1990 Fiscal Year Annual Research Report

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	02151006
Research Institution	Tohoku 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)
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 / 遺伝子転写調節蛋白 / アセチルトランスフェラ-ゼ / グルタチオンSトランスフェラ-ゼ / ヒト遺伝子のRFLPs
Research Abstract	1.P450、アセチルトランスフェラ-ゼ(AT)の遺伝子構造とその発現:メチルコラントレンで誘導される蟹食いサル肝IA1(ベンツピン代謝)、ハムスタ-肝IA2(芳香族アミン類代謝)、IIA3(アフラトキシン代謝)の、またラット肝培養細胞からP450IICのcDNAを分離した。サル肝IA1、ヒトとビ-グル犬肝のIA2、ヒト肝IIIA4は酵母で、ATはCOS細胞と大腸菌で発現させ、それぞれのcDNAよりの推定アミノ酸配列がそれぞれのたんぱくであることを確かめ、併せて特異的代謝活性の確認も行われた。 2.P450遺伝子の転写調節:ラット肝IA1のXRE(シス転写調節域)に結合するリセプタ-たんぱく(AhR)の部分精製が進行中である。またIA1のプロモ-タ-要素であるBTEに結合するBTEーBのcDNAを分離し、そのアミノ酸組成が転写調節因子Sp1に類似していることを確かめた。ハムスタ-IA1上流域では4ヶのXRE、1ヶのBTEの存在が確かめられた。 3.P450、グルタチオントランスフェラ-ゼ(GT)のたんぱく構造と機能:発癌剤アリルメタノ-ルを不活性化する新しいラット肝GTの分離、ヒト肝からはGTMuの新しい分子種の分離が行われた。ジニトロピレンの不活性化を変異原性テストで調べると、ラットではIA、ヒトではIII4酵素が強かった。 4.ヒトP450遺伝子の多型:白血球DNAを制限酵素で切断するとRFLPが見られ、IA1のMsp1多型、またはIIE1(ジアルキルニトロサミン代謝)のDra1の多型と肺癌発生の感受性との相関が認められた。さらにIIE1の5'上流域にも多型があることが確かめられた。特にIA1のMsp1多型は、喫煙量、扁平上皮癌発生との関連で注目されている。

Research Products

(43 results)

All Other

All Publications (43 results)

