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HUMAN CYTOCHROME P450 ISOZYMES RESPONSIBLE FOR THE METABOLISM OF ORGANIC SOLVENTS AND THEIR ROLES IN THE TOXICITY

Research Project

Project/Area Number 03454202
Research Category

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

Allocation TypeSingle-year Grants
Research Field Hygiene
Research InstitutionSHINSHU UNIVERSITY

Principal Investigator

MURAYAMA Ninzo  SHINSHU UNIVERSITY SCHOOL OF MEDICINE, PROFESSOR, 医学部, 教授 (90020718)

Co-Investigator(Kenkyū-buntansha) NASU Tamie  SHINSHU UNIVERSITY SCHOOL OF MEDICINE, LECTURER, 医学部, 講師 (10020794)
AOYAMA Toshifumi  SHINSHU UNIVERSITY SCHOOL OF MEDICINE, ASSOCIATE PROFESSOR, 医学部, 助教授 (50231105)
Project Period (FY) 1991 – 1993
Project Status Completed (Fiscal Year 1993)
Budget Amount *help
¥5,600,000 (Direct Cost: ¥5,600,000)
Fiscal Year 1993: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 1992: ¥2,100,000 (Direct Cost: ¥2,100,000)
Fiscal Year 1991: ¥2,700,000 (Direct Cost: ¥2,700,000)
Keywordscytochrome P450 / organic solvents / human liver / human lungs / metabolism / toxicity / smoking / drinking / 有機溶剤の代謝 / トルエン / スチレン / トリクロロエチレン / キシレン / ヒトチトクロームP450 / マウスチトクロームP450 / ラットチトクロームP450 / ベンゼン / フェノール / 代謝活性化 / 種差 / ワクシニアウイルス / ヒトP450 / ラット / マウス
Research Abstract

1. Metabolisms of organic solvents by cDNA-expressed human hepatic and pulmonary cytochrome P450 were investigated. CYP2B6 was the most effective for the metabolism of toluene, ethlbenzene and stirene, followed by CYP2F1, CYP2E1, CYP1A2, CYP2C8 and CYP4B1, in decreasing order. CYP3A3, CYP3A4 and CYP3A5 showed a little activity for the metabolism, but CYP2A6, CYP2A9 and CYP2D6 did not. On the other hand, CYP2E1 was the most active for the metabolism of benzene and phenol. Although CYP1A2, CYP2B6, CYP2C8 and CYP2F1 were also responsible for the metabolism, the catalytic activity was significantly smaller than that of CYP2E1. CYP1A2 was expressed in human bone marrow, but CYP2E1 could not be seen, suggesting that CYP1A2, not CYP2E1, plays an important role in benzene-induced hematotoxicity. 2.Structure of CYP2B1 cDNA and activity for the metabolism of toluene was investigated. Introduction of 58Phe in place of Leu58 catalysed the formation of benzylalcohol (BA) by 60% of that of CYP2B1, whereas lost the catalitic activity for the formation of o- and p-cresol. The introduction of Phe114 in place of Ile114 catalyzed the formation of all toluene metabolites less than 50% of that by CYP2B1. The introduction of Val282 in place of Glu282 did not influence the activity for the formation of all toluene metabolites. These results suggest the importance of 58Leu of CYP2B1 cDNA in the formation of toluene ring products. 3.Many organic solvents were metabolized in not only human liver but also in lungs.However, the catalitic activity in the latter was only a few percentage of that in the former. Smoking enhanced the activity for the formation of o-cresol from toluene in liver, and of stirene glycol from stirene in lungs. Drinking habit, however, did not influence the metabolism of organic solvents. The metabolic pattern of toluene in human lungs was different from that in liver : the ratio of o- and p-cresol to total metabolites was less than 10% in liver, whereas the ratio o- an

Report

(4 results)
  • 1993 Annual Research Report   Final Research Report Summary
  • 1992 Annual Research Report
  • 1991 Annual Research Report
  • Research Products

    (18 results)

All Other

All Publications (18 results)

