Many factors contribute to cataract in the human population. Senile catarct cocurs most frequently, but dietary deficiencies or excesses and genetic components may contribute to abnormal lens development and function. Our goal is to further understand causal relationships in cataractogenesis. Experimental models allow careful examination of how cellular metabolism maintains lens transparency, and thus contribute to our understanding of the pathogenesis of cataract. Sodium selenite causes rapid nuclear cataract formation in l0-15-day old rats. This experimental model can be used to establish sequential events which occur in vivo over time intervals of hours. Furthermore, as selenite effects on lens metabolism are described and quantified, much is learned about the action of selenite. This aspect of the proposed work has broad implications since selenium has current prominence as a therapeutic agent, particularly in treating cancer. Obvious nuclear cataract appears within 72 h of a single subcutaneous dose of sodium selenite (20-30 Mumol/g body wt). When rats older than 21 days are treated with selenite, cataract does not form. Prior to cataract formation significant changes in metabolite levels accompany shifts in metabolic flux rates in those lenses which accumulate selenium. Among the many effects attributed to selenium action are inhibited mitochondrial function, altered membrane permeability and sulfhydryl oxidation. Such phenomena accompany cataract formation in other experimental cataractogenic systems but over much longer time periods. We propose to quantify effects of selenite on glycolysis and glutaminolysis using both in vivo and in vitro exposure techniques. Using appropriate radio-labelled substrates, we plan to measure both rate and flux through the major metabolic pathways for generation of energy and reducing equivalents and for synthesis of glutathione, membrane lipids and structural proteins. We intend to map the sequence and interrelatedness of selenite effects and their roles in cataract formation. The selenite model is a relevant, efficient and rapid means of recognizing and characterizing the metabolic progenitors of cataract.
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