• Search Research Projects
  • Search Researchers
  • How to Use
  1. Back to project page

1998 Fiscal Year Final Research Report Summary

APPLICATION OF TRANSGENIC MICE TO THE TOXICOLOGICAL TESTING

Research Project

Project/Area Number 09557208
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section展開研究
Research Field 応用薬理学・医療系薬学
Research InstitutionHOKKAIDO UNIVERSITY

Principal Investigator

NAKAYAMA Kazuo  Fac.of Pharm.Sci., Hokkaido Univ., Instructor, 大学院・薬学研究科, 助手 (20261323)

Co-Investigator(Kenkyū-buntansha) FUJITA Ken-ichi  Fac.of Pharm.Sci., Hokkaido Univ., Instructor, 大学院・薬学研究科, 助手 (60281820)
KAMATAKI Tetsuya  Fac.of Pharm.Sci., Hokkaido Univ., Prof., 大学院・薬学研究科, 教授 (00009177)
Project Period (FY) 1997 – 1998
KeywordsMutagenicity testing / HITEC mouse / Cytochrome P450 / CYP3A7 / Fetus-specific / Metabolic activation / Aflatoxin B1 / DNA damage
Research Abstract

We have six lines of transgenic mice carrying human CYP3A7 cDNA.In M10 mouse, CYP3A7 is expressed in the small intestine but not in the kidney, while M2 mouse expresses CYP3A7 in the kidney. HITEC mouse is a transgenic mouse developed to detect mutagenic potency of various chemicals in vivo. The CYP3A7/HITEC mice were established by crossmating of these two strains of mice. When a 9,000 x g supernatant fraction prepared from the small intestine of M10/HITEC mouse was added to an incubation mixture for Ames test with Salmonella typhimurium TA98 strain to examine the mutagen-producing activity from aflatoxin B_1 (AEB_1) , the mutagen-producing activities of the 9,000 x g supernatant fraction from the small intestine was found to be 1.7-fold higher in the M10/HITEC mice than that seen with HITEC mice. Such a difference in the capacity to activate AFB1 was not seen with the 9,000 x g supernatant fraction from the kidney from M10/HITEC mice and HITEC mice. Male CYP3A7/HITEC mice of 8 weeks old were treated with a single i. p. injection of AFB1 (8 mg/kg body weight). The mutation of the introduced rpsL gene in the genomic DNA from the small intestine and the kidney was analyzed. The mutation frequency in the small intestine of M10/HITEC mice was significantly higher (p<0.05) than that of HITEC mice, while the mutation frequency in both strains was similar in the kidney. On the other hand, the mutation frequency of the rpsL gene from the kidney of M2/HITEC mice tended to be higher than that of HITEC mice. These results provide the first evidence that human CYP3A7 metabolically activate AFB1 in vivo.
In conclusion, the CYP3A7/HITEC mice is a useful model to detect mutations in vivo induced by chemicals through the metabolic activations.

  • Research Products

    (54 results)

All Other

All Publications (54 results)

