An antioxidant Trolox restores decreased oral absorption of cyclosporine A after liver ischemia-reperfusion through distinct mechanisms between CYP3A and P-glycoprotein in the small intestine
An antioxidant Trolox restores decreased oral absorption of cyclosporine A after liver ischemia-reperfusion through distinct mechanisms between CYP3A and P-glycoprotein in the small intestine
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DOI：
10.1016/j.ejphar.2012.06.031
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发表时间：
2012-09-05
影响因子：
5
通讯作者：
Okuda, Masahiro
中科院分区：
文献类型：
--
作者：
Ikemura, Kenji;Inoue, Koichi;Okuda, Masahiro
氧化应激是与器官移植相关的缺血再灌注（I/R）后各种损伤的关键介质。虽然环孢素A（CsA）的口服生物利用度在肝脏I/R后通过CYP 3A和P-糖蛋白（P-gp）在小肠上段的首过代谢增加而降低，但其机制尚不清楚。在本研究中，研究了Trolox（R）（一种α-生育酚类似物）通过升高肝脏I/R后肠道CYP 3A和P-gp对CsA口服吸收减少的影响及其调节。大鼠肝脏缺血60 min，再灌注12 h。再灌注前5 min静脉注射Trolox。Trolox减少了肝脏I/R引起的血浆中丙二醛和总谷胱甘肽水平的升高，同时防止了口服CsA的血药浓度-时间曲线下面积的降低以及小肠上部CsA的初始吸收率。Trolox可降低肝I/R后小肠上段CYP 3A mRNA和活性的升高以及小肠上段、中段和下段P-gp的表达水平。I/R大鼠小肠上段的CYP 3A水平升高与胆汁中的石胆酸水平相关。这些结果表明，Trolox通过升高肠道CYP 3A和P-gp，通过预防氧化应激，改善CsA口服吸收减少，其中胆汁石胆酸可能是肝脏I/R后小肠上部CYP 3A转录升高的原因。(C)2012爱思唯尔有限公司版权所有。
Oxidative stress is a critical mediator of various injuries following ischemia-reperfusion (I/R) associated with organ transplantation. Although oral bioavailability of cyclosporine A (CsA) was decreased by increased first-pass metabolism through CYP3A and P-glycoprotein (P-gp) specifically in the upper small intestine after liver I/R, the mechanism responsible for them remained to be clarified. In the present study, the effect of Trolox (R) (an alpha-tocopherol analogue) on the decreased oral absorption of CsA through elevated intestinal CYP3A and P-gp after liver I/R and their regulations were investigated. Rats were subjected to 60min of liver ischemia followed by 12 h of reperfusion. Trolox was administered intravenously 5 min before reperfusion. Trolox diminished the increased malondialdehyde and total glutathione levels in plasma by liver I/R and concomitantly prevented the decreased area under the blood concentration-time curve of orally administered CsA as well as initial absorption rate of CsA from upper small intestine. The elevated CYP3A mRNA and activity in the upper small intestine as well as expressionlevels of P-gp in upper, middle, and lower small intestines after liver I/R were attenuated by Trolox administration. The elevations of CYP3A levels specifically in the upper small intestine of I/R rats were correlated with the lithocholic acid levels in the bile. These results demonstrate that Trolox ameliorates the decreased oral absorption of CsA through elevated intestinal CYP3A and P-gp by preventing oxidative stress, where the biliary lithocholic acid may be responsible for the elevated transcription of CYP3A specifically in the upper small intestine after liver I/R. (C) 2012 Elsevier B.V. All rights reserved.