Methylmercury transport across cell membranes

甲基汞跨细胞膜运输

• 批准号: 6788718
• 负责人: NAZZARENO BALLATORI
• 金额: $ 31.9万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-09-01 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6788718
• 关键词: Xenopus; acetylcysteine; aminoacid transport; antidotes; biological transport; biomarker; blood brain barrier; cysteine; environmental exposure; environmental toxicology; excretion; glutathione; hair; laboratory rat; liver metabolism; membrane transport proteins; mercury poisoning; metal metabolism; methionine; methylmercury; renal tubular transport

The overall objective of this 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 in neurologic damage characterized by ataxia, sensory disturbances and changes in mental state. The only way to prevent or ameliorate toxicity once MeHg has been ingested is to accelerate its removal from the body. Our goal is to identify and characterize the mechanisms by which MeHg crosses cell membranes to reach its target sites, or conversely, to be eliminated from the cell. This information is critical both for defining mechanisms of toxicity, and for developing effective biomarkers of exposure and therapeutic strategies. Our previous work provided the first direct demonstration of the mechanism by which MeHg crosses the blood-brain barrier to reach its target tissue, and of the mechanism by which MeHg is transported across the liver cell canalicular membrane into bile, a major route for its excretion. Recent studies have also identified a novel antidote for MeHg, namely N-acetylcysteine (NAC). Our working hypothesis is that NAC enhances urinary MeHg excretion because it leads to the formation of the anionic MeHg-NAC complex, which is a substrate for the renal organic anion transporters. The proposed studies aim to characterize these MeHg transport mechanisms at the molecular and cellular level. Our Specific Aims are: I. Examine the mechanism by which the MeHg-L-cysteine complex is transported on the L-type amino acid transporters LAT1 and LAT2. II. Test whether the MeHg-glutathione complex (MeHg-SG) is a substrate for some members of the MRP family of transporters. III. Evaluate the molecular mechanism by which NAC stimulates renal excretion of MeHg. IV. Test the hypothesis that urinary excretion of MeHg following an NAC oral challenge may be used as a new biomarker of MeHg exposure.

该实验室的总体目标是确定导致人类对甲基汞 (MeHg) 中毒易感性的因素。 甲基汞是一种剧毒环境污染物：临床和实验研究表明，接触甲基汞会导致神经损伤，表现为共济失调、感觉障碍和精神状态改变。 一旦摄入甲基汞，预防或减轻毒性的唯一方法是加速其从体内的清除。 我们的目标是确定和表征甲基汞穿过细胞膜到达其目标位点或相反地从细胞中消除的机制。 这些信息对于确定毒性机制以及开发有效的暴露生物标志物和治疗策略都至关重要。 我们之前的工作首次直接证明了甲基汞穿过血脑屏障到达靶组织的机制，以及甲基汞穿过肝细胞小管膜进入胆汁的机制，胆汁是甲基汞排泄的主要途径。 最近的研究还发现了一种新的甲基汞解毒剂，即 N-乙酰半胱氨酸 (NAC)。 我们的工作假设是 NAC 增强尿液 MeHg 排泄，因为它导致阴离子 MeHg-NAC 复合物的形成，该复合物是肾脏有机阴离子转运蛋白的底物。 拟议的研究旨在在分子和细胞水平上表征这些甲基汞转运机制。 我们的具体目标是： I. 检查 MeHg-L-半胱氨酸复合物在 L 型氨基酸转运蛋白 LAT1 和 LAT2 上转运的机制。二.测试 MeHg-谷胱甘肽复合物 (MeHg-SG) 是否是 MRP 转运蛋白家族某些成员的底物。三．评估 NAC 刺激肾脏排泄 MeHg 的分子机制。四．检验以下假设：NAC 口服激发后尿液中甲基汞的排泄可用作甲基汞暴露的新生物标志物。