[Publications] Kikuchi,H.: "Complementary DNA sequence of 3ーmethylcholanthreneーinducible Pー450 from the rat lung." Tohoku J.Exp.Med.160. 323-332 (1990)
[Publications] Uematsu,F.: "Association between restriction fragment length polymorphism of the human cytochrome Pー450IIE1 gene and susceptibility to lung cancer." Jpn.J.Cancer Res.82(3). (1991)
[Publications] Uematsu,F.: "Two common RFLPs of the human P450IIE1 gene." Nucleic Acid Res.19. (1991)
[Publications] Yokotani,N.: "cDNA cloning of cytochrome Pー450 related to Pー450_<pー2> from the cDNA library of human placenta.Gene structure and expression." Eur.J.Biochem.187. 23-29 (1990)
[Publications] Minowa,O.: "Cytochrome Pー450 (d and SCC) in COSー7 cells from cloned cDNA." Cell Structure and Function. 15. 21-30 (1990)
[Publications] Yanagida,A.: "A novel cisーacting DNA element required for a high level of inducible expression of the rat Pー450c gene." Mol.Cell.Biol.10. 1470-1475 (1990)
[Publications] Emi,Y.: "A different cytochrome P450 form is induced in primary cultures of rat hepatocytes." Proc.Natl.Acad.Sci.U.S.A.87. 9746-9750 (1990)
[Publications] Kuroiwa,T.: "Structural requirements for interruption of protein translocation across rough endoplasmic reticulum membrane." J.Biochem.108. 829-834 (1990)
[Publications] Sato,T.: "The aminoーterminal structures that determine topological orientation of cytochrome P450 in microsomal membrane." EMBO J.9. 2391-2397 (1990)
[Publications] Ohta,K.: "Interspecies homology of cytochrome Pー450: Purification and toxicological significance of a high spin form of cytochrome Pー450(Pー450ーD2) from liver microsomes of polychlorinated biphenyl (PCB)ーtreated beagle dogs." J.Biopharm.Sci.1. 59-71 (1990)
[Publications] Komori,M.: "Fetusーspecific expression of a form of cytochrome Pー450 in human livers." Biochemistry. 29. 4430-4433 (1990)
[Publications] Kitada,M.: "Metabolic activation of aflatoxin B1 and 2ーaminoー3ーmethylーimidazo(4,5ーf)quinoline by human adult and fetal livers." Cancer Res.50. 2641-2645 (1990)
[Publications] Uchida,T.: "Isolation of cDNAs coding for three different forms of liver microsomal cytochrome Pー450 from polychlorinated biphenylーtreated beagle dogs." Mol.Pharmacol.38. 644-651 (1990)
[Publications] Ozawa,S.: "Monomorphic and polymorphic isozymes of arylamine Nーacetyltransーferase in hamster liver: purification of the isozymes and genetic basis of Nーacetylation polymorphism." Carcinogenesis. 11. 2137-2144 (1990)
[Publications] Ozawa,S.: "Decrease in the metabolic activating capacities of arylamines in livers bearing hyperplastic nodules: Association with the selective changes in hepatic Pー450 isozymes." Jpn.J.Cancer Res.81. 247-252 (1990)
[Publications] Nemoto,N.: "Aquisition of aryl hydrocarbon hydroxylase inducibility by aromatic hydrocarbons in monolayerーcultured hepatocytes from nonresponsive mouse strains." Cancer Res.50. 3226-3230 (1990)
[Publications] Imaoka,S.: "Characterization of three cytochrome P450s purified from renal microsomes of untreated male rats and comparison with human renal cytochrome P450." Arch.Biochem.Biophys.276. 473-480 (1990)
[Publications] Imaoka,S.: "Changes in the amount of cytochrome Pー450s in rat hepatic microsomes with starvation." Arch.Biochem.Biophys.278. 168-178 (1990)
[Publications] Tanaka,S.: "ωーand (ωー1)ーhydroxylation of arachidonic acid,lauric acid and prostaglandin A_1 by multiple forms of cytochrome Pー450 purified from rat hepatic microsomes." Biochim.Biophys.Acta.1043. 177-181 (1990)
[Publications] Imaoka,S.: "Purification and characterization of rat pulmonary cytochrome Pー450." J.Biochem.108. 33-36 (1990)
[Publications] Aoyama,T.: "Clofibrateーinducible rat hepatic P450s IVA1 and IVA3 catalyze the ωーand (ωー1)ーhydroxylation of fatty acids and the ωーhydroxyーlation of prostaglandins E_1 and F_<2α>." J.Lipid Res.31. 1477-1482 (1990)
