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

AL 3 毒性：影响因素，AL 形式

• 批准号: 3072738
• 负责人: Robert Allen Yokel
• 金额: $ 5.15万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-08-01 至 1992-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3072738
• 关键词: aluminum; antidotes; atomic absorption spectrometry; calcium disorder; calmodulin; chelating agents; chickens; detoxification; dietary calcium; dosage; gastrointestinal toxin absorption; high performance liquid chromatography; human tissue; kidney function; laboratory rabbit; laboratory rat; metal poisoning; neurophysiology; neurotransmitters; poison control; toxicant interaction; toxicant screening; toxin metabolism

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.

申请人的长期目标是为 了解铝 (A1) 毒理学的病因学和 制定预防和治疗策略。 该工作至 在研究职业发展奖期间进行 将遵循多种研究途径。 一是确定 可能有助于吸收的因素的重要性 和A1的积累。 这些研究正在进行中，正在 由 NIH 拨款 ES 2676 支持。急性生物利用度研究是 正在澄清A1形式的作用， 肾功能受损、胃完整性改变和钙 A1 吸收和静脉药代动力学缺陷 兔子。 口服 A1 盐正在兔子肾脏中进行研究 兔子因部分肾动脉结扎而受损 胃完整性受损的兔子的缺钙饮食 由阿司匹林悬浮液产生，并在适当的对照兔子中进行。 进行血清 A1 的药代动力学分析。 结果 急性研究将应用于亚慢性的设计 A1 暴露研究以确定影响因素 A1 的药代动力学也影响 A1 的组织积累和 毒性。 众多生理测量（行为、A1 组织 水平和神经病理学）将用于确定毒性。 正在进行研究以阐明 A1 的作用机制 吸收，使用分离的大鼠肠道切片和原位灌注 大鼠肠道准备。 研究也在进行中，以阐明 A1 被肾脏消除的机制，使用兔子 肾皮质切片和 Sperber 鸡技术。 研究是 建议利用海马切片技术来确定 A1 对神经递质释放和长期的影响 增强作用。 该结果可能解释A1-的机制 诱发神经行为毒性。 用辛醇/水进行研究 分区系统建议识别可能有用 不具有 A1 螯合潜力的化合物与具有潜力的化合物 螯合 A1，并定义 A1 的亲水性，螯合剂 和 A1 螯合剂复合物。 测试的潜在 A1 螯合剂 在 A1 负载兔子体内评估了体内 A1- 螯合活性。 使用这两种方法进一步发挥潜力 A1 螯合剂将进行测试，目的是鉴定口服 有效、安全的 A1 螯合剂。 最后确定化学成分 A1 中毒哺乳动物中 A1 的形式，建议进行研究 选择分离技术来确定化学物质 生物组织中 A1 的形态。