Effect of sodium benzoate and sodium phenylacetate on brain serotonin turnover in the ornithine transcarbamylase-deficient sparse-fur mouse.
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 (spf/y) 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 as well as 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 spf/y and control CD-1/y 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. We 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.
Batshaw
M L
ML
Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
Hyman
S L
SL
Coyle
J T
JT
Robinson
M B
MB
Qureshi
I A
IA
Mellits
E D
ED
Quaskey
S
S
D000284:Administration, Oral; D000592:Amino Acid Metabolism, Inborn Errors / Q000188:drug therapy; D000641:Ammonia / Q000097:blood; D000818:Animals; D001565:Benzoates / Q000494:pharmacology* / Q000627:therapeutic use; D019817:Benzoic Acid; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002648:Child; D002956:Citrulline / Q000378:metabolism; D006801:Humans; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D020163:Ornithine Carbamoyltransferase Deficiency Disease; D010648:Phenylacetates / Q000494:pharmacology* / Q000627:therapeutic use; D012701:Serotonin / Q000378:metabolism*
D001565:Benzoates; D010648:Phenylacetates; D002956:Citrulline; D012701:Serotonin; D000641:Ammonia; D019817:Benzoic Acid; C025136:phenylacetic acid