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Relation between CYP1B1 polymorphism and susceptibilities to breast and lung cancers

Research Project

Project/Area Number 11671349
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Thoracic surgery
Research InstitutionOsaka Prefectural Institute of Public Health

Principal Investigator

SHIAMDA Tsutomu  Osaka Prefectural Institute of Public Health Pharmaceutical Affairs Senior Researcher, 薬事指導部, 主任研究員 (50158961)

Co-Investigator(Kenkyū-buntansha) INOUE Kiyoshi  Osaka Prefectural Institute of Public Health Bacteriology Senior Researcher, 公衆衛生部, 主任研究員 (10250276)
ABE Tatsuo  Kyoto Prefectural University Medical School Hygine Professor, 医学部, 教授 (60079746)
Project Period (FY) 1999 – 2000
Project Status Completed (Fiscal Year 2000)
Budget Amount *help
¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 2000: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 1999: ¥2,000,000 (Direct Cost: ¥2,000,000)
KeywordsP450 / CYP1B1 / Breast cancer / Lung cancer / Estrogen / Genetic polymorphism / Carcinogens / Metabolic activation / CYP1B1乳癌
Research Abstract

Eight forms of cytochrome P450 1B1 (CYP1B1) allelic variants, namely Arg48Ala119Leu432Asn453, Arg48Ala119Val432Asn453, Gly48Ala119Leu432Asn453, Gly48Ala119Val432Asn453, Arg48Ser119Leu432Asn453, Arg48Ser119Val432Asn453, Gly48Ser119Leu432Asn453, and Gly48Ser119Val432Asn453, were expressed in Escherichia coli together with human NADPH-P450 reductase and their catalytic specificities towards oxidation of 7-ethoxyresorufin, 7-ethoxycoumarin, bufuralol, benzo[a]pyrene, and 17b-estradiol were determined. All the CYP1B1 variants expressed in bacterial membranes showed Fe2+・CO vs Fe2+ difference spectra with wavelength maxima at 446 nm and reacted with antibodies raised against recombinant human CYP1B1 in immunoblots. Kinetic analysis showed that the Vmax/Km ratio of these eight CYP1B1 variants was the highest for 7-ethoxyresorufin O-deethylation (9-16 min-1μM-1 CYP1B1), followed by 7-ethoxycoumarin O-deethylation (0.2-0.7), 17b-estradiol 4-hydroxylation (0.3-0.6), 17b-estradiol 2-hydroxylation … More (0.1-0.5), benzo[a]pyrene metabolism (to the 7, 8-dihydoxy-7, 8-dihydrodiol ; 0.1-0.4, in the presence of epoxide hydrolase), and (±) bufuralol 1'- and 6-hydroxylations (0.001-0.01). Interestingly, the Vmax/Kmratio for 7-ethoxyresorufin O-deethylation by the eight CYP1B1 variants was rather constant, yet both Vmax and Km values were different among the eight forms. In contrast, Vmax values for 7-ethoxycoumarin O-deethylation were not very different in these CYP1B1 variants but Km values were, leading to large variations in Vmax/Km ratio. These results suggest that alterations in CYP1B1 structures have different effects on catalytic capacities depending on the substrates examined. The Vmax/Km ratio for 17b-estradiol 4-hydroxylation was found to be the highest with the Gly48Ser119Val432Asn453 variant. The ratio of Vmax/Km of 4-hydroxylation vs 2-hydroxylation of 17b-estradiol was higher in the Val432 compared to the Leu432 CYP1B1 variants. In contrast, Leu432-forms of CYP1B1 showed higher rates of oxidation of benzo[a]pyrene to the 7, 8-dihydoxy-7, 8-dihydrodiol metabolite than did the Val432-froms. These results collectively indicate that polymorphic human CYP1B1 variants show altered catalytic specificities towards the substrates used and suggest that these polymorphisms may influence susceptibilities of individuals towards endogenous and exogenous carcinogens such as 17b-estradiol and benzo[a]pyrene. Polymorphisms of the genes whose products known to contribute to lung cancer development in cigarette smokers were analysed in lung cancer and control sample groups. These sample groups included thirty-six lung cancer patients who underwent thoracic surgery at the Princess Alexandra hospital in Brisbane, Queensland in 1996-1998 and thirty-five non-cancer cases drawn from the sample of Queensland residents who had died of accidental causes in 1997-1998. The two groups were not different in terms of frequencies of allelic variants of the AhR, GSTT1, GSTM1 and CYP1A1 genes. However, a statistically significant higher frequency of CYP1B1 m1 mutant allele was found in the lung cancer sample group (17%) compared to the control sample group (3%). This may suggest increased lung cancer risk in people who have homozygous m1 mutant allele of the CYP1B1 gene. Less

