Ornithine Restores Ureagenesis Capacity And Mitigates Hyperammonemia In Otc(Spf-Ash) Mice

We showed that Otc(spt-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 mu mol/(kg(.)h)] on urea and glutamine kinetics in conscious Otc(spf-ash) mice under a glycine-alanine load [6.06 mmol/(kg(.)h)], a multiple tracer infusion protocol ([(CO)-C-13-O-18]urea, [5-N-15]glutamine, [2,3,3,4,4 D-5]glutamine and [ring-D-5] 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 mu mol/L, P < 0.001), and prevented acute hepatic enlargement (P < 0.006) in Otc(spf-ash) mice. Ornithine supplementation also increased [96 +/- 20 vs. 120 16 mu moI/(kg(.)h), P < 0.001] the transfer of N-15 from glutamine to urea, to values observed in the control mice [123 +/- 17 mu mol/(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 N-15 from glutamine to urea. These data strongly suggest that ornithine has the potential for the biochemical correction of OTCD in Otc(spf-ash) mice.