| Project/Area Number |
11557175
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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 |
Biological pharmacy
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| Research Institution | HOKKAIDO UNIVERSITY |
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Principal Investigator |
KAMATAKI Tetsuya Hokkaido Univ. Grad. Sch. Pharm. Sci., Prof., 大学院・薬学研究科, 教授 (00009177)
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| Co-Investigator(Kenkyū-buntansha) |
KOBAYASHI Satoshi Kyowa Hakko, Director, 医薬総合研究所, 所長(研究・開発担当)
KAMIDATE Tamio Hokkaido Univ, Grad. Sch. Eng., Prof., 大学院・工学研究科, 教授 (70185990)
FUJITA Ken-ichi Hokkaido Univ, Grad. Sch. Pharm. Sci., Res. Assoc., 大学院・薬学研究科, 助手 (60281820)
有吉 範高 北海道大学, 大学院・薬学研究科, 助教授 (00243957)
高橋 芳樹 北海道大学, 大学院・薬学研究科, 助手 (80292019)
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| Project Period (FY) |
1999 – 2001
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| Project Status |
Completed (Fiscal Year 2001)
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| Budget Amount *help |
¥8,200,000 (Direct Cost: ¥8,200,000)
Fiscal Year 2001: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 2000: ¥4,500,000 (Direct Cost: ¥4,500,000)
Fiscal Year 1999: ¥2,400,000 (Direct Cost: ¥2,400,000)
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| Keywords | P450 / HIGH THROUGH PUT / PLATE READER / INHIBITION / DRUG METANBOISM / DRUG INTERACTION / RECOMBINANT / DRUG DEVELOPMENT / ハイスループットシステム / チトクロームP450 / CYP3A4 / 大腸菌発現系 / チトクロームb_5 / 薬物間相互作用 / 水溶性ポリマー |
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| Research Abstract |
The role of human cytochrome P450 (CYP) in the metabolic activation of N-alkylnitrosamines was examined by Ames test using genetically engineered Salmonella typhimurium (S. typhimurium)YG7108 cells expressing each form of human CYP together with human NADPH-cytochrome P450 reductase (OR). The relationship between the structure of N-alkylnitrosamines and CYP form(s) involved in the activation was evaluated. Eleven strains of S. typhimurium YG7108 cells expressing each form of CYP (CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4 or CYP3A5) were employed. Eight N-alkylnitrosamines These N-alkylnitrosamines were mainly activated by CYP2E1, CYP2A6 and CYP1A1. N-alkylnitrosamines with relatively short alkyl chains such as NDMA and NMEA were primarily activated by CYP2E1 as judged by mutagen-producing capacity. With the increase of the number of the carbon atoms of the alkyl chains, the contribution of CYP2A6 increased. CYP2A6 played major roles in the activation of NDEA, NDPA, NMPA, NMBA and NEBA. Interestingly, CYP1A1 became a molecular form of CYP playing a major role in the metabolic activation of NDBA.
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