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チトクロ-ムPー450を中心とした薬物代謝酵素遺伝子発現と化学発癌

Research Project

Project/Area Number 03151005
Research Category

Grant-in-Aid for Cancer Research

Allocation TypeSingle-year Grants
Research InstitutionTohoku University

Principal Investigator

渡辺 民朗  東北大学, 抗酸菌病研究所, 教授 (40006101)

Co-Investigator(Kenkyū-buntansha) 山添 康  慶應義塾大学, 医学部, 助教授 (00112699)
藤田 正一  北海道大学, 獣医学部, 教授 (10143314)
十川 和博  東北大学, 理学部, 助教授 (80175421)
佐藤 清美  弘前大学, 医学部, 教授 (50006079)
鎌滝 哲也  北海道大学, 薬学部, 教授 (00009177)
Project Period (FY) 1991
Project Status Completed (Fiscal Year 1991)
Budget Amount *help
¥22,000,000 (Direct Cost: ¥22,000,000)
Fiscal Year 1991: ¥22,000,000 (Direct Cost: ¥22,000,000)
Keywordsチトクロ-ムPー450遺伝子 / チトクロ-ムPー450cDNA / チトクロ-ムPー450蛋白 / 癌原性化学物質の代謝 / 転写調節蛋白 / アセチルトランスフェラ-ゼ / グルタチオンSートランスフェラ-ゼ / ヒト遺伝子のRFLPs
Research Abstract

1)P450遺伝子構造と誘導機構:ラットとハムスタ-P450IA1(ベンツピレン代謝)の5'上流域のDREとBTE領域の存在を確かめた。BTEに結合するBTEーBは転写調節因子Sp1と同じ結合性を持つ。DREと結合するリセプタ-蛋白は精製を試みているが成功していない。また培養肝細胞におけるベンツピレン代謝の誘導能は転写前と共に転写後の調節もある。
2)P450遺伝子導入とその発現:ヒト胎児肝P450IIIA7をヒト乳癌由来細胞(MCFー7)、または昆虫由来細胞(Sf7)で、ヒトP450IIC9、IIC10、IIIA4を酵母で、イヌP450IA1をショウジョウバエに導入し、発現させた。そしてIIIA7、IIIA4はAFB_1代謝能、また、IIIA4とIA1はベンツピレン代謝能をもっていた。
精製P450酵素の代謝特性:ヒト肝よりP450IIA6とIIIA4を精製し、それぞれクマリンの代謝と4,4'ーメチレンーbisー(2ークロロアニリン)の活性化能を示していた。また、ブニトロロ-ルの基質濃度により、触媒活性を示すP450IID2とIA1への依存性が異なっていることを確かめた。
4)アセチルとグルタチオンのトランスフェラ-ゼについての検討:塩基配列の異なる2種のATcDNAを分取し、ATーBに遺伝子多型がある。また、GSTーmuがヒト食道癌で新たに発現していた。
5)ヒトP450の遺伝子多型:P450IIE1(ジアルキルニトロサミン代謝)の制限酵素Dra1により遺伝子多型の分布において、癌患者と対称群の間で異なっており、その変異はイントロンVIにある。また、P450IA1のMsp1による多型は肺癌患者と対称群で有意差があり、ベンツピレン代謝活性の差異をもたらす、エクソン部位の変異の連鎖が確かめられた。特に、喫煙との関連が明らかである。

Report

(1 results)
  • 1991 Annual Research Report
  • Research Products

    (61 results)

All Other

All Publications (61 results)

