Effect of sodium benzoate on cerebral and hepatic energy metabolites in spf mice with congenital hyperammonemia.

The sparse-fur (spf) mutant mouse has an X-linked deficiency of ornithine transcarbamylase and develops congenital hyperammonemia similar to that seen in human patients. We studied the effect of sodium benzoate (2.5, 5 and 10 mmol/kg body wt) on ammonia, glutamine and glutamate, as well as various intermediates of energy metabolism in brain and liver of normal CD-1/Y and hyperammonemic spf/Y mice. The ammonia concentration of brain was decreased with 2.5 mmol sodium benzoate in spf/Y mice, whereas higher doses resulted in a significant increase in both liver and brain. Cerebral glutamine content decreased generally in a dose-dependent manner, both in normal and affected mice, following treatment with various doses of sodium benzoate. Cerebral glutamate concentrations were increased only in spf mice treated with sodium benzoate, whereas ATP and acetyl CoA were decreased (P < 0.001), in both normal and affected mice, indicating that glutamine synthesis may be affected by ATP availability. Free CoA levels were decreased (P < 0.05) only in liver in both groups of treated mice, whereas pyruvate concentrations were elevated (P < 0.05) in affected mice following sodium benzoate administration. The results demonstrate that a dose of 2.5 mmol sodium benzoate/kg body wt has a beneficial effect in reducing cerebral ammonia with a concomitant decrease in glutamine. However, the results suggest that many of the metabolite changes observed following higher doses of benzoate could be due to depletion of ATP, free CoA and acetyl CoA levels, possibly secondary to benzoyl CoA accumulation. The response of the spf/Y mouse to sodium benzoate was different from that of the control CD-1/Y mouse, which could be due to its urea cycle dysfunction and a chronic hyperammonemic state. Hence, the spf/Y mouse may be the ideal animal model for studying the pharmacology of sodium benzoate in hyperammonemic disorders at both the cerebral and hepatic levels.