2000 Fiscal Year Final Research Report Summary
Search for the new, endogenous compound with multidrug resistance modulating activity and its application to cancer chemotherapy
| Project/Area Number |
11672169
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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 |
Biological pharmacy
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| Research Institution | Hiroshima University |
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Principal Investigator |
TAKANO Mikihisa Hiroshima University, Faculty of Medicine, Professor, 医学部, 教授 (20211336)
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| Co-Investigator(Kenkyū-buntansha) |
NAGAI Junya Hiroshima University, Faculty of Medicine, Instructor, 医学部, 助手 (20301301)
MURAKAMI Teruo Hiroshima University, Faculty of Medicine, Associate Professor, 医学部, 助教授 (20136055)
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| Project Period (FY) |
1999 – 2000
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| Keywords | P-glycoprotein / renal failure / hepatic failure / endogenous inhibitor / corticosterone / estrogen / multidrug resistance / endocrine disrupting chemical |
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| Research Abstract |
P-Glycoprotein (P-gp) is a drug efflux pump and confers multidrug resistance to cancer cells. In order to reverse multidrug resistance, compounds having the inhibitory potency on P-gp is now actively searched. On one hand, P-gp in normal tissues is important as a determinant of drug handling in the body. In the present study, the function of P-gp under disease states was examined, and the involvement of endogenous P-gp inhibitors was shown. In addition, to find out the new multidrug resistance modulators, we attempted to identify the endogenous P-gp inhibitors.
In-vivo P-gp function was examined in acute renal or hepatic failure rats, by measuring the handling of rhodamine 123, a P-gp substrate, in various tissues. Interestingly, the function of P-gp was suppressed not only in target injury tissue but also in other tissues. The expression levels of P-gp in these tissues did not decrease, rather increased in injury tissue. In addition, the inhibitory potency of the plasma from disease rats on P-gp was stronger than that from normal rats, indicating the involvement of endogenous P-gp inhibitors. In fact, the plasma concentration of corticosterone, an endogenous P-gp-related compound, increased in disease rats. In volunteers with normal kidney function, endogenous P-gp inhibitors were found to be excreted into the urine, one of which was identified to be equilin, an estrogen. During the study, di-2-ethylhexyl phthalate (DEHP), which is assumed to be an endocrine disrupting chemicals (EDCs), was found in the urine, though DEHP itself did not have direct inhibitory effect on P-gp. Further studies on endogenous P-gp inhibitors would help to identify new and useful multidrug resistance modulators for cancer chemotherapy.
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