  • [Publications] Y. Takahashi et al.: "Inhibition of transcription of CYP1A1 gene by the upstream stimulatory factor 1 (USF1)" J.Biol.Chem.272. 30025-30031 (1997)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] E.M.J.Gillam et al.: "Expression of cytochrome P450 3A7 in Escherichia coli : Effects of 5′modification and catalytic characterization of recombinant enzyme expressed in bicistronic format with NADPH-cytochrome P450 reductase." Arch.Biochem.Biophys.346. 81-90 (1997)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] T. Mori et al.: "Regulation of CYP1A and CYP3A mRNAs by ascorbic acid in guinea pigs." Arch.Biochem.Biophys.348. 268-277 (1997)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Y. Takahashi et al.: "Upstream stimulatory factor 1 (USF1) suppresses induction of CYP1A1 mRNA by 3-methylcholanthrene (MC) in HepG2 cells." Biochem.Biophys.Res.Commun.240. 293-297 (1997)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] T. Tateishi et al.: "A comparison of hepatic cytochrome P450 protein expression between infancy and post infancy." Life Sci.61. 2567-2574 (1997)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] T.Mori et al.: "Molecular cloning and regulation of a novel guinea pig cytochrome P450 (CYP3A20) which differs from guinea pig CYP3A14 in only two amino acid residues." Biochem.Mol.Biol.Intern.44. 1245-1253 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] A. Suzuki et al.: "Establishment of a salmonella tester strain highly sensitive to mutagenic heterocyclic amines." Cancer Res.58. 1833-1838 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] K. Nakamura et al.: "Oxidation of Histamine H1 antagonist mequitazine is catalyzed by cytochrome P450 2D6 in human liver microsomes." J.Pharmacol.Exp.Ther.284. 437-442 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] H. Iwata et al.: "High catalytic activity of human cytochrome P450 co-expressed with human NADPH-cytochrome P450 reductase in Escherichia coli." Biochem.Pharmacol.55. 122-127 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] A. Yamada et al.: "In vivo detection of mutation induced by aflatoxin B1 using human CYP3A7/HITEC hybrid mice." Biochem.Biophys.Res.Commun.250. 150-153 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Y. Ando et al.: "The UGT1A1_*28 allele is relatively rare in a Japanese population." Pharmacogenetics. 8. 357-360 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] K. Nunoya 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) thiazoldin-4-one hydrochloride (SM-12502)." Pharmacogenetics. 8. 239-249 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] T. Tasaki et al.: "Expression and characterization of dog CYP2D15 using baculovirus expression system." J.Biochem.123. 162-168 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] K. Takasuna et al.: "Inhibition of intestinal microflora β-glucuronidase modifies the distribution of the active metabolite of the antitumor agent, irinotecan hydrochloride (CPT-11) in rats." Cancer Chemother.Pharmacol.42. 280-286 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Y. Ando et al.: "Potent and non-specific inhibition of cytochrome P450 by JM216, a new oral platinum agent." Brit.J.Cancer. 78. 1170-1174 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Y. Takahashi et al.: "Silencing of CYP1A1 expression in rabbits by DNA methylation." Biochem.Biophys.Res.Commun.247. 383-386 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] H. Tani et al.: "Separation of microsomal cytochrome b5 via phase separation in a mixed solution of Triton X-114 and charged dextran." J.Chromatogr.B Biomed.Sci.Appl.708. 294-298 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] T. Sakuma et al.: "Molecular cloning and functional analysis of cynomolgous monkey CYP1A2." Biochem.Pharmacol.56. 131-139 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Y. Ando et al.: "UGT1A1 genotypes and glucuronidation of SN-38, the active metabolite of irinotecan." Ann.Oncol.9. 