| 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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| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2000: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 1999: ¥2,200,000 (Direct Cost: ¥2,200,000)
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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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