[Publications] Imaoka,S.: "Induction and regulation of cytochrome Pー450 Kー5 (lauric acid hydroxylase) in rat renal microsomes by starvation." Biochim.Biophys.Acta.1036. 18-23 (1990)
[Publications] Imaoka,S.: "Lidocaine metabolism by human cytochrome Pー450s purified from hepatic microsomes: Comparison of those with rat hepatic cytochrome Pー450s." J.Pharmacol.Exp.Ther.255. 1385-1391 (1990)
[Publications] Chiba,M.: "Kinetic properties of the metabolism of imipramine and desipramine in isolated rat hepatocytes." Biochem.Pharmacol.39. 367-372 (1990)
[Publications] Chiba,M.: "Pharmacokinetic correlation between in vitro hepatic microsomal enzyme kinetics and in vivo metabolism of imipramine and desipramine in rat." J.Pharm.Sci.79. 281-287 (1990)
[Publications] Fujita,S.: "Ageーassociated alterations in diazepam metabolizing enzyme activities in male and female rats." Drug Metabol.Dispos.18. 812-814 (1990)
[Publications] Fujita,S.: "Alteration of plasma sex hormone levels associated with old age and its effect on hepatic drug metabolism in rats." J.Pharmacol.Expr.Ther.253. 369-374 (1990)
[Publications] Tsuchida,S.: "Rat spleen glutathione transferases; A new acidic form belonging to the Alpha class." Biochem.J.266. 461-465 (1990)
[Publications] Tsuchida,S.: "Purification and characterization of glutathione transferases with an activity toward nitroglycerin from human aorta and heart; Multiplicity of the human class Mu forms." J.Biol.Chem.265. 7150-7157 (1990)
[Publications] Hiratsuka,A.: "A new class of rat glutathione Sーtransferase YrsーYrs inactivating reactive sulfate esters as metabolites of carcinogenic arylmethanols." J.Biol.Chem.265. 11973-11981 (1990)
[Publications] Tamai,K.: "Specific inactivation of glutathione Sーtransferases in class Pi by SHーmodifiers." Biochem.Biophys.Res.Commun.167. 331-338 (1990)
[Publications] Murata,T.: "Activation of rat glutathione transferases in class Mu by active oxygen species." Biochem.Biophys.Res.Commun.171. 845-851 (1990)
[Publications] Satoh,K.: "Biochemical characteristics of a preneoplastic marker enzyme,glutathione Sーtransferase Pーform (7ー7)." Arch.Biochem.Biophys.(1991)
[Publications] Shen,H.: "Modulation of class Pi glutathione transferase activity by sulfhydryl group modification." Arch.Biochem.Biophys.(1991)
[Publications] Kawajiri,K.: "Identification of genetically high risk individuals to lung cancer by DNA polymorphisms of the cytochrome P450IA1 gene." FEBS Letters.263. 131-133 (1990)
[Publications] Watanabe,J.: "PstI and RsaI RFLPs in complete linkage disequilibrium at the CYP2E gene." Nucleic Acids Res.18. 7194 (1990)
[Publications] Shimada,T.: "Metabolic deactivation of furylfuramide by cytochrome Pー450 in human and rat liver microsomes." Carcinogenesis. 11. 103-110 (1990)
[Publications] Shimada,T.: "Inactivation of 1,3ー,1,6ー,and 1,8ーdinitropyrenes by cytochrome Pー450 enzymes in human and rat microsomes." Cancer Res.50. 2036-2043 (1990)
[Publications] Brian,W.R.: "Catalytic activities of human liver microsomal cytochrome Pー450 expressed in Saccharomyces cerevisiae." Biochemistry. 29. 11280-11292 (1990)
[Publications] Yamazaki,H.: "Roles of different cytochrome Pー450 enzymes in bioactivation of the potent hepatocarcinogen 3ーmethoxyー4ーaminoazobenzene." Carcinogenesis. 12. 133-139 (1991)
[Publications] Fujii,H.: "Biological Reactive Intermediates IV.ed.by Snyder,R.et al." Plenum Publ.Inc.,New York., 413-417 (1990)
[Publications] Yamazoe,Y.: "Mutagens in Food: Detection and Protection.ed.by Hayatsu,H.et al." CRC Press,Boca Raton FL., 125-141 (1991)
[Publications] Sato,K.: "Glutathione Sーtransferases and drug resistance.ed.by Hayes,J.D.et al." Taylor and Francis,London., 389-398 (1990)

