Hyperammonemia is observed in a variety of diseased states, including genetic defects in amino acid metabolism and the urea cycle, carnitine deficiency, drug intoxification, hepatic coma, and Reye's syndrome. In 1979, the clinical use of benzoate was introduced to combat the hyperammonemia of urea cycle enzymopathies, through the elimination of waste nitrogen as hippurate. The success of benzoate therapy in these patients aroused interest in the use of benzoate to combat hyperammonemia in a broader spectrum of diseases. But laboratory studies suggest that, except in specific urea cycle defects, benzoate therapy may be harmful. These and other findings prompted a proposal with the following specific aims: 1. It is suggested that benzoate potentiates ammonia toxicity in the normal animal by interfering with the urea cycle. Studies on the incorporation of precursors into citrulline and urea in isolated hepatocytes are proposed to test this hypothesis, identify the site of inhibition, and establish the mechanism. 2. A similar experimental plan is proposed to determine whether benzoate inhibits pyrimidine biosynthesis by the same mechanism. 3. Disposal of waste nitrogen as hippurate is limited by replenishment of glycine. The influence of non-nitrogenous precursors, waste nitrogen, redox state, impaired ureagenesis, and fatty metamorphosis of liver on the capacity of isolated hepatocytes for the synthesis of glycine and hippurate will be examined. 4. Assays of the incorporation of various precursors into hippurate are proposed to discriminate between the possible sources of glycine under a nitrogen load. The pathway from waste nitrogen is unresolved. 5. The protective effect of benzoate against a challenge of ammonia will be examined with animals in a physiological state more representative of clinical conditions than in previous studies. The proposed work is expected to reconcile apparent contradictions between laboratory and clinical findings, and to contribute toward the effective use of benzoate in the management of hyperammonemia.
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