AL+3 TOXICITY:CONTRIBUTING FACTORS, AL FORM & CHELATION

申请人的长远目标是致力于 了解铝(A1)毒理学的病因学和 制定预防和治疗战略。这项工作将 将在研究职业发展奖期间进行 将遵循几种研究途径。一是确定 可能有助于吸收的因素的意义 和A1的积累。这些研究正在进行中， 由美国国立卫生研究院拨款ES 2676支持。急性生物利用度研究是 正在进行的是澄清A1形式的作用， 肾功能受损，胃完整性和钙离子改变 儿童A1吸收不足与静脉药代动力学 兔子。口服A1盐正在对兔肾脏进行研究 部分肾动脉结扎致兔肾功能受损 缺乏钙的饮食，对胃完整性受损的兔 制成阿司匹林混悬液，并设适当对照组。 对血清A1进行了药代动力学分析。结果 来自急性的研究将应用于亚慢性的设计 A1暴露研究，以确定是否影响 A1的药代动力学也影响A1的组织蓄积和 毒性。多种生理指标(行为、A1组织 水平和神经病理学)将被用来确定毒性。 目前正在进行研究，以阐明A1的作用机制 用大鼠离体肠切片和原位灌流的方法吸收 大鼠肠道准备。研究也在进行中，以澄清 家兔肾脏清除A1的机制 肾皮质切片和斯珀伯鸡技术。研究是 建议利用海马区切片技术来确定 A1对神经递质释放及远期的影响 增强功能。这一结果可能解释了A1-的形成机制。 诱发的神经行为毒性。辛醇/水的研究 分区系统表明，识别 无A1配位的化合物与有配位的化合物 为了螯合A1，并定义A1的亲水性，螯合剂 和A1络合物。测试的潜在A1螯合剂 在体外对A1负荷的兔进行体内A1- 螯合活性。使用这两种方法，这两种方法进一步潜力 将对A1螯合剂进行测试，目的是口头识别 有效、安全的A1螯合剂。最后，要确定化学物质 在A1中毒的哺乳动物中，A1的形式被提出研究 选择分离技术来确定化学物质 生物组织中A1的形态。

The long term objectives of the applicant are to contribute to the understanding of the etiology of aluminum (A1) toxicology and the development of prevention and treatment strategies. The work to be conducted during the Research Career Development Award will follow several avenues of research. One is to determine the significance of the factors that may contribute to the absorption and accumulation of A1. These studies are underway, being supported by NIH grant ES 2676. Acute bioavailability studies are being conducted to clarifying the roles of the form of A1, impaired renal function, altered gastic integrity, and calcium deficiency on A1 absorption and intravenous pharmacokinetics in rabbits. Oral A1 salts are being studied in rabbits renally impaired by partial renal artery ligation, in rabbits maintained on Ca-deficient diets, in rabbits with compromised stomach integrity produced by aspirin suspension, and in appropriate control rabbits. Pharmacokinetic analyses of serum A1 are conducted. Results from the acute studies will be applied to the design of sub-chronic A1 exposure studies to determine if the factors that influence the pharmacokinetics of A1 also influence A1 tissue accumulation and toxicity. Numerous physiological measures (behavior, A1 tissue levels, and neuropathology) will be used to determine toxicity. Studies are underway to elucidate the mechanisms by which A1 is absorbed, using isolated rat gut sections and the in situ perfused rat gut preparation. Studies are also underway to elucidate the mechanisms by which A1 is eliminated by the kidney, using rabbit renal cortex slices and the Sperber chicken technique. Studies are proposed to utilize the hippocampal slice technique to determine the influence of A1 on neurotransmitter release and on long term potentiation. The results may explain the mechanism of A1- induced neurobehavioral toxicity. Studies with an octanol/water partitioning system suggested that it may be useful to identify compounds with no A1 chelation potential vs. those with potential to chelate A1, and to define the hydrophilicity of A1, chelators and the A1 chelator complex. The potential A1 chelators tested in vitro were evaluated in the A1-loaded rabbit for in vivo A1- chelation activity. Using, these two approaches further potential A1 chelators will be tested, with the goal of identifying orally effective, safe A1 chelators. Finally, to determine the chemical forms of A1 in the A1-intoxicated mammal, studies are proposed to select separation techniques to determine the chemical speciation of A1 in biological tissue.