  • [Publications] Sagami,I.: "Hamster cytochrome P-450 IA gene family,P-450IA1 and P-450IA2 in lung and liver:cDNA cloning and sequence analysis." J.Biochem.110. 641-647 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Uematsu,F.: "Association between restriction fragment length polymorphism of the human cytochrome P-450IIE1 gene and susceptibility to lung cancer." Jpn.J.Cancer Res.82. 254-256 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Uematsu,F.: "Mspl polymorphism of the human CYP2E gene." Nucl.Acid Res.19. 5797 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Uematsu,F.: "Two common RFLPs of the human CYP2E gene." Nucl.Acid Res.19. 2803 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Yokotani,N.: "cDNA cloning and expression of the mRNA for cytrochrome Pー450kd which shows a fatty acid ωーhydroxylating activity." Eur.J.Biochem.196. 531-536 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Kubota,M.: "Xenobiotic responsive element in the 5'-upstream region of the human P-450c gene." J.Biochem.110. 232-236 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Kikuta,Y.: "A novel species of cytochrome P-450 (P-450ib) specific for the intestine of rabbits.cDNA cloning and its expression in COS cells." J.Biol.Chem.266. 17821-17825 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Kuroiwa,T.: "Systematic analysis of stop-transfer sequence for microsomal membrane." J.Biol.Chem.266. 9251-9255 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Sakaguchi,M.: "Functions of signal and signal-anchor sequences are determined by the balance between the hydrophobic segment and amino terminal charge." Proc.Natl.Acad.Sci,USA. 89. 16-19 (1992)

    • Related Report
      1991 Annual Research Report
  • [Publications] Kanazawa,Y.: "Ascorbic acid deficiency decreases specific forms of cytochrome P-450 in liver microsomes of guinea pigs." Mol.Pharmacol.39. 456-460 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Mori,T.: "The in vitro effects of lipid peroxidation on the content of individual forms of cytochrome P-450 in liver microsomes of guinea pigs." Pharmacol.Res.24. 143-148 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Kitada,M.: "Four formes of cytochrome P-450 in human fetal livers:Purification and their capacity to activate promutagens." Jpn.J.Cancer Res.82. 426-432 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Watnabe,K.: "Comparison of cytochrome P-450 species which catalyze the hydropxylations of the aromatic ring of estradiol and estradiol 17-sulfate." J.Steroid Biochem.Mol.Biol.39. 737-743 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Kitamura,R.: "Stable expression of cytochrome P-450IIIA7 cDNA in human breast cancre cell line MCF-7 and its application to cytotoxicity testing." Arch.Biochem.Biophys.292. 136-140 (1992)

    • Related Report
      1991 Annual Research Report
  • [Publications] Nakura,H.: "Formation of an antibacterial metabolite from a new macrolide compound 123-O-benzyl-5-mycaminosyl-tylonolide (TMC-101),by a hepatic microsomal drug-metabolizing enzyme system." J.Pharmacobio-Dyn.14. 377-383 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Nagayama,S.: "Occurence of autoimmune antibodies to liver microsomal proteins in association with fulminant hepatitis in the LEC strain of rats." Biochem.Biophys.Res.Commu.179. 1134-1140 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Abu-Zeid,M.: "An arylamine N-acetyltransferase (AT-I) from Syrian golden hamster liver:Cloning complete nucleotide sequence,and expression in mammalian cells." Mol.Carcinogenesis. 4. 81-88 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Nemoto,N.: "Regulation of mouse P_1450 gene expression in monolayer-cultured hepatocytes from responsive and non-responsive strains." Caricinogenesis. 12. 623-629 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Imaoka,S.: "Age-dependent expression of cytochrome P-450s in rat liver." Biochim.Biophys.Acta. 1097. 187-192 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Imaoka,S.: "Induction of cytochrome P-450 isozymes rat liver by methyl n-alkyl ketones and n-alkylbenzenes:Effects of hydrophobicity of inducers on inducibility of cytochrome P-450." Biochem.Pharmacol.42. S143-S150 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Guengerich,F.P.: "Oxidation of toxic and carcinogenic chemicals by human cytochrome P-450 enzymes." Chem.Res.Toxicol.4. 391-407 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Shimada,T.: "Activation of aminoーαーcarboline,2ーaminoー1ーmethylー6ーphenylimidazoー[4,5ーb]pyridine,and a copper phthalocyanine cellulose extract of cigerette smoke condensate by cytochrome Pー450 enzyme in rat and human liver microsomes." Cancer Res.51. 5284-5291 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Yun,C.H.: "Purification and characterization of human liver microsomal cytochrome P-450 2A6." Mol.Pharmacol.40. 679-685 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Yamazaki,H.: "Participation of rat liver cytochrome P450 2E1 in the activation of N-nitrosodimethylamine and N-nitrosodiethylamine to products genotoxic in Salmonella typhimurium NM2009." Carcinogenesis. (1992)