845-847 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] K. Nunoya et al.: "CYP2A6 gene deletion responsible for the in vivo polymorphic metabolism of (+)-cis-3, 5-dimethyl-2-(3-pyridyl) thiazolidin-4-one hydrochloride (SM-12502) in humans." J.Pharmacol.Exp.Ther.in press. (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] S. Muto et al.: "Inhibition of benzo [a] pyrene-induced mutagenesis by (-)-epigallocatechin gallate in the lung of rpsL transgenic mice." Carinogenesis. in press. (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] M. Nakajima et al.: "Genetic polymorphism in the 5′-flanking region of human CYP1A2 gene : effect on the CYP1A2 inducibility in humans." J.Biochem.in press. (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] M. Chida et al.: "A new variant CYP2D6 allele (CYP2D6/C8) with a single insertion in exon 5 in a Japanese population associated with a poor metabolizer phenotype" Pharmacogenetics. in press. (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] M. Chida et al.: "Genetic polymorphism of CYP2D6 in Japanese population." Pharmacogenetics. in press. (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] T. Kamataki et al.: "Establishment of cell lines carrying human genes : applications in pharmacology and toxicity testing. ″Animal alternatives, welfare and ethics″" Tokyo Elsevier, 809-812 (1997)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 鎌滝 哲也 他: "肝臓での代謝レベルでの相互作用 ″抗癌剤の相互作用″" 医薬ジャーナル社, 41-52 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 鎌滝 哲也 他: "環境要因感受性を支配する遺伝的要因 ″環境と健康″" へるす出版, 245-259 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 鎌滝 哲也 他: "P450と多型″呼吸器疾患の分子生物学″" 医学書院, 268-274 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Elizabeth M.J.Gillam, Rebecca M.Wunsch, Yune-Fang Ueng, Tsutomu Shimada, Paul E.B.Reilly, Tetsuya Kamataki and F.Peter Guengerich: "Expression of cytochrome P450 3A7 in Escherichia coli : Effects of 5' modification and catalytic characterization of recombinant enzyme expressed in bicistronic format with NADPH-cytochrome P450 reductase" Arch.Biochem.Biophys.346. 81-90 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Yoshiki Takahashi, Kazuo Nakayama, Susumu Itoh, Yoshiaki Fujii-Kuriyama and Tetsuya Kamataki: "Inhibition of the transcription of CYP1A1 gene by the upstream stimulatory factor 1 in rabbits" J.Biol.Chem.272. 30025-30031 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Toshiyuki Mori, Susumu Itoh, Satoru Ohgiya, Kozo Ishizaki and Tetsuya kamataki: "Regulation of CYP1A and CYP3A mRNAs by ascorbic acid in guinea pigs" Arch.Biochem.Biophys.348. 268-277 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Yoshio Kase, Terumasa Hayakawa, Yuji Togashi and Tetsuya Kamataki: "Relevance of irinotecan hydrochloride-induced diarrhea to the level of prostaglandin E_2 and water absorption of large intestine in rats" Jpn.J.Pharmacol.75. 399-405 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Yoshio Kase, Terumasa Hayakawa, Masaki Aburada, Yasuhiro Komatsu and Tetsuya Kamataki: "Preventive effects of Hange-shashin-to on irinotecan hydrochloride-caused diarrhea and its relevant to the colonic prostaglandin E_2 and water absorption in the rat" Jpn.J.Pharmacol.75. 407-413 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Yoshiki Takahashi, Kazuo Nakayama, Susumu Itoh and Tetsuya Kamataki: "Upstream stimulatory factor 1 (USF1) suppresses induction of CYP1A1 mRNA by 3-methylcholanthrene (MC) in HepG2 cells" Biochem.Biophys.Res.Commun.240. 293-297 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Tomonori Tateishi, Hironori Nakura, Masao Asoh, Minoru Watanabe, Masami Tanaka, Toshio Kumai, Sachio Takashima, Susumu Imaoka, Yoshihiko Funae, Yoshiyasu Yabusaki, Tetsuya Kamataki and Shin-ichi Kobayashi: "A comparison of hepatic cytochrome P450 protein expression between infancy and post infancy" Life Sci.61. 2567-2574 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Katsunori Nakamura, Tsuyoshi Yokoi, Takao Kodama, Kazuaki Inoue, Kazuo Nagashima, Noriaki Shimada, Toshiaki Shimizu and Tetsuya Kamataki: "Oxidation of Histamine H_1 antagonist mequitazine is catalyzed by cytochrome P450 2D6 in human liver microsomes" J.Pharmacol.Exp.Ther.284. 437-442 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Ken-ichi Nunoya, Tsuyoshi Yokoi, Kanzo Kimura, Kazuaki Inoue, Takao Kodama, Masato Funayama, Kazuo Nagashima, Yoshihiko Funae, Carol Green, Moritoshi Kinoshita and Tetsuya Kamataki: "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. 8. 239-249 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Hiroshi Iwata, Ken-ichi Fujita, Hirotaka Kushida, Akihiro Suzuki, Yuko Konno, Katsunori Nakamura, Akiharu Fujino and Tetsuya Kamataki: "High catalytic activity of human cytochrome P450 co-expressed with human NADPH-cytochrome P450 reductase in Escherichia coli" Biochem.Pharmacol.55. 1315-1325 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Toshiyuki Mori, Susumu Itoh and Tetsuya Kamataki: "Molecular cloning and regulation of a novel guinea pig cytochrome P450 (CYP3A20) which differs from guinea pig CYP3A14 in only two amino acid residues" Biochem.Mol.Biol.Intern.44. 1245-1253 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Yuichi Ando, Michihiro Chida, Kazuo Nakayama, hideo Saka and Tetsuya Kamataki: "The UGT1A1^*28 allele is relatively rare in a Japanese population" Pharmacogenetics. 