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Regulation of expression of cytochrome P-450 by hormonal factor in primary cultured rat hepatocytes.

Research Project

Project/Area Number 02404025
Research Category

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

Allocation TypeSingle-year Grants
Research Field General pharmacology
Research InstitutionKeio University

Principal Investigator

KATO Ryuichi  Keio Univ., Sch. of Med. Prof., 医学部, 教授 (40112685)

Co-Investigator(Kenkyū-buntansha) MURAYAMA Norie  Keio Univ., Sch. of Med. Assistant, 医学部, 助手 (90219949)
NAGATA Miki  Keio Univ., Sch. of Med. Assistant, 医学部, 助手 (10196488)
NAGATA Kiyoshi  Keio Univ., Sch. of Med. Assistant, 医学部, 助手 (80189133)
YAMAZOE Yasushi  Keio Univ., Sch. of Med. Associate Prof., 医学部, 助教授 (00112699)
Project Period (FY) 1990 – 1992
Project Status Completed (Fiscal Year 1992)
Budget Amount *help
¥28,000,000 (Direct Cost: ¥28,000,000)
Fiscal Year 1992: ¥8,500,000 (Direct Cost: ¥8,500,000)
Fiscal Year 1991: ¥7,300,000 (Direct Cost: ¥7,300,000)
Fiscal Year 1990: ¥12,200,000 (Direct Cost: ¥12,200,000)
KeywordsCytochrome P-450 / Phenobarbital / Hepatocyte / Thyroid hormone / Growth hormone / GRE / HNF-4 / Dexamethasone / フェノバルビタール誘導 / トリヨードチロニン / チトクロ-ムPー450 / 単離肝細胞 / 薬物代謝酵素 / 酵素誘導 / 初代培養肝細胞
Research Abstract

Summary
We used primary culture of hepatocytes to investigate a direct effect of hormonal factors on the expression at the molecular level of rat hepatic cytochrome P-450. The levels of a variety of hepatic cytochrome P-450 are rapidly decreased during primary culture of hepatocytes. We used, therefore,matrigel to prevent the decrease of P-450s and we successed induction of P-450 2B1(CYP2B1)by phenobarbital(PB)in the hepatocytes. Thyroid hormone showed a marked inhibition of PB induction. In addition,growth hormone showed synergistic inhibition with thyroid hormone of PB induction. On the other hand,dehydroepiandrosterone antagonized the induction by growth hormone. By using derivatives of phenobarbital, we showed the structure specificity of barbiturates on the potency of induction of each cytochrome P-450,such as CYP2B1, CYP2B2 and CYP3A. We succeeded in an effective transfection of P-450 gene by Ca^<++>-coprecipition method. We used chloramphenicol-acetyltransferase gene as a receptor gene and the mechanism of induction with phenobarbital was investigated. We revealed one position,which is related with PB induction and locates near TATA box of CYP2B1 gene. Moreover,we observed five sequences of glucocorticoid responsive element(GRE)in CYP3A2 gene 6betaA and two sequences related with hepatic nuclear factor 4(HNF-4). The mechanism of expression of by dexamethasone is now under investigation by using a variety of lengthes of CYP3A2(6betaA)-CAT fusion gene.

Report

(4 results)
  • 1992 Annual Research Report   Final Research Report Summary
  • 1991 Annual Research Report
  • 1990 Annual Research Report
  • Research Products

    (29 results)

All Other

All Publications (29 results)