  • [Publications] Wang RS,Nakajima T,et al.: "Monoclonal antibody-directed assessment of toluene induction of rat hepatic cytochrome P450 isozymes" Biochemical Pharmacology. 46. 413-419 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Nakajima T and Wang RS: "Induction of cytochrome P450 by toluene" International J Biochemistry. (in press). (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Nakajima T et al.: "Butadiene and Styrene:Assessment of Health Hazards(分担)" International Agency for Research on Cancer, 412(101-108) (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] 1) Wang RS, Nakajima T, Park SS, Gelboin HV and Murayama N.: "Monoclonal antibody-directed assessment of toluene induction of rat hepatic cytochrom P450 isozymes." Biochemical Pharmacology. 46. 413-419 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] )2 Nakajima T and Wang RS.: "Induction of cytochrome P450 by toluene." International Journal of Biochemistry.(in press). (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Nakajima T, Elovaara E, Gonzalez FJ, Gelboin HV, Vainio H and Aoyama T.: "Characterization of the human cytochrome P450 isozymes responsible for stirene metabolism." In Butadiene and Stirene : Assessment of Health Hazards, ed by Sorsa M, Pelkonene K, Vainio H and Hemminki K.IARC, Lyon. 101-108 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Nakajima T et al.: "Induction of cytochrome P450 by toluene" Int J Biochem. (in press). (1994)

    • Related Report
      1993 Annual Research Report
  • [Publications] Nakajima T et al.: "Butadiene and Styrene:Assessment of Health Hazards(分担)" International Agency for Research on Cancer, 412(101-108) (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Nakajima T et al.: "A comparative study on the contribution of cytochrome P450 isozymes to metabolism of benzene,toluene and trichloroethylene in rat liver" Biochem Pharmacol. 43. 251-257 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] Nakajima T et al.: "Sex-,age- and pregnancy-induced changes in the metabolism of toluene and trichloroethylene in rat liver in relation to the regulation cytochrome P450IIEl and P450IICll content" J Pharmacol Exp Ther. 261. 869-874 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] Nakajima T et al.: "Cytochrome P450-related differences between rats and mice in the metabolism of benzene,toluene and trichloroethylene in liver microsomes" Biochem Pharmacol. (1993)

    • Related Report
      1992 Annual Research Report
  • [Publications] Nakajima T et al.: "International Symposium on Health Hazards of Butadiene and Styrene (Characterization of human cytochrome P450 responsible for styrene metabolism)" International Agency for Research on Cancer, (1993)

    • Related Report
      1992 Annual Research Report
  • [Publications] Tamie Nakajima et al.: "Monoclonal antibodyーdirected characterization of cytochrome P450 isozymes responsible for toluene metabolism in rat liver" Biochemical Pharmacology. 41. 395-404 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Tamie Nakajima et al.: "Immunochemical detection of cytochrome P450 isozymes induced in rat liver by nーhexane,2ーhexanone and acetonyl acetone" Archives of Toxicology. 65. 542-547 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] RuiーSheng;Wang,Tamie Nakajima: "Kinetic studies on toluene metabolism in ethanolー and phenobarbitalーinduced rat liver microsomes in vitro" Archives of Toxicology. 65. 39-44 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Tomonori Okino,Tamie Nakajima,Masayuki Nakano: "Morphological and biochemical analyses of trichloroethylene hepatotoxicity: differences in ethanolー and phenobarbitalーpretreated rats" Toxicology and Applied Pharmacology. 108. 379-389 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Tamie Nakajima et al.: "Enhancement of ethanolーinduced lipid peroxidation in rat liver by lowered carbohydrate intake" Biochemical Pharmacology. 43. 245-250 (1992)

    • Related Report
      1991 Annual Research Report
  • [Publications] Tamie Nakajima et al.: "A comparative study on the contribution of cytochrome P450 isozymes to metabolism of benzene,toluene and trichloroethylene in rat liver" Biochemical Pharmacology. 43. 251-257 (1992)

    • Related Report
      1991 Annual Research Report

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Published: 1991-04-01   Modified: 2016-04-21  

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