1990 Fiscal Year Annual Research Report

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

Principal Investigator

渡辺 民朗 東北大学, 抗酸菌病研究所, 教授 (40006101)

Research Products

[Publications] Kikuchi,H.: "Complementary DNA sequence of 3ーmethylcholanthreneーinducible Pー450 from the rat lung." Tohoku J.Exp.Med.160. 323-332 (1990)

[Publications] Uematsu,F.: "Association between restriction fragment length polymorphism of the human cytochrome Pー450IIE1 gene and susceptibility to lung cancer." Jpn.J.Cancer Res.82(3). (1991)

[Publications] Uematsu,F.: "Two common RFLPs of the human P450IIE1 gene." Nucleic Acid Res.19. (1991)

[Publications] Yokotani,N.: "cDNA cloning of cytochrome Pー450 related to Pー450_<pー2> from the cDNA library of human placenta.Gene structure and expression." Eur.J.Biochem.187. 23-29 (1990)

[Publications] Minowa,O.: "Cytochrome Pー450 (d and SCC) in COSー7 cells from cloned cDNA." Cell Structure and Function. 15. 21-30 (1990)

[Publications] Yanagida,A.: "A novel cisーacting DNA element required for a high level of inducible expression of the rat Pー450c gene." Mol.Cell.Biol.10. 1470-1475 (1990)

[Publications] Emi,Y.: "A different cytochrome P450 form is induced in primary cultures of rat hepatocytes." Proc.Natl.Acad.Sci.U.S.A.87. 9746-9750 (1990)

[Publications] Kuroiwa,T.: "Structural requirements for interruption of protein translocation across rough endoplasmic reticulum membrane." J.Biochem.108. 829-834 (1990)

[Publications] Sato,T.: "The aminoーterminal structures that determine topological orientation of cytochrome P450 in microsomal membrane." EMBO J.9. 2391-2397 (1990)

[Publications] Ohta,K.: "Interspecies homology of cytochrome Pー450: Purification and toxicological significance of a high spin form of cytochrome Pー450(Pー450ーD2) from liver microsomes of polychlorinated biphenyl (PCB)ーtreated beagle dogs." J.Biopharm.Sci.1. 59-71 (1990)

[Publications] Komori,M.: "Fetusーspecific expression of a form of cytochrome Pー450 in human livers." Biochemistry. 29. 4430-4433 (1990)

[Publications] Kitada,M.: "Metabolic activation of aflatoxin B1 and 2ーaminoー3ーmethylーimidazo(4,5ーf)quinoline by human adult and fetal livers." Cancer Res.50. 2641-2645 (1990)

[Publications] Uchida,T.: "Isolation of cDNAs coding for three different forms of liver microsomal cytochrome Pー450 from polychlorinated biphenylーtreated beagle dogs." Mol.Pharmacol.38. 644-651 (1990)

[Publications] Ozawa,S.: "Monomorphic and polymorphic isozymes of arylamine Nーacetyltransーferase in hamster liver: purification of the isozymes and genetic basis of Nーacetylation polymorphism." Carcinogenesis. 11. 2137-2144 (1990)

[Publications] Ozawa,S.: "Decrease in the metabolic activating capacities of arylamines in livers bearing hyperplastic nodules: Association with the selective changes in hepatic Pー450 isozymes." Jpn.J.Cancer Res.81. 247-252 (1990)

[Publications] Nemoto,N.: "Aquisition of aryl hydrocarbon hydroxylase inducibility by aromatic hydrocarbons in monolayerーcultured hepatocytes from nonresponsive mouse strains." Cancer Res.50. 3226-3230 (1990)

[Publications] Imaoka,S.: "Characterization of three cytochrome P450s purified from renal microsomes of untreated male rats and comparison with human renal cytochrome P450." Arch.Biochem.Biophys.276. 473-480 (1990)

[Publications] Imaoka,S.: "Changes in the amount of cytochrome Pー450s in rat hepatic microsomes with starvation." Arch.Biochem.Biophys.278. 168-178 (1990)

[Publications] Tanaka,S.: "ωーand (ωー1)ーhydroxylation of arachidonic acid,lauric acid and prostaglandin A_1 by multiple forms of cytochrome Pー450 purified from rat hepatic microsomes." Biochim.Biophys.Acta.1043. 177-181 (1990)

[Publications] Imaoka,S.: "Purification and characterization of rat pulmonary cytochrome Pー450." J.Biochem.108. 33-36 (1990)

[Publications] Aoyama,T.: "Clofibrateーinducible rat hepatic P450s IVA1 and IVA3 catalyze the ωーand (ωー1)ーhydroxylation of fatty acids and the ωーhydroxyーlation of prostaglandins E_1 and F_<2α>." J.Lipid Res.31. 1477-1482 (1990)

[Publications] Imaoka,S.: "Induction and regulation of cytochrome Pー450 Kー5 (lauric acid hydroxylase) in rat renal microsomes by starvation." Biochim.Biophys.Acta.1036. 18-23 (1990)

