| Project/Area Number |
09557208
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 展開研究 |
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| Research Field |
応用薬理学・医療系薬学
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| Research Institution | HOKKAIDO UNIVERSITY |
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Principal Investigator |
NAKAYAMA Kazuo Fac.of Pharm.Sci., Hokkaido Univ., Instructor, 大学院・薬学研究科, 助手 (20261323)
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| 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)
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| Project Period (FY) |
1997 – 1998
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| Project Status |
Completed (Fiscal Year 1998)
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| Budget Amount *help |
¥5,400,000 (Direct Cost: ¥5,400,000)
Fiscal Year 1998: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 1997: ¥3,700,000 (Direct Cost: ¥3,700,000)
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| Keywords | Mutagenicity testing / HITEC mouse / Cytochrome P450 / CYP3A7 / Fetus-specific / Metabolic activation / Aflatoxin B1 / DNA damage |
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| 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.
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