Effect of Sodium Benzoate and Sodium Phenylacetate on Brain Serotonin Turnover in the Ornithine Transcarbamylase-Deficient Sparse-Fur Mouse

Abstract

Herein we examine the effects of sodium benzoate and sodium phenylacetate on feeding and central serotonin turnover in a child with citrullinemia and in an animal model of congenital hyperammonemia, the ornithine transcarbamylase-deficient sparse-fur (spfly) mouse. In the child, when the benzoate/phenylacetate dosage was increased from 200 to 375 mg/kg/day each, feeding decreased. There was an accumulation of benzoate and phenylacetate in blood and cerebrospinal fluid a s well a s an increased concentration of 5-hydroxyindoleacetic acid, a neurochemical marker for serotonin turnover, in cerebrospinal fluid. In the mouse, sodium benzoate had a biphasic effect on both plasma ammonium levels and brain serotonin turnover. Two percent oral benzoate was associated with an increase in ammonium level, while a 3% dose led to a decrease in ammonium. There was a similar effect on serotonin turnover noted in both the hyperammonemic spfly and control CD-lly mice. Sodium phenylacetate did not have a consistent effect on serotonin turnover. The mechanism by which benzoate increases brain serotonin turnover appears to involve competition with tryptophan for albumin binding sites. This results in increased free tryptophan in serum and brain. W e speculate that some of the clinical symptoms of benzoate intoxication may be a consequence of altered serotonin turnover in the brain. We suggest that drug levels be monitored during therapy. 36excretion in children with inborn errors of urea synthesis (1). This has resulted in prolonged survival. However, both intravenous drugs used to treat acute hyperammonemia and inadvertent oral overdoses have been associated with clinical toxicity including anorexia, irritability, lethargy, and coma (1, 2). Symptoms of intoxication in part simulate those of hyperammonemia. The mechanism of these behavioral alterations is unclear. Bachmann et al. (3) re~orted increased brain uvtake of Tm. the precursor of serotbnin,tn rats injected with 1 mmol/kg of sddium benzoate. Increased brain uvtake of T m and increased brain serotonin turnover have also been reported in experimentally induced and naturally occurring hyperammonemia (4-7). These findings, together with data showing an association of anorexia with increased serotonin turnover in children with urea cycle disorders (8), suggest that benzoate intoxication may involve altered serotonin turnover.In studying the effect of benzoate and phenylacetate on serotonin turnover, we initially present a case report of a child with citrullinemia who developed toxic symptoms during high dose therapy and was found to have increased levels of the metabolite of serotonin, HIAA, in cerebrospinal fluid. We then examine in more detail the interaction of hyperammonemia and benzoate/ phenylacetate treatment on brain serotonin turnover in the chronically hyperammonemic ornithine transcarbamylase deficient sparse-fur (spf/y) mouse. METHODSBiochemical methods. Plasma ammonium was measured by a microfluorometric adaptation of a glutamate dehydrogenase method as previously d...

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