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

点击翻译按钮获取中文摘要

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.