Consequences of Mrp2 deficiency for diclofenac toxicity in the rat intestine ex vivo.
Consequences of Mrp2 deficiency for diclofenac toxicity in the rat intestine ex vivo.
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Mrp2 缺乏对离体大鼠肠道双氯芬酸毒性的影响。
DOI：
10.1016/j.tiv.2014.10.004
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Groothuis GM.
中科院分区：
文献类型：
--
作者：
Niu X;de Graaf IA;van de Vegte D;Langelaar-Makkinje M;Sekine S;Groothuis GM.
非甾体抗炎药双氯芬酸（DCF）在人类和大鼠中的肠道副作用发生率很高。据报道，Mrp 2转运蛋白缺陷型大鼠（Mrp 2 −）对DCF诱导的肠道毒性更具抵抗力。这在体内被解释为DCF-酰基葡糖苷酸（DAG）的Mrp 2依赖性胆汁转运受损，导致DAG和DCF的肠道暴露减少。然而，目前尚不清楚Mrp 2 −肠本身的适应性变化在多大程度上影响其对DCF毒性的敏感性，而不受肝脏代谢物的影响。为了研究这一点，使用野生型（WT）和Mrp 2 −大鼠的肠道，通过精密切割的肠切片和Ussing室在体内研究了DCF毒性和处置。结果表明，Mrp 2缺乏引起的适应性变化在肝脏和肠道中表现为Mrp 2、Mrp 3和BCRP基因表达、GSH含量和DAG形成的差异。此外，Mrp 2 −肠本质上比其WT对侧体内对DCF毒性更具抗性。这至少可以部分解释为Mrp 2 −肠道对DCF的摄取减少，但与肠道中的其他适应性变化无关。由于转运蛋白活性和调节的种属差异，将该数据外推至MRP 2缺乏症患者尚不确定。
The non-steroidal anti-inflammatory drug diclofenac (DCF) has a high prevalence of intestinal side effects in humans and rats. It has been reported that Mrp2 transporter deficient rats (Mrp2−) are more resistant to DCF induced intestinal toxicity. This was explainedin vivoby impaired Mrp2-dependent biliary transport of DCF-acylglucuronide (DAG), leading to decreased intestinal exposure to DAG and DCF. However, it is not known to what extent adaptive changes in the Mrp2−intestine itself influence its sensitivity to DCF toxicity without the influence of liver metabolites. To investigate this, DCF toxicity and disposition were studiedex vivoby precision-cut intestinal slices and Ussing chamber using intestines from wild type (WT) and Mrp2−rats. The results show that adaptive changes due to Mrp2 deficiency concerning Mrp2, Mrp3 and BCRP gene expression, GSH content and DAG formation were different between liver and intestine. Furthermore, Mrp2−intestine was intrinsically more resistant to DCF toxicity than its WT counterpartex vivo. This can at least partly be explained by a reduced DCF uptake by the Mrp2−intestine, but is not related to the other adaptive changes in the intestine. The extrapolation of this data to humans with MRP2 deficiency is uncertain due to species differences in activity and regulation of transporters.
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DOI：
--
发表时间：
2000-10
期刊：
Drug metabolism and disposition: the biological fate of chemicals
影响因子：
--
作者：
A. Nishino;Y. Kato;T. Igarashi;Y. Sugiyama
通讯作者：
A. Nishino;Y. Kato;T. Igarashi;Y. Sugiyama
影响因子：
6.1
作者：
Niu, Xiaoyu;de Graaf, Inge A. M.;Groothuis, Geny M. M.
通讯作者：
Groothuis, Geny M. M.
DOI：
10.1073/pnas.87.5.1715
发表时间：
1990-03-01
影响因子：
11.1
作者：
MARTENSSON, J;JAIN, A;MEISTER, A
通讯作者：
MEISTER, A
影响因子：
29.4
作者：
Seitz, S;Boelsterli, UA
通讯作者：
Boelsterli, UA
测定 Mrp2 缺陷 TR- 和 EHBR 大鼠肝微粒体中 I 相代谢酶活性。
影响因子：
6.1
作者：
D. Newton;Regina W. Wang;D. C. Evans
通讯作者：
D. C. Evans