Transport of valproate at intestinal epithelial (Caco-2) and brain endothelial (RBE4) cells: Mechanism and substrate specificity
Transport of valproate at intestinal epithelial (Caco-2) and brain endothelial (RBE4) cells: Mechanism and substrate specificity
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DOI：
10.1016/j.ejpb.2008.05.022
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发表时间：
2008-10-01
影响因子：
4.9
通讯作者：
Brandsch, Matthias
中科院分区：
文献类型：
--
作者：
Fischer, Wiebke;Praetor, Katrin;Brandsch, Matthias
为了到达其靶细胞，抗癫痫药物丙戊酸盐必须以完整的形式以及足够的量穿过肠上皮屏障和血脑屏障。本研究旨在表征丙戊酸盐在肠（Caco-2）和血脑屏障（RBE 4）细胞中的上皮转运。在两种细胞类型中，[H-3]丙戊酸盐的摄取与内向Na+、Ca 2+、Mg 2+、K+或Cl-梯度无关。然而，摄取强烈刺激的向内定向的H+梯度。细胞中丙戊酸盐的蓄积与浓度梯度相反，丙戊酸盐的摄取率可饱和，K-t值为0.6和0.8 mM。在Caco-2细胞单层中，[H-3]丙戊酸盐的总顶侧至基底侧通量超过基底侧至顶侧通量的14倍。各种一元羧酸，如水杨酸盐、苯甲酸盐、乙酸盐、丙酸盐、丁酸盐、己酸盐、双氯芬酸盐和布洛芬，在两种细胞类型中均抑制[H-3]丙戊酸盐摄取。乳酸盐和丙酮酸盐抑制RBE 4细胞的丙戊酸盐摄取，但不抑制Caco-2细胞。我们得出结论，丙戊酸盐通过与单羧酸转运蛋白1（MCTI）不同的单羧酸盐特异性H+依赖性DIDS不敏感转运系统的活性，逆着浓度梯度在肠细胞中蓄积。丙戊酸盐通过血脑屏障很可能是由MCTI介导的。(C)2008 Elsevier B. V.保留所有权利。
To reach its target cells, the antiepileptic drug valproate has to cross both the intestinal epithelial barrier and the blood-brain barrier in intact form as well as in sufficient amounts. This study was performed to characterize the epithelial transport of valproate at intestinal (Caco-2) and at blood-brain barrier (RBE4) cells. At both cell types, uptake of [H-3]valproate was independent of inwardly directed Na+, Ca2+, Mg2+, K+ or Cl- gradients. Uptake was, however, strongly stimulated by an inwardly directed H+ gradient. The cells accumulated valproate against a concentration gradient and the uptake rate of valproate was saturable with K-t values of 0.6 and 0.8 mM. At Caco-2 cell monolayers, the total apical-to-basolateral flux of [H-3]valproate exceeded the basolateral-to-apical flux 14-fold. Various monocarboxylic acids like salicylate, benzoate, acetate, propionate, butyrate, hexanoate, diclofenac and ibuprofen inhibited [H-3]valproate uptake at both cell types. Lactate and pyruvate inhibited valproate uptake at RBE4 cells but not at Caco-2 cells. We conclude that valproate is accumulated in intestinal cells against a concentration gradient by the activity of a specific H+-dependent DIDS-insensitive transport system for monocarboxylates not identical with monocarboxylate transporter 1 (MCTI). The passage of valproate across the blood-brain barrier is very likely mediated by MCTI. (C) 2008 Elsevier B.V. All rights reserved.