METHYLMERCURY TRANSPORT ACROSS CELL MEMBRANES

我们实验室的长期目标是确定这些因素 这是人类对甲基汞(MeHg)中毒易感性的基础。甲基汞 是一种剧毒的环境污染物：临床和实验 研究表明，接触甲基汞主要会导致 以共济失调、感觉障碍和 精神状态的变化。大脑是主要的目标组织， 甲基汞在成人和出生前的生活中。唯一的办法是防止或 一旦摄取甲基汞，减轻毒性就是加速其 从身体上移走。消除甲基汞的主要途径是 胃肠道：排泄物约占90% 暴露在甲基汞中的人或动物的总排泄量，因此 有效地决定了生物半衰期。胃肠道 排泄又主要由胆汁分泌物决定。 无论是甲基汞通过血脑屏障进入 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尚未 已确认身份。拟议研究的总体目标是 描述这些细胞和亚细胞的运输机制 水平，在一般假设下，影响利率和 运输的程度将影响处置，从而影响毒性 甲基汞。我们建议测试一种常见的工作模型，即甲基汞形成 与结构上模仿其他化合物的内源性硫醇化合物的络合物 内源底物通过细胞膜携带，由特定的 运输蛋白。 了解跨这两个键的膜转运机制 障碍，我们计划研究控制身体负担的新方法 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.