"Man-Earth System : A scientific approach to realize human society in harmony with the Earth"-Genetic Determinants Affecting Sensitivity to Environmental Factors-

• Project/Area Number: 05278118
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Research Institution: Kitasato University
• Principal Investigator: IMURA Nobumasa Kitasato University, Faculty of Pharmaceutical Sciences, Professor, 薬学部, 教授 (70012606)
• Co-Investigator(Kenkyū-buntansha): ICHIHASHI Masamitsu Kobe University, Faculty of Medicine, Professor, 医学部, 教授 (00030867) ; UTSUMI Hideo Kyushu University, Faculty of Pharmaceutical Sciences, Professor, 薬学部, 教授 (20101694) ; KAMATAKI Tetsuya Hokkaido University, Faculty of Pharmaceutical Sciences, Professor, 薬学部, 教授 (00009177) ; KUDO Ichiro Showa University, Faculty of Pharmaceutical Sciences, Professor, 薬学部, 教授 (30134612) ; 巽 純子 京都大学, 医学部, 助手 (80128222) ; 西村 泰治 熊本大学, 大学院・医学系研究科, 教授 (10156119) ; 八木 孝司 京都大学, 医学部, 助教授 (80182301)
• Project Period (FY): 1993 – 1997
• Project Status: Completed (Fiscal Year 1997)
• Budget Amount: ¥88,000,000 (Direct Cost: ¥88,000,000); Fiscal Year 1997: ¥19,000,000 (Direct Cost: ¥19,000,000); Fiscal Year 1996: ¥20,000,000 (Direct Cost: ¥20,000,000); Fiscal Year 1995: ¥15,000,000 (Direct Cost: ¥15,000,000); Fiscal Year 1994: ¥18,000,000 (Direct Cost: ¥18,000,000); Fiscal Year 1993: ¥16,000,000 (Direct Cost: ¥16,000,000)
• Keywords: Toxicity of Heavy metals / Species Difference / Drug Metabolism / Genetic Polymorphism / Ultraviolet Radiation B / Skin Cancer Risk Factor / Oxidative Stress / Antioxidative Enzymes / 大腸癌形成 / ホスホリパーゼA_2 / 活性酸素消去因子 / 重金属 / ダニアレルギー / HLAクラスII分子 / 電磁場 / 突然変異頻度 / 水銀化合物の腎毒性 / γ-グルタミルトランスペプチダーゼ / 抗原ペプチド / 極低周波電磁場 / DNA鎖修復 / 活性酸素 / 化学物質の毒性発現 / 免疫応答 / HLA分子 / 紫外線 / 色素性乾皮症

Research Abstract

The objectives of this research are to identify genetic determinants affecting the sensitivity of individuals to environmental factors and to study the implication of polymorphisms in determination of the sensitivity by utilizing gene technology and biochemical techniques. The following genetic factors were identified as modifying factors for environmental hazards, and biochemical mechanisms for the polymorphism were investigated. The intestinal handling of Cd by metallothionein for Cd accumulation in the kidney, a new type of mutation in cytpchrome P450 2D6 (CYP2D6) gene for the metabolic activation of procarcinogen in cigarette smoke, antioxidative enzymes for the toxicity of 2, 4, 6-trichlorophenol (TCP), outdoors work, skin type I, seborrheic keratosis, and severe sunburn in childhood for the risk of normelanoma skin cancers, and phospholipase A2 depletion for the risk of colon cancer.

