A Comprehensive Study on the Effects of Genetic Polymorphism on the Drug Metabolizing Activity of Human CYP
| Project/Area Number |
15390015
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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 | 一般 |
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| Research Field |
Physical pharmacy
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| Research Institution | Kumamoto University |
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Principal Investigator |
UNO Tadayuki Kumamoto University, Graduate School of Medical and Pharmaceutical Sciences, Professor, 大学院・医学薬学研究部, 教授 (00183020)
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| Co-Investigator(Kenkyū-buntansha) |
ISHIKAWA Yoshinobu Kumamoto University, Graduate School of Medical and Pharmaceutical Sciences, Instructor, 大学院・医学薬学研究部, 講師 (00305004)
TOMISUGI Yoshikazu Kumamoto University, Graduate School of Medical and Pharmaceutical Sciences, Assistant, 大学院・医学薬学研究部, 助手 (80322311)
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| Project Period (FY) |
2003 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥15,400,000 (Direct Cost: ¥15,400,000)
Fiscal Year 2004: ¥5,900,000 (Direct Cost: ¥5,900,000)
Fiscal Year 2003: ¥9,500,000 (Direct Cost: ¥9,500,000)
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| Keywords | Cytochrome P450 / Resonance Raman Spectroscopy / Drug Metabolism / Equilibrium Dialysis / Binding Constant / Substrate Specificity / 平衡透析 |
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| Research Abstract |
In this study, we focused on cytochrome P450(CYP) which is a dominant group in the human drug metabolizing enzymes, and we aimed at the establishment of a clinical principle which is applicable to order-made treatment, through comprehensive studies on the drug binding and metabolizing activities of mutants which are prepared on the bases of the information of human genomic single-nucleotide polymorphisms(SNPs). We used over-expression system of CYP2C9 which is already established by us, and prepared CYP2C9 and CYP2C19 mutants on the SNP information. We measured drug binding activities of the wild-type and mutant CYPs by micro-dialysis method. The amount of bound drugs was determined by HPLC and we found that diclofenac and warfarin, which are metabolized by CYP2C9, show high affinity to CYP2C9 as expected. However, it was also found that nifedipine, which has been supposed to be metabolized by CYP3A4, show higher affinity to CYP2C9 than diclofenac. In addition, diazepam has been assumed to be metabolized by CYP2C19, but it showed relatively higher affinity to CYP2C9 than that to CYP2C19. These results strongly suggest that we must re-consider the specificities of drug-CYP interactions. We further studied the drug binding affinities to SNP mutants, and we found that the affinity decreases in all of the mutants. This suggests that we should decrease administration doze to the patients who have SNP mutation. We also completed the cloning of CYP1A2,CYP2D6, and CYP3A4, and established the purification procedure of these proteins.
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Report
(3 results)
Research Products
(10 results)