    • Related Report
      1991 Annual Research Report
  • [Publications] Nemoto,N.: "Proline is required for transcriptional control of the aromatic hydrocarbon-inducible P_1450 gene in C57BL/6 mouse monolayer-cultured hepatocytes." Jpn.J.Cancer Res.82. 901-908 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Nemoto,N.: "Increase of CYP1A1 mRNA and AHH activity by inhibitors of either protein or RNA synthesis in mouse hepatocytes in primary culture." Carcinogenesis. 12. 2115-2121 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Tanaka,E.: "Characterization of liver microsomal cytochrome P450 from rats treated with muscone (3-methylcyclopentadecanone)." Biochem.Pharmacol.41. 472-473 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Yamazaki,H.: "Roles of different cytochrome P450 enzymes in bioactivation of the potent hepatocarcinogen 3-methoxy-4-aminoazobenzene by rat and human liver microsomes." Carcinogenesis. 12. 133-139 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Watanbe,K.: "Catalytic activity of cytochrome P450 isozymes purified from rat liver in converting 11ーoxoーΔ8ーterahydrocannabinol to Δ8ーtetrahydrocannabinolー11ーoic acid." Biochem.Pharmacol.42. 1255-1259 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Imaoka,S.: "Hepatic and renal cytochrome P-450s in spontaneously hypertensive rats." Biochim.Biophys.Acta. 1074. 209-213 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Hayashi,S-I.: "Genetic linkage of lung cancer-associated Msp I polumorphisms with amino acid replacement in the heme binding region of the human cytochrome P450 IA1 gene." J.Biochem.101. 407-411 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Hayashi,S-I: "PCR detection of an A/G polymorphism within exon 7 of the CYP1A1 gene." Nucl.Acid Res.19. 4797 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Nakachi,K.: "Genetic susceptibility to squamous cell carcinoma of the lung in relation to cigarette smoking dose." Cencer Res.51. 5177-5180 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Hayashi,S-I.: "Genetic polymorphisms in the 5'-flanking region change transcriptional regulation of the human cytochrome P450IIE1 gene." J.Biochem.110. 559-565 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Kawajiri,K.: "P450 and human cancer." Jpn.J.Cancer Res.82. 1325-1335 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Satoh,K.: "Biochemical characteristics of preneoplastic marker enzyme glutathione S-transferase P-form (7-7)." Arch.Biochem.Biophys.285. 312-316 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Shen,H.: "Modulation of class Pi glutathione transferase activity by sulfhydryl group modification." Arch.Biochem.Biophys.286. 178-182 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Hatayama,I.: "Induction of glutathione S-transferase P-form in primary cultured rat hepatocytes by epidermal growth factor and insulin." Jpn.J.Cancer Res.82. 807-814 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Tamai,K.: "Role of cystenine residues in the activity of rat glutathine transferase P (7-7):elucidation by oligonucleotide site-directed mutagenesis." Biochem.Biophys.Res.Commun.179. 790-797 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Hanada,K.: "Experssion of glutathione Sーtransferaseーπ in malignant skin tumors." J.Dermatol.Sci.2. 18-23 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Fujita,S.: "Hepatic microsomal propranolol metabolism in aging male and female rats." J.Pharmaceut.Sci.80. 199-200 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Masubuchi,Y.: "Impairment of debrisoquine 4-hydroxylase and related monooxy-genase activities in the rat following treatment with propranolol." Biochem.Pharmacol.41. 861-865 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Nakura,H.: "Decrease in the content of cytochrome P-450IIE by fasting in liver microsomes of house musk shrew (Suncus murinus)." Biochem.Pharmacol.(1992)

    • Related Report
      1991 Annual Research Report
  • [Publications] Raney,K.D.: "Oxidation of alfatoxin B_1 and related dihydrofurans by human liver microsome:role of aflatoxin Q1 as a detoxication product." Chem.Res.Toxicol.(1992)

