2002 Fiscal Year Final Research Report Summary
Investigation of drug transport function through biological membranes and physiological role in endotoxemia
| 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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| Keywords | endotoxin / membrane transport / transporters / P-glycoprotein / blood-brain barrier / cytokines |
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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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[Publications] Hidemura,K., Zhao,Y.L., Ito,K., Nakao,A., Kanazawa,H., Tafcagi,K., Ohta,M., Hasegawa,T.: "Shiga-like toxin II impairs hepatobiliary transport of doxorubicin by down-regulation of hepatic P-glycoprotein and multidrug resistance-associated protein (Mrp2) in rats"Antimicrob. Agents Chemother.. in press. (2003)
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「研究成果報告書概要(欧文)」より
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[Publications] Kitaichi,k,, Morishita,Y, Doi,Y, Ueyama,J., Matsushima,Y, Zbao,Y.L, Takagi,K., Hasegawa,T.: "Increased plasma concentration and brain penetration of methamphetamine in benaviorally sensitized rats"Eur.J.Pharmacol.. 464. 39-48 (2003)
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「研究成果報告書概要(欧文)」より
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[Publications] Zhao Y.L., Du,J., Kanazawa,H., Cen,X.B., Takagi,K., Kitaichi,K., Tatsumi,Y., Takagi,K., Ohta,M. and Hasegawa,T.: "Shiga-like toxin II modifies brain distribution of a P-glycopibtein substrate, doxorubicin, and P-glycoprotein expression in mice"Brain Res.. 956. 246-253 (2002)
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「研究成果報告書概要(欧文)」より
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[Publications] Zhao,Y.L, Du,J., Kanazawa,H., Sugawara,K., Takagi,K., Kitaichi,K., Tatsumi,K., Takagi,K. and Hasegawa,T.: "Effect of endotoxin on doxorubicin transport across blood-brain barrier and P-glycoprotein function in mice"Eur.J.Pharmacol.. 445. 115-123 (2002)
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「研究成果報告書概要(欧文)」より
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[Publications] Zhao,Y.L., Cen,X.B., Ito,M., Yokoyama,K., Kitaichi,K., Nadai,M., Ohta,M., Takagi,K. and Hasegawa,T.: "Shiga-like Toxin II derived from Escherichia coli O157 : H7 modifies renal handling of levofloxacin in rats"Antimicrob. Agents Chemother.. 46. 1522-1528 (2002)
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