Physiologically-based kinetic models are increasingly being incorporated into the assessment of risk arising from exposure to toxicants, and development of models on the kinetic behavior of metals, including arsenic, has been actively investigated for several years. A rational approach to the development of models on the kinetic behavior of metals, including arsenic, has been actively investigated for several years. A rational approach to the development of a complex kinetic model such as that required for arsenic (with the several chemical forms that it can take) involves establishing the most fundamental components of the model first, upon which higher levels of interaction can be built. Exposure of the cells of target tissues requires first that the toxicant cross cell membranes to access intracellular sites of intoxication. This can be followed by export of chemically different forms of the toxicant which can then serve as substrate for distant sites. Consequently, knowledge of the pathways and rates of arsenic flux across target tissue cell membranes must be considered a fundamental element in the development and ultimate calibration and validation of a physiological kinetic model of arsenic behavior. The present proposal has two principal aims, namely the elucidation of the major arsenic transport processes within cells of two tissue/organ systems which play central roles in the elimination of arsenic from the body: the kidney (with an emphasis on the proximal tubule), and the urinary bladder (which is an important target of arsenic carcinogenicity). The studies outlined in this proposal will determine, for the first time, how the major forms of arsenic enter and leave cells of the kidney studies outlined in this proposal will determine, for the first time, how the major forms of arsenic enter and leave cells of the kidney and bladder. Specifically, we will define the mechanisms of cellular transport of As(III), As(V), methylarsonic acid and dimethylarsinic acid, and determine the kinetics of their transport in each test tissue. We will test the general hypothesis that interactions of several arsenic species with intracellular glutathione exerts a profound effect on the export of arsenic from cells and therefore, influences the nature of the arsenic species to which other target cells are exposed. We will also test the novel hypothesis that endocytosis plays a quantitatively significant role in the entry and exposure to arsenic in bladder cells. Our approach involves comparison of effects obtained with intact tissues with those obtained single cloned transport proteins. The latter system will permit a well- focused examination of the properties of single transporters, with the former provides the only means to assess how the integrate activity of a suite of processes influences net cellular transport of arsenic. These data will provide a means for transport processes on overall arsenic flux in these tissues. These results can be expected to provide needed refinements to ongoing efforts to develop a physiologically-based kinetic model for the behavior of arsenic in biological systems.
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