| Project/Area Number |
13672417
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Laboratory medicine
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| Research Institution | Nagoya University |
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Principal Investigator |
HASEGAWA Takaaki Nagoya University, School of Medicine, Professor, 医学部, 教授 (80198720)
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| Co-Investigator(Kenkyū-buntansha) |
KITAICHI Kiyoyuki Nagoya University, School of Medicine, Research Associate, 医学部, 助手 (40301220)
TAKAGI Kenji Nagoya University, School of Medicine, Associate Professor, 医学部, 助教授 (80126870)
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| Project Period (FY) |
2001 – 2002
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| Project Status |
Completed (Fiscal Year 2002)
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| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2002: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 2001: ¥2,800,000 (Direct Cost: ¥2,800,000)
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| Keywords | endotoxin / membrane transport / transporters / P-glycoprotein / blood-brain barrier / cytokines / 生体膜輸送機構 / TNF-α |
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| Research Abstract |
Results obtained from this research are represented as follows :
1. The involvement of cytokines and mediators, such TNF-α, IL-1 and PAF, in endotoxin-induced decreases in the content of CYP and protein levels of CYP3A2 and 2C11 appears to be small.
2. Some quinolone antimicrobial agents increased the intracellular accumulation of doxorubicin, a substrate of P-glycoprotein, in P-glycoprotein-dependent anticancer drug resistant cells, suggesting that they can reverse anticancer drug resistance of tumors. They are excreted into the bile by a P-glycoprotein-mediated transport system.
3. Endotoxin did not change the activity of glucuronidation, but decreased sparfloxacin and its glucuronide due to impairment of Mrp2- and/or P-glycoprotein-mediated hepatobiliary transport systems and renal handling.
4. The expression of Mdrla mRNA in both liver and kidney decreased 6 h after endotoxin injection and returned to control level. Endotoxin decreased P-glycoprotein-mediated biliary and renal excretion of rhodamine-123 by decreasing the expression of Mdrla, which is likely due to increased plasma TNF-α levels.
5. Endotoxin did not induce histopathological changes in the brain capillaries, and had no effect on the brain capillary integrity and doxorubicin transport across the blood-brain barrier (BBB) in mice. Endotoxin did not change the function and expression of P-glycoprotein in the brain. It is likely that P-glycoprotein function might be sufficient to transport doxorubicin despite of decreased levels of P-glycoprotein in the brain.
6. Shiga-like toxin II impairs the BBB function and doxorubicin transport across the BBB, while induces upregulation of P-glycoprotein, which are different from results by endotoxin injection. The discrepancy between endotoxin and Shiga-like toxin II may be explained by the difference in the contents of cytokine production.
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