8. 357-360 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Akihiro Suzuki, Hirotaka Kushida, hiroshi Iwata, Masahiko Watanabe, Takeshi Nohmi, Ken-ichi Fujita and Tetsuya Kamataki: "Establishment of a salmonella tester strain highly sensitive to mutagenic heterocyclic amines" Cancer Res.58. 1833-1838 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Takafumi Tasaki, Akio Nakamura, Susumu Itoh, Kazuhiko Ohashi, Yukio Yamamoto, Makihiko Masuda, hisato Iwata, Akio Kazusaka, Tetsuya Kamataki and Shoichi Fujita: "Expression and characterization of dog CYP2D15 using baculovirus expression system" J.Biochem.123. 162-168 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Tsutomu Sakuma, Minako Hieda, tomoko Igarashi, Satoru Ohgiya, Ryuichi Nagata, Nobuo Nemoto and Tetsuya Kamataki: "MOlecular cloning and functional analysis of cynomolgous monkey CYP1A2" Biochem.Pharmacol.56. 131-139 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kiyoshi Takasuna, Takehiro Hagiwara, Masaaki Hirohashi, Michiyuki Kato, Mamoru Nomura, Eiichi Nagai, Tsuyoshi Yokoi and Tetsuya Kamataki: "Inhibition of intestinal microflora beta-glucuronidase modifies the distribution of the active metabolite of the antitumor agent, irinotecan hydrochloride (CPT-11) in rats" Cancer Chemother.Pharmacol.42. 280-286 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Yuichi Ando, Takayoshi Shimizu, Katsunori Nakamura, Taisei Mushiroda, Tetsuya Nakagawa, Takao Kodama and Tetsuya Kamataki: "Potent and non-specific inhibition of cytochrome P450 by JM216, a new oral platinum agent" Brit.J.Cancer. 78. 1170-1174 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Yoshiki Takahashi, Chiharu Suzuki and Tetsuya Kamataki: "Silencing of CYP1A1 expression in rabbits by DNA methylation" Biochem.Biophys.Res.Commun.247. 383-386 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Yuichi Ando, Hideo Saka, Gyo Asai, Seiji Sugiura, Kaoru Shimokata and Tetsuya Kamataki: "UGT1A1 genotypes and glucuronidation of SN-38, the active metabolite of irinotecan." Ann.Oncol.9. 845-847 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Ayako Yamada, Ken-ichi Fujita, Tsuyoshi Yokoi, shigeharu Mutoh, Akihiro Suzuki, Yoichi Gondo, Motoya Katsuki and Tetsuya Kamataki: "In vivo detection of mutation induced by aflatoxin B_1 using human CYP3A7/HITEC hybrid mice" Biochem.Biophys.Res.Commun.250. 150-153 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Hirofumi Tani, Takashi Ooura, Tamio Kamidate, Tetsuya Kamataki and Hiroto Watanabe: "Separation of microsomal cytochrome b_5 via phase separation in a mixed solution of Triton X-114 and charged dextran" J.Chromatogr.B Biomed.Sci.Appl.708. 294-298 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Shigeharu Muto, Tsuyoshi Yokoi, Yoichi Gondo1, Motoya Katsuki, Yoshiyuki Shioyama, Ken-ichi Fujita and Tetsuya Kamataki: "Inhibition of benzo [a] pyrene-induced mutagenesis by (-) -epigallocatechin gallate in the lung of rpsL transgenic mice" Carcinogenesis. (in press). (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Miki Nakajima, Tsuyoshi Yokoi, Mayumi Mizutani, Moritoshi Kinoshita, Masato Funayama and Tetsuya Kamataki: "Genetic polymorphism in the 5'-flanking region of human CYP1A2 gene : effect on the CYP1A2 inducibility in humans" J.Biochem.(in press). (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Michihiro Chida, Tsuyoshi Yokoi, Nobuo Nemoto, Makoto Inaba, Moritoshi Kinoshita and Tetsuya Kamataki: "A new variant CYP2D6 allele (CYP2D6/C8) with a single insertion in exon 5 in a Japanese population associated with a poor metabolizer phenotype" Pharmacogenetics. (in press). (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Michihiro Chida, Tsuyoshi Yokoi, Yasuyuki Kosaka, Kan Chiba, Hidefumi Nakamura, Takashi Ishizaki, Jun Yokota, Moritoshi Kinoshita, Kunio Sato, Makoto Inaba, Yasuhiro Aoki, Frank J.Gonzalez and Tetsuya Kamataki: "Genetic polymorphism of CYP2D6 in Japanese population" Pharmacogenetics. (in press). (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Ken-ichi Nunoya, Tsuyoshi Yokoi, Kanzo Kimura, Tadashi Kainuma, Kunio Sato, Moritoshi Kinoshita and Tetsuya Kamataki: "CYP2A6 gene deletion responsible for the in vivo polymorphic metabolism of (+) -cis-3,5-dimethyl-2- (3-pyridyl) thiazolidin-4-one hydrochloride (SM-12502) in humans" J.Pharmacol.Exp.Ther.(in press). (1999)

    • Description
      「研究成果報告書概要(欧文)」より

URL: 

Published: 1999-12-08  

Information User Guide FAQ News Terms of Use Attribution of KAKENHI

Powered by NII kakenhi