This project is aimed at exploring the underlying biochemical mechanisms of two animal models for the human Fanconi syndrome. The first model is one produced in rat renal tubule by use of succinylacetone which is found in the urine of infants with hereditary tyrosinemia and the Fanconi syndrome; the second model is produced by use of maleic acid, the cis-isomer of fumaric acid. In the course of normal human tyrosine catabolism a unique compound, maleylacetoacetate, is produced; thus a potential explanation for the human renal tubular disorder involves intracellular cleavage of maleylacetoacetate, release of free maleate within the tubular epithelium and production of tubular dysfunction in a fashion similar to that of the animal model. In order to explore this possibility, the following are proposed: a. to characterize fully the in vitro effects of succinylacetone on membrane transport of sugars and amino acids, using both the isolated rat renal tubule and brushborder membrane vesicle preparations. b. to determine the effect(s) of succinylacetone and maleylacetoacetate on phosphate handling in vivo and in vitro by the rat kidney. 32Pi uptake will be studied in the isolated renal tubule. 32P incorporation into ATP will be examined in the presence of both inhibitor compounds. c. to determine the intracellular effects of succinylacetone and maleate on renal tubular heme biosynthesis and incorporation by monitoring 5-aminolevulinic and dehydratase activity, 14C-succinate incorporation into 5-aminolevulinate, cytochrome P450 content and 02 consumption. d. to determine in the newborn and developing rat renal tubule the membrane transport and heme biosynthetic effects of suddinylacetone as in (a)-(c), and to compare these effects to those of maleate. e. to determine the role of renal cortex in conversion of maleylacetoacetate to maleate by enzymatic hydrolysis during production of succinylacetone from tyrosine in cytosolic preparations.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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General Medicine B Study Section (GMB)
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Virginia Commonwealth University
Schools of Medicine
United States
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Roth, K S; Spencer, P D; Moses, L C et al. (1990) delta-Aminolevulinic acid dehydratase: is there a form unique to renal cortex? Enzyme 43:17-25
Roth, K S; Carter, B E; Moses, L C et al. (1990) On rat renal aminolevulinate transport and metabolism in experimental Fanconi syndrome. Biochem Med Metab Biol 44:238-46
Spencer, P D; Medow, M S; Moses, L C et al. (1988) Effects of succinylacetone on the uptake of sugars and amino acids by brush border vesicles. Kidney Int 34:671-7