Ornithine restores ureagenesis capacity and mitigates hyperammonemia in Otcspf-ash mice

Abstract

We showed that Otcspf-ash mice, a model of ornithine transcarbamylase deficiency, were able to sustain ureagenesis at the same rate as control mice, despite reduced enzyme activity, when a complete mixture of amino acids was provided. An unbalanced amino acid mixture, however, resulted in reduced ureagenesis and hyperammonemia. To study the effect of ornithine supplementation [316 μmol/(kg·h)] on urea and glutamine kinetics in conscious Otcspf-ash mice under a glycine-alanine load [6.06 mmol/(kg·h)], a multiple tracer infusion protocol ([13C 18O]urea, [5-15N]glutamine, [2,3,3,4,4 D 5]glutamine and [ring-D5] phenylalanine) was conducted. Ornithine supplementation increased ureagenesis [3.18 ± 0.88 vs. 4.56 ± 0.51 mmol/(kg·h), P < 0.001], reduced plasma ammonia concentration (1125 ± 621 vs. 193 ± 94 μmol/L, P < 0.001), and prevented acute hepatic enlargement (P < 0.006) in Otcspf-ash mice. Ornithine supplementation also increased [96 ± 20 vs. 120 ± 16 μmol/(kg·h), P < 0.001] the transfer of 15N from glutamine to urea, to values observed in the control mice [123 ± 17 μmol/(kg·h)]. De novo amido-N glutamine flux was higher [1.57 ± 0.37 vs. 3.04 ± 0.86 mmol/(kg·h); P < 0.001] in Otc spf-ash mice, but ornithine supplementation had no effect (P < 0.56). The flux of glutamine carbon skeleton was affected by both genotype (P < 0.0001) and by ornithine (P 0. 036). In conclusion, ornithine supplementation restored ureagenesis, mitigated hyperammonemia, prevented liver enlargement, and normalized the transfer of 15N from glutamine to urea. These data strongly suggest that ornithine has the potential for the biochemical correction of OTCD in Otcspf-ash mice. © 2006 American Society for Nutrition.