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THE ROLE OF CYP2D SUBFAMILY IN METABOLIC ACTIVATION OF THE DRUGS THAT CONTAIN NITROGEN ATOM IN THEIR CHEMICAL STRUCTURES

Research Project

Project/Area Number 06672166
Research Category

Grant-in-Aid for General Scientific Research (C)

Allocation TypeSingle-year Grants
Research Field Biological pharmacy
Research InstitutionCHIBA UNIVERSITY

Principal Investigator

NARIMATSU Shizuo  CHIBA UNIVERSITY,FACULTY OF PHARMACEUTICAL SCIENCES ASSOCIATE PROFESSOR, 薬学部, 助教授 (20113037)

Co-Investigator(Kenkyū-buntansha) MASUBUCHI Yasuhiro  CHIBA UNIVERSITY,FACULTY OF PHARMACEUTICAL SCIENCES RESEARCH ASSOCIATE, 薬学部, 助手 (10209455)
Project Period (FY) 1994 – 1995
Project Status Completed (Fiscal Year 1995)
Budget Amount *help
¥2,200,000 (Direct Cost: ¥2,200,000)
Fiscal Year 1995: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 1994: ¥1,400,000 (Direct Cost: ¥1,400,000)
KeywordsHuman liver micosomes / Propranolol / P450-2D6 / P450-1A2 / Superoxide / 1,4-Naphthoquinone / Covalent binding / Enzyme inhibition / P450‐2D6 / P450‐1A2 / 1,4‐ナフトキノン / CYP2D酵素 / 代謝的活性化 / 蛋白共有結合 / スーパーオキシドディスムターゼ
Research Abstract

Propranolol (PL), a beta-blocker, was oxidized to 4-hydroxylated (4-OH-PL), 5-hydroxylated (5-OH-PL) and N-desisopropylated (NDP) metabolites in human liver microsomes. The PL aromatic hydroxylations were suppressed by anti-rat cytochrome P450-2D2 (P450-2D2) antibody and its specific inhibitor (quinidine) concentration dependently. The PL N-desalkylation was decreased by alpha-naphthoflavone (a P450-1A inhibitor) and highly correlated with phenacetin O-deethylation, an index of P450-1A2 activity. These results suggest that the naphthalene ring hydroxylations and the side chain N-desalkylation were mediated by P450-2D6 and P450-1A2, respectively.
Purified rat P450-2D2 was incubated with [3H]-PL in the presence of NADPH,and relationship between radioactivity binding and decrease in enzyme activity was examined. Radioactivity bound to P450-2D2 was suppressed by anti-P450-2D2 antibody in a concentration dependent manner, and the enzyme activity was decereased time-dependently, which showed … More first-order kinetics. Radioactivity was localized at P450-2D2 apoprotein, and corresponded well to the decreased enzyme activity. From these results, it is thought that PL is biotransformed by P450-2D2 to a chemically reactive metabolite, which covalently binds to the enzyme itself, resulting in its inhibition.
4-OH-PL strongly suppressed P450-2D enzyme activity after preincubation with rat liver microsomes in the presence of NADPH.Further metabolism of 4-OH-PL was examined in rat liver microsomes, and the possibilityarose that superoxide was involved in the elimination of 4-OH-PL in the microsomes. It was found that 4-OH-PL was converted to 1,4-naphthoquinone in xanthine-xanthine oxidase system, a well known superoxide-generating system. The quinone was identified as an metabolite of 4-OH-PL also in the system containing rat liver microsomes. Taking these results and findings into account, it seems likely that PL is converted to 4-OH-PL by P450-2D enzymes in human and rat liver microsomes. 4-OH-PL thus obtained is converted by superoxide supplied from microsomal electron transfer system to 1,4-naphthoquinone, which covalently binds to P450-2D enzymes, resulting in the inhibition. Less

Report

(3 results)
  • 1995 Annual Research Report   Final Research Report Summary
  • 1994 Annual Research Report
  • Research Products

    (10 results)

All Other

All Publications (10 results)

  • [Publications] Yasuhiro Masubuchi,et al.: "Role of the CYP2D subfamily in metabolism-dependent covalent binding of propranolol to liver microsomal protein in rats" Biochem.Pharmacol.48. 1891-1898 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Yasuhiro Masubuchi,et al.: "Cytochrome P450 isozymes involved in propranolol metabolism in human liver microsomes : The role of CYP2D6 as ring-hydroxylase and CYP1A2 as N-desisopropylase" Drug Metab.Dispos.22. 909-915 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Shizuo Narimasu,et al.: "Characterization of a chemically reactive propranolol metabilite that binds to microsomal proteins of rat liver" Chem.Res.Toxicol.8. 721-728 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Y.MASUBUDHI et al.: "Role of the DYP2D subfamily in metabolism-dependent covalent binding of propranolol to liver microsomal protein in rats." Biochem. Pharmacol.48. 1891-1898 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Y.MASUBUDHI et al.: "Cytochrome P450 isozymes involved in propranolol metabolism in human liver microsomes : The role of CYP2D6 as ring-hydroxylase and CYP1A2 as N-desisopropylase." Drug Metab. Dispos.22. 909-915 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] S.NARIMATSU et al.: "Characterization of a chemically reactive propranolol metabolite that binds to microsomal proteins of rat liver." Chem. Res. Toxicol.8. 721-728 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Yasuhiro Masubuchi et al.: "Role of the CYP2D subfamily in metabolism‐dependent covalent binding of propranolol to liver microsomal protein in rats" Biochem. Pharmacol.48. 1891-1898 (1994)

    • Related Report
      1995 Annual Research Report
  • [Publications] Yasuhiro Masubuchi et al.: "Cytochrome P450 isozymes involved in propranolol metabolism in human liver microsomes: The role of CYP2D6 as ring‐hydroxylase and CYP1A2 as N‐desisopropylase" Drug Metab. Dispos.22. 909-915 (1994)

    • Related Report
      1995 Annual Research Report
  • [Publications] Shizuo Narimatsu et al.: "Characterization of a chemically reactive propranolol metabolite that bindsto microsomal proteins of rat liver" Chem. Res. Toxicol.8. 721-728 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] 成松鎮雄 その他: "交感神経β-受容体遮断薬プロプラノロールの代謝的活性化の分子機構-CYP2D酵素と活性酸素種の役割-" 薬物動態. 9. 168-171 (1994)

    • Related Report
      1994 Annual Research Report

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Published: 1994-04-01   Modified: 2016-04-21  

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