    • Related Report
      1991 Annual Research Report
  • [Publications] Shimada,T.: "Characterization of human lung microsomal cytochrome P-450 IA1 involved in oxidation of chemical carcinogens." Mol.Pharmacol.(1992)

    • Related Report
      1991 Annual Research Report
  • [Publications] Yun,C.H.: "Roles of human liver cytochrome P-450 2C and 3A enzymes in the 3-hydroxylation of benzo(a)pyrene." Cancer Res.(1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Yun,C.H.: "Contribution of human liver cytochrome P-450 enzymes to the N-oxidation of 4,4'-methylene-bis(2-chloroaniline)." Carcinogenesis. (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Shimada,T.: "Rat pulmonary microsomal cytochrome P-450 enzymes involved in the activation of procarcinogens." Biochem.Pharmacol.(1992)

    • Related Report
      1991 Annual Research Report
  • [Publications] Masubuchi,Y.: "Selective 3-hydroxylation deficiency of lidocaine and its metabolite in Dark Agouti rats." Biochem.Pharmacol.42. 693-695 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Sawada,M.: "Stable expression of monkey cytochrome P-450IA1 cDNA in Chinese hamster CHL cells and its application for detecion of mutagenicity of aflatoxin B_1." Mut.Res.(1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Ito,S.: "Genomic organization of human fetal specific P-450IIIA7 (cytochrome P-450HFLa)-related gene(S) and interaction of transcriptional regulatory factor with its DNA element in the 5'-flanking region." Biochim.Biophys.Acta. (1992)

    • Related Report
      1991 Annual Research Report
  • [Publications] Ubukata,K.: "A new form of cytochrome Pー450 responsible for the mutagenic activation of 2ーaminoー3ーmethylーimidazo [4,5ーf] quinoline (IQ) in human livers." Cancer Res.(1992)

    • Related Report
      1991 Annual Research Report
  • [Publications] Komori,M.: "Molecular cloning of monkey P-450IA1 cDNA and expression in yeast." Biochim.Biophys.Acta. (1992)

    • Related Report
      1991 Annual Research Report
  • [Publications] Yanagimoto,T.: "Mouse liver cytochrome P-450 (P-450IIIAM1):Its cDNA cloning and inducibility by dexamethasone." Biochim.Biophys.Acts. (1992)

    • Related Report
      1991 Annual Research Report
  • [Publications] Sato,K.: "Specific expression of glutathione S-transferase Pi forms in(pre)neoplastic tissues:their properties and functions." Tohoku J.Exp.Med.(1992)

    • Related Report
      1991 Annual Research Report
  • [Publications] Yamazoe,Y.: "Mutagens in Food:Detection and Protection.ed.by Hayatsu,H.et al." CRC Press,Boca Raton FL., 125-141 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Yamazoe,Y.: "Xenobiotics and Cancer Implications for Chemical Carcinogenesis and Cancer Chemotherapy.ed.by Ernster,L.et al." Japan Sci.Press,Tokyo.Taylor & Francis,London., 109-117 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Guengerich,F.P.: "Bioactivation of aflatoxins and sterigmatocystin by human liver cytochrome P-450 enzymes.In Pennington Center Nutrition Series Vol.1,Mycotoxins,Cancer,and Health.ed.by Bray,G.A.et al." Louisiana State University Press,Baton Rouge & London., 153-163 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Kawajiri,K.: "Individual differences in lung cancer susceptibility in relation to polymorphisms of P450IA1 gene and cigarette dose.I Xenobiotics and Cancer,ed.by Ernster,L.et al." Japanese Scientific Society Press,Tokyo.Taylor & Francis,London and Bristol., 55-61 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Sato,K.: "Glutathione transferases in normal,Preneoplastic,and neoplastic tissues:forms and functions.In Biochemical and Molecular Aspects of Selected Cancers,Vol.1.ed.by Pretlow,T.G.II.et al." Academic Press,San Diego., 177-226 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Tsuchida,S.: "Glutathione transferases and cancer.CRC Crit.Rev.Biochem.Mol.Biol." CRC Press,Boca Raton,Florida., (1992)

    • Related Report
      1991 Annual Research Report

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

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