Research Products

• [Publications] 「人間地球系」総括班: "平成9年度研究成果報告"「人間地球系」研究広報. 113-113 (1998)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Man-Earth Project Member: "1997 Research Results Report"113 (1998)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] T.Urano et al.: "Inhibitory effect of selenium on biliary secretion of methyl mercury in rats" Biochem.Biophys.Res. Commun.239. 862-867 (1997)
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• [Publications] T.Tanaka-Kagawa et al.: "Strain difference in sensitivity of mice to renal toxicity of inorganic mercury" J.Pharmacol.Exp.Therap.(in press). (1998)
• [Publications] T.Yokoi et al.: "A new deleted allele in human cytochrome P4502A6(CYP2A6)gene found in human liver subjects showing poor metabolic capacity to coumarin and(+)+cis-3,5-dimethyl-2-(3-pyridyl)-thiazolidin-4-one hydrochloride(SM-12502)" Pharmacogenetics. (in press). (1997)
• [Publications] K.Nakamura et al.: "Oxidation of histamine H1 antagonist mequitazine is catalysed by cytochrom P450 2D6 in human liver microsomes" J.Pharmacol.Exp.Therap.284. 437-442
• [Publications] T.Iwatsubo et al.: "Prediction of in vivo hepatic metabolic clearance of YM796 from in vitro data using human liver microsomes and recombinant P-450 isozymes" J.Pharmacol.Exp.Therap.282. 909-919 (1997)
• [Publications] Y.Li et al.: "In vivo activation of aflatoxin B1 in C57BL/6N mice carrying a human fet us-specific CYP3A7 gene" Cancer Res.57. 641-645 (1997)
• [Publications] S-、K.Han et al.: "Generation of p-semiquinone radicals from chlorophenols in water during ozonation" Water Res.(in press). (1998)
• [Publications] H.Utsumi et al.: "Non-invasive measurement of free radical reaction in disease using in vivo ESR-CT technique" Physics Med.Biol.43(in press). (1998)
• [Publications] H.Sano et al: "Synthesis and imaging of blood-brain-barrier permeable nitroxyl-probes forfree radical reactions in brain of living mice" Biochem.Mol.Biol.Int.42. 641-647 (1997)
• [Publications] T.Suzuki et al.: "Incidence of actinic keratosis of Japanese in Kasai City,Hyogo" J.Dermatol.Sci.(in press).
• [Publications] K.Naruse et al.: "Prevalence of actinic Keratosis in Japan" J.Dermatol.Sci.15. 183-187 (1997)
• [Publications] N.U.Ahmed et al.: "Increased level of c-erbB-2/new/HER-2 protein in cutaneous squamous cell carcinoma" Br.J.Dermatol.136. 908-912 (1997)
• [Publications] T.Suzuki et al.: "Doses of solar ultraviolet radiation correlate with skin cancer rates in Japan" Kobe J.Med.Sci.42. 375-388 (1996)
• [Publications] H.Kuwata et al.: "Cytosolic phospholipase A_2 is required for cytokine-induced expression of type IIA phospholipase A_2 that mediates optimal cyclooxygenase-2-dependent delayed prostaglandin E_2 generation in rat 3Y1 fibroblasts" J.Biol.Chem.(in press).
• [Publications] M.Murakami et al.: "Prostaglandin E_2 amplifies cytosolic phospholipase A_2 and cyclooxygenase-2-dependent delayed prostaglandin E_2 generation in mouse osteoblast cells:Enhancement by secretory phospholipase A_2" J.Biol.Chem.272. 19891-19897 (1997)
• [Publications] Q.-R.Chen et al.: "Activation of cytosolic phospholipase A_2 by platelet-derived growth factor is essential for cyclooxygenase-2-dependent prostaglandin E_2 synthesis in mouse osteoblasts cultured with interleukin-" J.Biol.Chem.272. 5952-5958 (1997)
• [Publications] H.Matsumoto et al.: "Concordant induction of prostaglandin E_2 synthase with cyclooxygenase-2 leads to preferred production of prostaglandin E_2 to thromoboxane and prostaglandin D2 in lipopolysaccharide-stimulated rat" Biochem.Biophys.Res.Commun.230. 110-114 (1997)
• [Publications] 井村伸正 他: "環境と健康II" 池永満生 他編集 へるす出版, 310 (1998)
• [Publications] Nakagawa I.et al.: "Effect of glutathione depletion on metallothionein synthesis induced by paraquat in mice" Tohoku J.Exp.Med.177. 249-262 (1995)
• [Publications] Kamataki T.et al.: "Characterization of CYP2A6 involved in 3'-hydroxylation of cotinine in human liver microsomes" J.Pharmacol.Exptl.Therap.277. 1010-1015 (1996)
• [Publications] Kamataki,T.et al.: "A new CYP2D6 allele with a nine base insertion in exon 9 in a Japanese population associated with poor metabolizer phenotype" Pharmacogenetics. 6. 395-401 (1996)
• [Publications] Utsumi H.et al.: "In vivo ESR measurements of free radical reactions in living mice" Toxicol.Lett.82/83. 561-565 (1996)
• [Publications] Han J-Y.et al.: "In vivo measurement of radical reaction induced by diesel exhaust particle in lung" Proc.Free Radical Res.321- (1996)
• [Publications] Oka M.et al.: "Enhanced expression of protein kinase C subspecies in melanogenic compartments in B16 melanoma cells by UVB or MSH" J.Invest.Deramtol.106. 377-378 (1996)
• [Publications] Ueda M.et al.: "The expression of retinoblastoma protein in epidermis is induced by ultraviolet B exposure" Br.J.Dermatol. 135. 406-411 (1996)
• [Publications] Ashraf MD.M.et al.: "Type II phospholipase A_2 is linked to cyclooxygenase-2-mediated delayed prostaglandin D_2 generation by cultured mouse mast cells following FcεPI-and cytokine-dependent activation" Biochem.Biophys.Res.Commun.229. 726-732 (1996)
