| Budget Amount *help |
¥3,930,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥330,000)
Fiscal Year 2007: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2006: ¥2,500,000 (Direct Cost: ¥2,500,000)
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| Research Abstract |
The enteric nervous system (ENS), independent of the central nervous system (CNS), regulates the movement of small intestine and the transport of water and/or electrolytes in the small intestine. However, there is little information about the effect of ENS on drug absorption from the small intestine. We have been continuing systematically to investigate the role of ENS in drug absorption from the small intestine. In this project, we focused on the effect of ENS on function of P-glycoprotein (P-gp), which is well known to pump out many important drugs. Employing rhodamine123, a typical substrate for P-gp, as a model compound, the effect of addition of adrenaline on P-gp function was investigated with three different methods such as the vascular-luminal perfusion study, the transport study with the isolated intestinal sheet and Caco-2 cells. As a result, the stimulation of adrenergic neuron by adrenaline attenuated P-gp activity in all the three methods. Western blot analysis showed that
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the expression level of P-gp in brush border membrane (BBM) decreased, which was significantly correlated with the decrease in P-gp activity, indicating that the decrease in the expression level in BBM could be partly responsible for the decrease in P-gp activity On the other hand, the whole expression level of P-gp in the epithelial cells was found not to be changed by the addition of adrenaline, suggesting that the trafficking rate of P-gp from intracellular pool to BBM was decreased by the addition of adrenaline. Since clonidine, a selective α_2 agonist, provided the results similar with adrenaline, as receptor could be involved in the regulation of P-gp activity. It was also found that adrenaline decreased the intracellular level of cAMP and that PICA inhibitor decreased P-gp activity Furthermore, dibutyryl cAMP significantly enhanced P-gp activity. Taken all together, adrenaline decreases P-gp activity by attenuating the expression level of P-gp on BBM, which could be mediated by the decrease in cyclic AMP level and subsequent decrease in PKA activity. Less
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