Report

(3 results)
  • 2000 Annual Research Report   Final Research Report Summary
  • 1999 Annual Research Report
  • Research Products

    (34 results)

All Other

All Publications (34 results)

  • [Publications] Watanabe,J.,Shimada,T., et al.: "Association of CYP1B1 genetic polymorphism with incidence to breast and lung cancer"Pharmacogenetics. 10. 25-33 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Inoue,K.,Shimada,T. et al.: "CYP2A6 genetic polymorphisms and liver microsomal coumarin and nicotine oxidation activities in Japanese and Caucasians"Arch.Toxicol.. 73. 532-539 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Inoue,K.,Shimada,T. et al.: "Ethnic-related differences in frequency distribution of genetic polymorphisms in CYP1A1 and CYP1B1 genes in Japanese and Caucasian populations"Xenobiotica. 30. 285-295 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Inoue,K.,Shimada,T. et al.: "Characterization of liver microsomal 7-ethoxycoumarin O-deethylation and chlorzoxazone 6-hydroxylation activities in Japanese and Caucasian subjects genotyped for CYP2E1 gene"Arch.Toxicol. 74. 372-378 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Shimada,T., et al.: "Role of NADPH-P450 reductase in the O-deethlation of 7-ethoxycoumarin by recombinant human cytochrome P450 1B1 variants in Escherichia coli."Protein Expression. Purification. 20. 73-80 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Shimada,T., et al.: "Catalytic specificity of 17β -estradiol and benzo[a]pyrene oxidations by polymorphic human cytochrome P450 1B1 variants substituted at residues 48, 119, and 432"Xenobiotica.