• [Publications] Murakami M.et al.: "Type II secretory phospholipase A_2 associated with cell surfaces via C-terminal heparin-binding lysine residues augments stimulus-initiated delayed prostaglandin generation" J.Biol.Chem.271. 30041-30051 (1996)
• [Publications] Kitahara J.et al.: "Genetic Response to Metals" DNA strand breakage and lipid peroxidation as possible mechanisms of selenium toxicity, (1995)
• [Publications] Nakagawa I.et al.,: "Effect of glutathione depletion on metallothionein synthesis induced by paraquat in mice" Tohoku J.Ext.Med.(in press).
• [Publications] Seko Y.et al.,: "Applications of HeLa cells with high catalase activity in toxicological investigations" Jpn.J.Toxicol.Health.41. 18- (1995)
• [Publications] Miura K.et al.,: "Important role of glutathione in susceptibility of mammalian cells to methylmercury" In vitro Toxicol.,. 7. 59-64 (1994)
• [Publications] Sakuma T.et al.,: "Isolation and characterization of a new cDNA clone belonging to the cytochrome P450 2C gene subfamily in hamsters" Arch.Biochem.Biophys.319. 267-273 (1995)
• [Publications] Hashimoto H.et al.,: "Fetus-specific CYP3A7 and adult-specific CYP3A7 expressed in Chinese hamster CHL cells have similar capacity to activate carcinogenic mycotoxins" Cancer Res.55. 787-791 (1995)
• [Publications] Murakami S.et al.,: "Binding of Ras-or p53-derived peptides to HLA-DR molecules:possible candidates of targets for tumor specific T lymphocytes" Immunol.Lett.(in press).
• [Publications] Ikagawa S.et al.,: "Single amino acid substitutions on a Japanese cedar pollen(Cry j 1)-derived peptide induced alterations in human T cell responses and T cell receptor antagonism" J.Allergy Clin.Immuno.(in press).
• [Publications] Miyakoshi J.et al.,: "A newly designed experimental system for exposure of mammalian cells to extremely low frequency magnetic fields" J.Radiation Res.35. 26-34 (1994)
• [Publications] Kuepper J.-H.et al.,: "trans-Dominant inhibition of poly(ADP-rebosyl)ation sensitizes cells against δ-irradiation and N-methyl-N'-nitro-N-nitrosoguanidine but does not limit DNA replication of a polyomavirus replicon" Molec.Cell Biol.15. 3154-3163 (1995)
• [Publications] Kitahara J.et al.,: "Genetic Response to Metals(DNA strand breakage and lipid peroxidation as possible mechanisms of selenium toxicity)" 512 (1995)
• [Publications] Nishimura Y.et al.,: "New research trends in immunological diseases(HLA-DR binding peptides triggering autoimmunity and altered T cell responses)" in press),
• [Publications] Miura.K.,Imura,N.,et al.: "Establishment and characterization of methylmercury-resistant PC12 cell line." Environ.Health Perspect.102. 313-315 (1994)
• [Publications] 鈴木美恵子,香川(田中)聡子,永沼章,井村伸正,山中宣昭.: "マウスにおける無機水銀腎毒性の系統差とメタロチオネイン及びグルタチオン濃度との関係" 生化学. 66. 753 (1994)
• [Publications] Nakajima,M.,Kamataki,T.,et al.: "Phenotyping of CYP1A2 in Japanese population by analysis of caffeine urinary metabolites;absence of mutation prescribing the phenotype in the CYP1A2 gene." Cancer Epidem.Biomark.Prevent.3. 413-421 (1994)
• [Publications] Yanakawa,Y.,Kamataki,T.,et al.: "Stable expression of human CYP1A2 and N-acetyltransferase:Mutagenic activation of 2-amino-3-methylimidazo [4,5-f]-quinoline(IQ)and 2-amino-3,4-dimethylimidazo[4,5-f]quinozaline(melQX)." Cancer Res.54. 3422-3427 (1994)
• [Publications] Nishimura,Y.,et al.: "Allele specificity of structural requirement for peptides bound to HLA-DRB1^*0405 complexes:Implication for the HLA-linked susceptibility to methimazole-induced insulin autoimmune syndrome." J.Exp.Med.180. 873-883 (1994)
• [Publications] Miyakoshi,J.,Ohtsu,S.Tatsumi-Miyajima,J.,Takebe,H.: "A newly designed experimental system for exposure of mammalian cells to extremely low frequency magnetic fields." J.Radiat.Res.35. 26-34 (1994)
• [Publications] Miura,K.,Naganuma,A.,Himeno,S.,Imura,N.: "Mercury Toxicity.In Toxicology of Metals" Ed.by Goyer,R.A.and Cherian,M.G.,Springer-Verlag, 467 (1995)
• [Publications] N.Imura: "Tissue-specific expression of glutathione peroxidase gene in guinea pigs." Biochim.Biophys.Acta. 1173. 283-288 (1993)
• [Publications] N.Imura: "Possible involvement of active oxygen species in selenite toxicity in isolated rat hepatocytes." Arch.Toxicol.67. 497-501 (1993)
• [Publications] T.Kamataki: "Oxidative metabolism of omeprazole in human liver microsomes:Cosegregation with S-mephenytoin 4′-hydroxylation." J.Pharmacol.Exp.Ther.266. 52-59 (1993)
• [Publications] Y.Nishimura: "Difference in HLA-linked genetic background between mixed connective tissue disease and systemic lupus erythematosus." Tissue Antigens. 41. 20-25 (1993)
• [Publications] T.Yagi: "Ultraviolet-specific mutations inp53 gene in skin tumors in xeroderma pigmentosum patients." Cancer Res.53. 2944-2946 (1993)
• [Publications] T.Yagi: "A case of xeroderma pigmentosum complementation group F with neurological abnormalities." British J.Dermatology. 1280. 91-94 (1993)