Changes in the Localization of Ileal P-Glycoprotein Induced by Intestinal Ischemia/Reperfusion

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  • Takizawa Yusuke
    Department of Drug Absorption and Pharmacokinetics, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences
  • Kishimoto Hisanao
    Department of Drug Absorption and Pharmacokinetics, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences
  • Kitazato Takuya
    Department of Drug Absorption and Pharmacokinetics, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences
  • Tomita Mikio
    Department of Drug Absorption and Pharmacokinetics, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences
  • Hayashi Masahiro
    Department of Drug Absorption and Pharmacokinetics, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences

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P-Glycoprotein is one of the most important transporters in the ATP binding cassette transporter. Moreover, it is well known that the efficacy of immunosuppressants, which are used after organ transplantation, is controlled by P-glycoprotein (P-gp). We investigated how ischemia/reperfusion (I/R), which occurs after transplantation, influences the expression level and function of P-gp. To clarify the influence of intestinal I/R on the localization of P-gp, an intestinal ischemia model was produced using a spring scale and surgical sutures for 1 h, followed by reperfusion for 24 h. The expression levels of mRNA and protein of P-gp were examined. The protein expression levels of P-gp in ileal homogenate and the brush border membrane (BBM) were significantly decreased until 3 h after reperfusion. While the protein expression level of P-gp in homogenate showed a tendency to increase, that in the BBM continued to significantly decrease until 24 h after reperfusion. In contrast, the protein expression level of P-gp in the basolateral membrane (BLM) increased significantly until 24 h after reperfusion. While no significant change in multidrug resistance (mdr)-1a mRNA was found, the levels of mdr-1b and mdr-2 significantly increased during intestinal I/R. In addition, the levels of inflammatory cytokines mRNA and nitric oxide (NO) also significantly increased. It was shown that mdr-1b and mdr-2 mRNA strongly participate in the recovery of P-gp protein level after intestinal I/R. We detected the abnormal localization of P-gp in the ileal membrane during intestinal I/R, suggesting NO and/or inflammatory cytokines participate in the abnormal localization of P-gp.

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