  • [Publications] Sasamura,H.: "Effect of growth on rat hepatic cytochrome P-450f mRNA:a new mode of regulation." Mol.Cell.Endocrinol.68. 53-60 (1990)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Yamazoe,Y.: "Modulation of hepatic level of microsomal testosterone 7a-hydroxylase,P-450a(P450IIA),by thyroid hormone and growth houmone in rat liver." J.Biochem.108. 599-603 (1990)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Nagata,K.: "Regulations of male dominant P-450Md mRNA in rat liver by hormonal factors and xenobiotics." Jpn.J.Pharmacol.57. 123-126 (1991)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Miyata,M.: "A Gene structure of testosterone 6b-hydroxylase(P450IIIA)." Biocnem.Biophys.Res.Commun.177. 68-73 (1991)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Murayama,N.: "Difference in the susceptibility of two phenobarbital-inducible forms,P450IIB1 and P450IIB2,to thyroid hormone-induced and growth hormone-induced suppression in rat liver:Phenobarbital-inducible P450IIB2 suppression by thyroid hormone acting directly,but not through the pituitary system." Mol.Pharmacol.39. 811-817 (1991)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] 山添 康: "癌原物質の活性化酸素とその内分泌による発現の調節" 薬学雑誌. 112. 679-692 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Kato,R.: "Frontiers in Biotransformation:Principles,Mechanisms and Biological Consequences of Induction.(Sex-dependent regulation of cytochrome P-450 expression.)" Akademie-Verlag, 31 (1990)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Kato,R.: "Cytochrome P450(Hormonal regulation of cytochrome P450 in rat liver)" Springer-Verlag, (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Sasamura,H: "Effect of growth hormone on rat hepatic cytochrome P-450f mRNA: a new mode of regulation." Mol.Cell.Endocrinol. 68. 53-60 (1990)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Yamazoe,Y: "Modulation of hepatic level of microsomal testosterone 7a-hydroxylase,P-450a(P450IIA),by thyroid hormone and growth hormone in rat liver." J.Biochem. 108. 599-603 (1990)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Natgata,K: "Regulations of male dominant P-450MD mRNA in rat liver hormanal factors and xenobiotics." Japan.J.Pharmacol. 57. 123-126 (1991)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Miyata,M: "A Gene structure of testosterone 6b-hydroxylase (P450IIIA)." Biochem.Biophys.Res.Commun. 177. 68-73 (1991)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Murayama,N: "Difference in the susceptibility of two phenobarbital-inducible forms,P450IIB1 and P450IIB2,to thyroid hormone-induced and growth hormone-induced suppression in rat liver: Phenobarbital-inducible P450IIB2 suppression by thyroid hormone acting directly,but not through the pituitary system." Mol.Pharmacol. 39. 811-817 (1991)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Yamazoe,Y: "Enzymes involved in metabolic activation of carcinogenic chemicals and their hormonal regulation." Yakugaku Zasshi. 112. 679-692 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Kato,R: "Frontiers in Biotransformation: Principles,Mechanisms and Biological Consequences of Induction.(Sex-dependent regulation of cytochrome P-450 expression)" Akademie-Verlag. 31. (1990)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Kato,R: "Cytochrome P450 (Hormonal regulation of cytochrome P450 in rat liver)" Springer-Verlag. (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Kato,R.: "Sex-specific cytochrome P450 as a cause of Sex-and species-related differences in drug toxecety." Toxicol.Lett.64/65. 661-667 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] 加藤 隆一: "薬物代謝酵素に関する分子薬理学的研究" 日本医師会雑誌. 109. 69-75 (1993)

    • Related Report
      1992 Annual Research Report
  • [Publications] Kato,R.: "(Hormonal regulation of cytochrome P450 in rat liver)Cyochome P450" Springer-Verlag, (1993)

    • Related Report
      1992 Annual Research Report
  • [Publications] Yasumori,T.: "Cytochrome Pー450 humanー2(Pー450IIC9)in mephenytoin hydroxylation Polymorphism in human livers:Differences in substrate and stereoselectivities among microheterogeneous Pー450IIC species expressed in yeast." J.Biochem.109. 711-717 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Miyata,M.: "A Gene structure of testosterone 6βーhydroxylase(P450IIIA)." Biochem.Biophys.Res.Commun.177. 68-73 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Nagata,K.: "Regulations of male dominant pー450Md mRNA in rat liver by hormonal factors and xenobiotics." Japan.J.Pharmacol.57. 123-126 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Murayama,N.: "Difference in the susceptibility of two phenobarbitalーinducible forms,P450IIB1 and P450IIB2.to thyroid hormoneーinduced and growth hormoneーinduced suppression in rat liver:Phenobarbitalーinducible P450IIB2 suppression by thyroid hormone acting directly,but not through the pituitary system." Mol.Pharmacol.39. 811-817 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Kato,R.: "Cytochrome P450" Academic Press, (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Kato,R.: "Xenobiotics and Cancer Imprications for Chemical Carcinogenesis and Cancer Chemotherapy" Japan Sci.Press/Taylor & Francis, 9 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Sasamura,H.: "Effect of growth hormone on rat hepatic cytochrome P__ーー450f mRNA:a new mode of regulation" Mol.Cell.Endocrinol.68. 53-60 (1990)

    • Related Report
      1990 Annual Research Report
  • [Publications] Yamazoe,Y.: "Modulation of hepatic level of microsomal testosterone 7αーhydroxylase Pー450a (P450IIA) by thyroid hormone and growth hormone in rat liver." J.Biochem.108. 599-603 (1990)

    • Related Report
      1990 Annual Research Report
  • [Publications] Murayama,N.: "Difference in the susceptibility of two phenobarbitalーinducible forms,P450IIB1 and IIB2,on thyroid hormoneーand growth hormoneーinduced suppression in rat liver." Mol.Pharmacol.

    • Related Report
      1990 Annual Research Report
  • [Publications] Kato,R.: "Endogenous factors that selectively modify drug metabolism." Eur.J.Pharmacol.183. 41-42 (1990)

    • Related Report
      1990 Annual Research Report

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Published: 1990-04-01   Modified: 2016-04-21  

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