Transient up-regulation of P-glycoprotein reduces tacrolimus absorption after ischemia-reperfusion injury in rat ileum.
Transient up-regulation of P-glycoprotein reduces tacrolimus absorption after ischemia-reperfusion injury in rat ileum.
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DOI：
10.1016/j.bcp.2004.10.016
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发表时间：
2005-02
影响因子：
5.8
通讯作者：
Takanori Omae;Maki Goto;Masahiro Shimomura;S. Masuda;Kimitaka Ito;M. Okuda;K. Inui
中科院分区：
文献类型：
--
作者：
Takanori Omae;Maki Goto;Masahiro Shimomura;S. Masuda;Kimitaka Ito;M. Okuda;K. Inui
缺血再灌注损伤是包括小肠移植在内的器官移植中不可避免的问题，并导致他克莫司(FK506)的药代动力学存在较大的个体内变异。目前对组织再生过程中肠道P-糖蛋白表达的调控知之甚少。在本研究中，我们研究了大鼠回肠缺血再灌注后P-糖蛋白的分子和功能变化。形态学观察显示再灌流后24小时肠壁迅速再生。逆转录-竞争性聚合酶链式反应和Western印迹分析显示，P-糖蛋白在肠组织中的表达在再灌流后随时间延长而恢复。再灌流后24小时，回肠P-糖蛋白水平一过性升高至对照组的2倍，二氢-[~3H]FK506从原位回肠环进入门静脉的吸收率明显低于对照组。再灌流后6h，隐窝区和绒毛细胞中均可检测到P-糖蛋白，24小时后P-糖蛋白定位于根尖表面，与细胞的增殖和分化一致。而P-糖蛋白水平在48h后恢复正常。他克莫司吸收率的个体内差异可能受肠上皮细胞的形态状态和肠细胞P-糖蛋白表达水平的调节。因此，监测肠上皮细胞P-糖蛋白水平将为确定小肠移植术后即刻他克莫司的用量提供有用的信息。
Ischemia–reperfusion injury is an unavoidable problem for organ transplantation including small bowel transplantation, and causes a large intra-individual variation of tacrolimus (FK506) pharmacokinetics. Little information is available about the regulation of the intestinal P-glycoprotein expression during tissue regeneration. In the present study, we have examined the molecular and functional variations of ileum P-glycoprotein using rats after ischemia–reperfusion treatment. Morphological study revealed a rapid regeneration of the intestinal wall during 24h after reperfusion. A reverse transcription-coupled competitive PCR and Western blot analysis revealed that the intestinal expression of P-glycoprotein recovered with time after reperfusion. At 24h after reperfusion, the ileum P-glycoprotein level was transiently increased to two-fold, and the absorption rate of dihydro-[3H]FK506 from in situ ileum loop into portal vein was markedly low in comparison with the control. P-glycoprotein was detected in the crypt area as well as in villous cells at 6h after reperfusion, and then localized to the apical surface at 24h consistent with the cell proliferation and differentiation. However, the P-glycoprotein level returned to normal at 48h. The intra-individual variation in the absorptive rate of tacrolimus was suggested to be regulated by the morphological status of the intestinal epithelium and enterocyte expression level of P-glycoprotein. Therefore, the monitoring of the enterocyte P-glycoprotein level would provide useful information for determining the dosage of tacrolimus immediately after small bowl transplantation.