[Publications] Imaoka,S.: "Lidocaine metabolism by human cytochrome Pー450s purified from hepatic microsomes: Comparison of those with rat hepatic cytochrome Pー450s." J.Pharmacol.Exp.Ther.255. 1385-1391 (1990)

[Publications] Chiba,M.: "Kinetic properties of the metabolism of imipramine and desipramine in isolated rat hepatocytes." Biochem.Pharmacol.39. 367-372 (1990)

[Publications] Chiba,M.: "Pharmacokinetic correlation between in vitro hepatic microsomal enzyme kinetics and in vivo metabolism of imipramine and desipramine in rat." J.Pharm.Sci.79. 281-287 (1990)

[Publications] Fujita,S.: "Ageーassociated alterations in diazepam metabolizing enzyme activities in male and female rats." Drug Metabol.Dispos.18. 812-814 (1990)

[Publications] Fujita,S.: "Alteration of plasma sex hormone levels associated with old age and its effect on hepatic drug metabolism in rats." J.Pharmacol.Expr.Ther.253. 369-374 (1990)

[Publications] Tsuchida,S.: "Rat spleen glutathione transferases; A new acidic form belonging to the Alpha class." Biochem.J.266. 461-465 (1990)

[Publications] Tsuchida,S.: "Purification and characterization of glutathione transferases with an activity toward nitroglycerin from human aorta and heart; Multiplicity of the human class Mu forms." J.Biol.Chem.265. 7150-7157 (1990)

[Publications] Hiratsuka,A.: "A new class of rat glutathione Sーtransferase YrsーYrs inactivating reactive sulfate esters as metabolites of carcinogenic arylmethanols." J.Biol.Chem.265. 11973-11981 (1990)

[Publications] Tamai,K.: "Specific inactivation of glutathione Sーtransferases in class Pi by SHーmodifiers." Biochem.Biophys.Res.Commun.167. 331-338 (1990)

[Publications] Murata,T.: "Activation of rat glutathione transferases in class Mu by active oxygen species." Biochem.Biophys.Res.Commun.171. 845-851 (1990)

[Publications] Satoh,K.: "Biochemical characteristics of a preneoplastic marker enzyme,glutathione Sーtransferase Pーform (7ー7)." Arch.Biochem.Biophys.(1991)

[Publications] Shen,H.: "Modulation of class Pi glutathione transferase activity by sulfhydryl group modification." Arch.Biochem.Biophys.(1991)

[Publications] Kawajiri,K.: "Identification of genetically high risk individuals to lung cancer by DNA polymorphisms of the cytochrome P450IA1 gene." FEBS Letters.263. 131-133 (1990)

[Publications] Watanabe,J.: "PstI and RsaI RFLPs in complete linkage disequilibrium at the CYP2E gene." Nucleic Acids Res.18. 7194 (1990)

[Publications] Shimada,T.: "Metabolic deactivation of furylfuramide by cytochrome Pー450 in human and rat liver microsomes." Carcinogenesis. 11. 103-110 (1990)

[Publications] Shimada,T.: "Inactivation of 1,3ー,1,6ー,and 1,8ーdinitropyrenes by cytochrome Pー450 enzymes in human and rat microsomes." Cancer Res.50. 2036-2043 (1990)

[Publications] Brian,W.R.: "Catalytic activities of human liver microsomal cytochrome Pー450 expressed in Saccharomyces cerevisiae." Biochemistry. 29. 11280-11292 (1990)

[Publications] Yamazaki,H.: "Roles of different cytochrome Pー450 enzymes in bioactivation of the potent hepatocarcinogen 3ーmethoxyー4ーaminoazobenzene." Carcinogenesis. 12. 133-139 (1991)

[Publications] Fujii,H.: "Biological Reactive Intermediates IV.ed.by Snyder,R.et al." Plenum Publ.Inc.,New York., 413-417 (1990)

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

[Publications] Sato,K.: "Glutathione Sーtransferases and drug resistance.ed.by Hayes,J.D.et al." Taylor and Francis,London., 389-398 (1990)

渡辺民朗東北大学, 抗酸菌病研究所, 教授 (40006101)