic microsomes. The oxidation mechanism may proceed as follows: the α- and β-epimers of 7-OH-Δ^8-THC or 8-OH^Δ^9-THC may be converted to ketone through dehydration of an enzyme-bound gem-diol by P450JM-E(CYP3A8), although this stereoselective dehydration differentiates between two epimers.

• 社団法人日本薬学会の論文
• 2002-01-01

著者

• YAMAMOTO IKUO

  Department of Laboratory Medicine, Miyazaki Medical College

• 景山 節

  京大・霊長類研・生化学

• Yamamoto Ikuo

  Department Of Hygienic Chemistry School Of Pharmaceutical Sciences Kyushu University Of Health And W

• Watanabe Kazuhito

  Department of Hygienic Chemistry, Faculty of Pharmaceutical Sciences, Hokuriku University

• MATSUNAGA Tamihide

  Department of Pharmacy, Shinshu University Hospital

• YAMAMOTO Ikuo

  School of Pharmaceutical Sciences, Kyushu University of Health and Welfare

• KAGEYAMA Takashi

  Department of Cellular and Molecular Biology, Primate Research Institute, Kyoto University

• Yamamoto Ikuo

  北陸大学 薬 衛化

• Yamamoto Ikuo

  Department Of Hygienic Chemistry Faculty Of Pharmaceutical Sciences Hokuriku University

• IWAWAKI Yasuyuki

  Department of Hygienic Chemistry, Faculty of Pharmaceutical Sciences, Hokuriku University

• KOMURA Akiko

  Department of Hygienic Chemistry, Faculty of Pharmaceutical Sciences, Hokuriku University

• YAMAMOTO IKUO

  Hygienic Chemistry

• Kimura T

  Department Of Hygienic Chemistry Faculty Of Pharmaceutical Sciences Hokuriku University

• 景山 節

  京都大学霊長類研究所人類進化モデル研究センター

• 景山 節

  京大・霊長研

• Watanabe Kazuhito

  Department Of Hygienic Chemistry Faculty Of Pharmaceutical Sciences Hokuriku University

• Watanabe Kazuhito

  Department Of Chemistry And Chemical Engineering Faculty Of Engineering Yamagata University

• Kimura T

  Department Of Medicinal Chemistry Center For Frontier Research In Medicinal Science 21st Century Coe

• Komura Akiko

  Department Of Hygienic Chemistry Faculty Of Pharmaceutical Sciences Hokuriku University

• Yamamoto I

  Hokuriku Univ. Kanazawa Jpn

• Yamamoto I

  Hygienic Chemistry

• Matsunaga Tamihide

  Department Of Pharmacy Shinshu University Hospital

• Watanabe Kazuhito

  Faculty Of Pharmaceutical Sciences Kyushu University

• Yamamoto Ikuo

  Hygienic Chemistry School Of Pharmacy Hokuriku University

• Iwawaki Yasuyuki

  Department Of Hygienic Chemistry Faculty Of Pharmaceutical Sciences Hokuriku University

• Yamamoto Ikuo

  Department Of Bioapplied Chemistry Faculty Of Engineering Osaka City University

• Kimura T

  Peptide Inst. Inc. Minoh Jpn

• Matsunaga Tamihide

  Department of Clinical Pharmacy, Graduate School of Pharmaceutical Sciences, Nagoya City University

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