N-Acetylglutamate Content in Liver and Gut of Normal and Fasted Mice, Normal Human Livers, and Livers of Individuals with Carbamyl Phosphate Synthetase or Ornithine Transcarbamylase Deficiency

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Abstract
N-acetylglutamate (NAG) content was measured in homogenates of liver and small intestine obtained from normal and 24-h starved syngeneic mice. Subsequently, NAG was determined in normal, and in carbamyl phosphate synthetase I and ornithine transcarbamylase enzyme-deficient human liver tissue homogenates. The method used in this study, which is direct and highly specific, used anion exchange extraction, gas chromatographic separation, and mass spectrometric detection and quantitation. Hepatic NAG content in the fed animals was 94.8 ± 19.8 nmol/g tissue or 602.5 ± 168.4 nmol/g protein (mean ± SD, n = 5), whereas it was much lower in the fasted mice (49.4 ± 13.0 nmol/g tissue or 330.1 ± 113.9 nmol/g protein, mean ± SD, n = 5). The magnitude of the difference was much smaller for intestinal NAG content, 19.8 ± 5.4 nmol/g tissue or 205.3 ± 70.3 nmol/g protein (mean ± SD, n = 5) in the fed mice and 14.2 ± 4.3 nmol/g tissue or 168.1 ± 80.8 nmol/g protein (mean ± SD, n = 5) in the fasted mice. The concentrations of hepatic NAG in normal human livers (controls) ranged from 19.3 to 67.1 nmol/g tissue (41.6 ± 19.3, mean ± SD, n = 5) or from 193 to 764.3 nmol/g of protein (437.5 ± 233.4, mean ± SD, n = 5). In three patients with apparently complete carbamyl phosphate synthetase I or ornithine transcarbamylase deficiency, hepatic NAG levels were lower than controls (2.2-12.8 nmol/g tissue 42.3-140.7 nmol/g protein), two patients with ornithine transcarbamylase deficiency had levels similar to the controls and one patient with carbamyl phosphate synthetase I deficiency had elevated levels (98.4 nmol/g tissue, 1185.5 nmol/g protein). The livers of two patients with cirrhosis and hyperammonemia contained amounts of NAG within the range of normal livers. The marked variability in tissue NAG concentrations in various nutritional and metabolic conditions favors the hypothesis that NAG plays a role in the regulation of urea synthesis. Hepatic NAG levels are markedly reduced in some but not all patients with defects in urea cycle enzymes.