A Comprehensive Study on the Effect of Human Genetic Polymorphism on the Drug Metabolizing, Properties of CYP
| Project/Area Number |
18390013
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (B)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Physical pharmacy
|
|---|
| Research Institution | Osaka University |
|---|
Principal Investigator |
UNO Tadayuki Osaka University, Graduate School of Pharmaceutical Sciences, Professor (00183020)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
TOMISUGI Yoshikazu Osaka University, Graduate School of Pharmaceutical Sciences, Assistant Professor (80322311)
前田 初男 大阪大学, 薬学研究科, 助教授 (00229311)
|
|---|
| Project Period (FY) |
2006 – 2007
|
| Project Status |
Completed (Fiscal Year 2007)
|
| Budget Amount *help |
¥17,410,000 (Direct Cost: ¥15,400,000、Indirect Cost: ¥2,010,000)
Fiscal Year 2007: ¥8,710,000 (Direct Cost: ¥6,700,000、Indirect Cost: ¥2,010,000)
Fiscal Year 2006: ¥8,700,000 (Direct Cost: ¥8,700,000)
|
|---|
| Keywords | Cvtochrome P450 / Drug Metabolism / Single Nucleotide Polymorphism / Resonance Raman Spectroscopy |
|---|
| 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 on human genomic single-nucleotide polymorphisms (SNPs). We prepared CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4, along with mutants of these CYPs based on the SNP information, and measured drug metabolizing properties of these CYPs. In addition, we measured resonance Raman spectra of them in order to clarify structural factors that are affected by SNPs. Furthermore, we measured drug metabolizing properties of the mutants in order to investigate the effect of SNPs. We could establish that a parameter Kd, which is an index of drug binding affinity, is linearly correlated with Km, a measure of metabolizing activity. In addition, Vmax was found to linearly correlate with the content of 5-coordinated heme. Because the value Vmax/Km is correlated with drug clearance, it is now clear that static values of Kd and 5-coordination reveals the drug clearance. On the other hand, we succeeded in the preparation of CYP3A4 and CYP2D6 by adding a substrate drug to stabilize the protein, and modifying surfactants during the purification step. Thus, we finally established that drug metabolism by CYPs can be conprehensively investigated using these CYPs.
|
Report
(3 results)
Research Products
(2 results)
-
-
[Presentation] Correlations between SNPs and Drug Petabolizing Properties of Human CYPs2007
Author(s)
Tadayuki, Uno, Yusuke, Kagawa, Ryosuke, Watanabe, Teruaki, Shigetomi, Noritsugu, Ueda, Yoshikazu, Tomisugi, Yoshinobu, Ishikawa, Hatsuo, Maeda
Organizer
17th Symposium on the Reactions of Metals
Place of Presentation
Kyoto Tersa
Year and Date
2007-06-21
Description
「研究成果報告書概要(欧文)」より
Related Report
