ORGANIC ANION TRANSPORT AT THE BILE CANALICULUS

有机氯杀虫剂类似物灭蚁灵和十氯酮损害胆汁 易排出的有机阴离子在大鼠体内的排泄 多氯联苯和丙咪胺、酚酞葡萄糖醛酸化物的代谢物，以及 外源牛磺胆酸盐)。肝胆功能障碍与 显著的胆汁淤积或肝细胞坏死，但能力减弱 浓缩胆汁中的有机阴离子。抑制细胞内ATPase活性 这些药物的各种亚细胞组份(特别是Na，K- 和肝血浆寡霉素不敏感的镁-ATPase(OIMATPase) 膜)表明能量传递是一种毒性部位。纳， K-ATPase为钠偶联的胆盐摄取提供能量 进入肝脏的循环，很可能是负责 电解质和伴随的水进入胆汁。美国政府的角色 胆小管富集组分中OIMATPase活性较高 (BCEF)不被理解。这项研究的一个主要目标是 确定BCEF OIMATPase抑制是否是灭蚁灵的主要事件 和十氯酮所致的肝胆功能障碍和A 这种毒性的机理模型。该酶作用的定义 胆汁排泄和胆汁形成过程本身是一个整体 这是这个目标的一部分。工作假设是BCEF OIMATPase活性 代表一种H-ATPase，它为小管运输提供能量 有机溶质和/或“肌球蛋白样”ATPase在 胆小管收缩与胆管内“张力”的维持 树。上述总体目标将通过生理学和 生化方法。肝血流和肝动脉血流的潜在作用 氧合作用、胆盐成分和浓度以及质膜 灭蚁灵和十氯酮诱导的肝胆管脂质组成 将对功能障碍进行评估。完整的老鼠研究将检查 有机阴离子胆汁排泄受损的顺序，抑制BCEF OIMATPase和胆管树通透性在两个时间段均增加 疗程及药理逆转实验。囊泡转运 BCEF研究旨在确定OIMATPase在偶联蛋白中的作用 有机阴离子的运输正在进行中。旨在确定 有机氯在生物膜水平的作用部位和机制(BCEF) 都被提出了。这些将涉及灭蚁灵和十氯酮对 差示扫描量热法测定BCEF的物理性质 和自旋标记(ESR)研究。

The organochlorine insecticide analogs mirex and chlordecone impair biliary excretion of readily excretable organic anions in rats (i.e., polar metabolites of PCB's and imipramine, phenolphthalein glucuronide, and exogenous taurocholate). Hepatobiliary dysfunction is not associated with marked cholestasis or hepatocellular necrosis but diminished capacity to concentrate organic anions in bile. Inhibition ATPase activities in various subcellular fractions by these agents (particularly the Na+, K+- and oligomycin-insensitive Mg2+-ATPase (OIMATPase) of liver plasma membranes) indicates energy transduction as a site of toxicity. Na+, K+-ATPase provides energy for Na+-coupled uptake of bile salts from the circulation into the liver and is probably a "pump" responsible for electrolyte and accompanying water movement into bile. The role of the OIMATPase present in high activity in bile canaliculi enriched fractions (BCEF) is not understood. A major objective of this research is to determine whether inhibition of BCEF OIMATPase is a primary event in mirex and chlordecone-induced hepatobiliary dysfunction and development of a mechanistic model for this toxicity. Definition of the role of this enzyme in biliary excretion and the bile formation process per se is an integral part of this goal. The working hypothesis is that BCEF OIMATPase activity represents a H+-ATPase which provides energy for canalicular transport of organic solutes and/or a "myosin-like" ATPase which plays a role in contraction of bile canaliculi and maintenance of "tone" in the biliary tree. The above general objective will be approached by physiological and biochemical methods. The potential roles of hepatic blood flow and oxygenation, bile salt composition and concentration, and plasma membrane lipid composition in mirex- and chlordecone-induced hepatobiliary dysfunction will be evaluated. Intact rat studies will examine the sequence of impaired organic anion biliary excretion, inhibition of BCEF OIMATPase, and increased permeability of the biliary tree in both time course and pharmacological reversal experiments. Vesicular transport studies in BCEF aimed at determining the role of OIMATPase in coupled transport of organic anions are ongoing. Studies aimed at determining the site and mechanism of organochlorine action at the biomembrane level (BCEF) are proposed. These will involve the effects of mirex and chlordecone on BCEF physical properties as determined in differential scanning calorimetry and spin labeling (ESR) studies.