METHYLMERCURY TRANSPORT ACROSS CELL MEMBRANES

我们实验室的长期目标是确定这些因素 导致人类对甲基汞（MeHg）中毒的易感性。甲基汞 是一种高毒性的环境污染物：临床和实验 研究表明，接触甲基汞主要导致 以共济失调、感觉障碍和 精神状态的变化。大脑是主要的靶组织， 成年和产前生活中的甲基汞。唯一的方法来防止或 一旦摄入甲基汞，改善毒性的方法是加速其 从身体中移除。消除甲基汞的主要途径是 胃肠道：粪便排泄约占90% 接触甲基汞的人类或动物的总排泄量，因此 有效地确定了生物半衰期。胃肠 排泄又主要由胆汁分泌决定。 甲基汞穿过血脑屏障的机制， 到达其靶组织，也不是甲基汞运输的基本机制 穿过肝细胞小管质膜进入胆汁 鉴定拟议研究的总体目标是 在细胞和亚细胞上表征这些运输机制 水平，根据一般假设，影响率的因素和 运输的程度将影响处置，从而影响毒性 MeHg。我们建议测试一个共同的工作模型，即甲基汞形成 与内源性硫醇化合物的复合物， 内源性底物通过特异性 转运蛋白 了解跨这两个关键点的膜转运机制， 障碍，我们计划研究新的方法来控制身体负担 甲基汞。

The long term objective of our laboratory is to identify those factors that underlie human susceptibility to methylmercury (MeHg) poisoning. MeHg is a highly toxic environmental pollutant: clinical and experimental studies demonstrate that exposure to MeHg results primarily in neurological damage characterized by ataxia, sensory disturbances and changes in the mental state. The brain is the principal target tissue for MeHg in both adult and prenatal life. The only way to prevent or ameliorate toxicity once MeHg has been ingested is to accelerate its removal from the body. The principal pathway for eliminating MeHg is the gastrointestinal tract: fecal excretion accounts for approximately 90% of the total excretion in humans or animals exposed to MeHg, and therefore effectively determines the biological half-time. Gastrointestinal excretion is in turn determined primarily by biliary secretion. Neither the mechanism by which MeHg crosses the blood-brain barrier to reach its target tissue, nor the fundamental mechanism of MeHg transport across the liver cell canalicular plasma membrane into bile have yet been identified. The overall objective of the proposed studies is to characterize these transport mechanisms at the cellular and subcellular level, under the general hypothesis that factors influencing the rate and extent of transport will affect the disposition and therefore the toxicity of MeHg. We propose to test a common working model, that MeHg forms complexes with endogenous thiol compounds that structurally mimic other endogenous substrates carried across the cell membrane by specific transport proteins. Knowing the mechanisms of membrane transport across these two key barriers, we plan to examine new approaches to controlling the body burden of methylmercury.