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Oda, Y., Yamazaki, H., and Shimada, T.: "Role of human N-acetyltransferases, NAT1 or NAT2, in genotoxicity of nitroarenes and aromatic amines in Salmonella typhimurium NM6001 and NM6002."Carcinogenesis.. 20. 1079-1083 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Aryal, P., Yoshikawa, K., Terashita, T., Guengerich., F.P., Shimada, T., and Oda, Y.: "Development of a new genotoxicity test with Salmonella typhimurium OY1001/1A2 expressing human CYP1A2 and NADPH-P450 reductase."Mutat.Res.. 442. 113-120 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Shimada, T., Gillam, E.M.J., Oda, Y., Tsumura, F.Sutter, T.R., Guengerich, F.P., and Inoue, K.: "Metabolism of benzo[a]pyrene to trans-7, 8-dihydroxy-7, 8-dihydrobenzo[a]pyrene by recombinant human cytochrome P450 1B1 and purified liver epoxide hydrolase."Chem.Res.Toxicol.. 12. 623-629 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Shimada, T., Watanabe, J., Kawajiri, K., Sutter, T.R., Guengerich, F.P., Gillam, E.M.J., and Inoue, K.: "Catalytic properties of polymorphic human cytochrome P450 1B1 variants."Carcinogenesis.. 20. 1607-1613 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Yokose, T., Doy, M., Taniguchi, T., Shimada, T., Kakiki, M., Horie, T., Matsuzaki, Y., and Mukai, K.: "Immunohistochemical study of cytochrome P450 2C and 3A in human non-neoplastic and neoplastic tissues."Virchws Arch.. 434. 401-411 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Yamazaki, H., Tanaka, M., Shimada, T.: "Highly sensitive high-performance liquid chromatographic assay for coumarin 7-hydroxylation and 7-ethoxycoumarin O-deethylation by human liver cytochrome P450 enzymes."J.Chromatogr.B.. 721. 13-19 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Shimada, T.: "Human cytochrome P450 1B1 and chemical carcinogenesis."Rev.Toxicol.. 3. 139-166 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Watanabe, J., Shimada, T., Gillam, E.M.J., Ikuta, T., Suemasu, K., Highshi, Y., Gotoh, O., and Kawajiri, K.: "Association of CYP1B1 genetic polymorphism with incidence to breast and lung cancer"Pharmcogenetics.. 10. 25-33 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Inoue, K., Yamazaki, H., and Shimada, T.: "CYP2A6 genetic polymorphisms and liver microsomal cumarin and nicotine oxidation activities in Japanese and Caucasians."Arch.Toxicol.. 73. 532-539 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Inoue, K., Asao, T.and Shimada, T.: "Ethnic-related differences in frequency distribution of genetic polymorphisms in CYP1A1 and CYP1B1 genes in Japanese and Caucasian populations."Xenobiotica.. 30. 285-295 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Aryal, P., Terashita, T., Guengerich., F.P., Shimada, T., and Oda, Y.: "Use of genetically engineered Salmonella typhimurium OY1002/1A2 strain coexpressing human cytochrome P450 1A2 and NADPH-cytochrome P450 reductase and bacterial O-acetyltransferase in SOS/umu assay."Environm.Mol.Mutagenesis.. 36. 121-126 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Inoue, K., Yamazaki, H., and Shimada, T.: "Characterization of liver microsomal 7-ethoxycoumarin O-deethylation and chlorzoxazone 6-hydroxylation activities in Japanese and Caucasian subjects genotyped for CYP2E1 gene."Arch.Toxicol.. 74. 372-378 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Shimada, T., Tsumura, F., Gillam, E.M.J.Guengerich, F.P., and Inoue, K.: "Role of NADPH-P450 reductase in the O-deethlation of 7-ethoxycoumarin by recombinant human cytochrome P450 1B1 variants in Escherichia cole."Protein Expression., Purification.. 20. 73-80 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Shimada, T., Tsumura, F., Yamazaki, H., Guengerich, F.P., and Inoue, K.: "Characterization of (±)-bufuralol hydroxylation activities in liver microsomes of Japanese and Caucasian subjects genotyped for CYP2D6."Pharmacogenetics.. (in press). (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Oda, Y., Aryal, P., Terashita, T., Gillam, E.M.J.Guengerich, F.P.and Shimada, T.: "Metabolic activation of heterocyclic amines and other procarcinogens in Salmonella typhimurium umutester strains expressing human cytochrome P4501A1, 1A2, 1B1, 2C9, 2D6, 2E1, and 3A4 and human NADPH-P450 reductase and bacterial O-acetyltransferase."Mutat.Res.. (in press). (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Tsutomu Shimada, Junko Watanabe, F.Peter Guengerich, Kiyoshi Inoue, and Elizabeth M.J.: "Gillam Specificity of 17β-estradiol and benzo[a]pyrene oxidations by polymorphic human cytochrome P450 1B1 variants substituted at residues 48, 119, and 432."Xenobiotica.. (in press). (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Watanabe,J.,Shimada,T., et al.: "Association of CYP1B1 genetic polymorphism with incidence to breast and lung cancer"Pharmacogenetics. 10. 25-33 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Inoue,K.,Shimada,T. et al.: "CYP2A6 genetic polymorphisms and liver microsomal coumarin and nicotine oxidation activities in Japanese and Caucasians"Arch. Toxicol.. 73. 532-539 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Inoue,K.,Shimada,T. et al.: "Ethnic-related differences in frequency distribution of genetic polymorphisms in CYP1A1 and CYP1B1 genes in Japanese and Caucasian populations"Xenobiotica. 30. 285-295 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Inoue,K.,Shimada,T. et al.: "Characterization of liver microsomal 7-ethoxycoumarin O-deethylation and chlorzoxazone 6-hydroxylation activities in Japanese and Caucasian subjects genotyped for CYP2E1 gene"Arch.Toxicol. 74. 372-378 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Shimada,T., et al.: "Role of NADPH-P450 reductase in the 0-deethlation of 7-ethoxycoumarin by recombinant human cytochrome P450 1B1 variants in Escherichia coli."Protein Expression.Purification. 20. 73-80 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Shimada,T., et al.: "Catalytic specificity of 17β-estradiol and benzo[α]pyrene oxidations by polymorphic human cytochrome P450 1B1 variants substituted at residues 48,119,and 432"Xenobiotica.

    • Related Report
      2000 Annual Research Report
  • [Publications] Shimada, T., et al.: "Recombinant human cytochrome P450 1B1 expression in Escherichia coli"Arch. Biochem. Biophys.. 357. 111-120 (1998)

    • Related Report
      1999 Annual Research Report
  • [Publications] Shimada, T., et al.: "Selectivity of polycyclic inhibitors for human cytochromes P450 1A1, 1A2, and 1B1"Chem. Res. Toxicol.. 11. 1048-1056 (1998)

    • Related Report
      1999 Annual Research Report
  • [Publications] 島田力、鎌滝哲也: "薬物・毒物・癌原物質の代謝に関与するヒトのチトクロームP450"化学と生物. 36. 659-663 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] 島田力: "ヒトのP450遺伝子の多型と化学物質の生体影響"中毒研究. 12. 377-382 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Shimada, T., et al.: "Metabolism of benzo[a]pyrene to trans-7, 8-dihydroxy-7, 8-dihydrobenzo[a]pyrene by recombinant human cytochrome P450 1B1 and purified liver epoxide hydrolase"Chem. Res. Toxicol.. 12. 623-629 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Shimada, T., et al.: "Catalytic properties of polymorphic human cytochrome P450 1B1 variants"Carcinogenesis. 20. 1607-1613 (1999)

    • Related Report
      1999 Annual Research Report

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Published: 1999-04-01   Modified: 2016-04-21  

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