Ornithine restores ureagenesis capacity and mitigates hyperammonemia in Otc spf‐ash mice

Abstract

We have previously shown that Otcspf-ash mice, a model of ornithine transcarbamylase deficiency, were able to sustain ureagenesis at the same rate as control mice, despite vestigial enzyme activity, when a complete mixture of amino acids was provided. To study the effect of ornithine supplementation (Orn; 316 μmol kg−1 h−1) on urea and glutamine kinetics in conscious Otcspf-ash mice under a glycine-alanine load (86 mg N kg−1 h−1), a multiple isotope infusion protocol was conducted. 13C18O urea, 15N (amido) glutamine, 2H5 glutamine and 2H5 phenylalanine were infused for 4 h. Orn restored ureagenesis (3.18 vs 4.56 mmol kg−1 h−1, P < 0.001), reduced plasma ammonia concentration (1125 vs 193 μM, P < 0.001) and prevented acute hepatic enlargement (P < 0.006) in Otcspf-ash mice. Orn also increased (96 vs 120 μmol kg−1 h−1, P < 0.001) the transfer of 15N from glutamine to urea, to values observed in the control mice (123 μmol kg−1 h−1). Amido N glutamine flux increased (2.23 vs 3.65 mmol kg−1 h−1; P < 0.001) in Otcspf-ash mice, but Orn had no effect (P < 0.23). The flux of glutamine carbon skeleton was affected by both genotype (P < 0.0001) and by Orn (P 0. 024). Phenylalanine flux was increased (P < 0.003) by Orn supplementation and there was a trend (P < 0.06) to further increase in supplemented Otcspf-ash mice. In conclusion, Orn restored ureagenesis, mitigated hyperammonemia, prevented liver enlargement and normalized the transfer of 15N from glutamine to urea. These data strongly suggest that Orn has the potential for the biochemical correction of OTCD in Otcspf-ash mice.