ROLE OF ALTERED MEMBRANE FUNCTION IN XENOBIOTIC TOXICITY

溶质穿过上皮膜的运输是细胞的重要功能， 许多器官，例如，肾脏脉络丛肝脏和肠道上皮 转运依赖于位于顶端（BBM）的单个转运系统 和基底外侧（BLM）膜。他们复杂的组织，功能 重要性和暴露位置使得上皮膜特别 易受外来化学物质的毒性影响。最近的研究 着重于肾有机阴离子（OA）的机制和能量学 运输系统，它决定了许多有毒的外源性物质 从体内排出。分离的BLM囊泡用于证明 OA的进入是由向内的钠梯度驱动的，但只有 在戊二酸（GA）或α-酮戊二酸（cKG）的存在下。该系统 似乎通过摄取OA来交换内部GA或 alphaKG GA或alphaKG通过钠返回到内部 共转运，维持外向GA（alphaKG）梯度 需要推动净OA积累。因此，与钠梯度耦合 是间接的，这是三级主动运输的一个例子。肾BBM囊泡 显示OA进入肾小管的出口 管腔简单得多，由可以交换内部OA的载体介导 对于内腔阴离子，主要是氯离子或碳酸氢根。整个组织 大鼠、比目鱼肾和甲壳类膀胱制剂 已经证明了GA（alphaKG）/Na驱动的OA转运的存在， BLM进入完整的上皮细胞。此外，最近的研究使用 荧光OA，荧光素，已经允许直接证明 Na/GA依赖性OA跨大鼠完整肾上皮的转运 挣扎着进入内腔室，即，跨上皮转运 由基底外侧摄取步骤控制，如早期 囊泡研究。最后，作为评估控制的第一步， 转运蛋白的偶联系统和生化特性 参与这一系统，肾m-RNA携带OA系统的信息， 在非洲爪蟾卵母细胞中表达。

Transport of solutes across epithelial membranes is a vital function of many organs, e.g., kidney, choroid plexus, liver and gut. Epithelial transport depends upon individual transport systems located in apical (BBM) and basolateral (BLM) membranes. Their complex organization, functional importance and exposed location make epithelial membranes particularly susceptible to toxic effects of foreign chemicals. Recent research has focussed on the mechanism and energetics of renal organic anion (OA) transport system, which determines how effectively many toxic xenobiotics are excreted from the body. Isolated BLM vesicles were used to demonstrate that OA entry was driven by the inwardly directed sodium gradient, but only in the presence of glutarate (GA) or alpha-ketoglutarate (cKG). This system appears to function through uptake of OA in exchange for internal GA or alphaKG. The GA or alphaKG is returned to the interior via sodium cotransport, maintaining the outwardly directed GA (alphaKG) gradient needed to drive net OA accumulation. Thus, coupling to the sodium gradient is indirect, an example of tertiary active transport. Renal BBM vesicles from several species were used to show that exit of OA into the tubular lumen is much simpler, mediated by a carrier which can exchange internal OA for lumenal anions, largely chloride or bicarbonate. Whole tissue preparations from rat and flounder kidney and crustacean urinary bladder have demonstrated the presence of GA(alphaKG)/Na driven OA transport across the BLM into the intact epithelium. Furthermore, recent studies using the fluorescent OA, fluorescein, has permitted direct demonstration of Na/GA-dependent OA transport across the intact renal epithelium of the flounder into the lumenal compartment, i.e., that transepithelial transport is controlled by the basolateral uptake step as predicted by the earlier vesicle studies. Finally, as an initial step in assessing the control of the coupled system and biochemical characterization of the transporters involved in this system, renal m-RNA carrying the message for the OA system has been expressed in Xenopus oocytes.