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Nutrition and Disease

Reduced Ornithine Transcarbamylase Activity Does Not Impair Ureagenesis in Otc^spf-ash Mice¹

Juan C. Marini^*,2, Brendan Lee and Peter J. Garlick^*

^* Animal Science Department, University of Illinois, Urbana IL 61801 and Molecular and Human Genetics and Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030

² To whom correspondence should be addressed. E-mail: jcmarini{at}uiuc.edu.

Mouse models for urea cycle disorders have been available for the past 30 y; however, until now, no measurements of urea production in vivo have been conducted. Urea entry rate was determined in Otc^spf-ash and littermate controls employing a primed-continuous infusion of ¹⁵N¹⁵N urea. A saline infusion control, a complete mixture of amino acids (AA), or a glycine-alanine (GA) mixture was infused at 86 (AA₁ and GA₁) and 172 mg N · kg^–1 · h^–1 (AA₂ and GA₂) to impose a defined nitrogen load on the urea cycle. Urea entry rate and plasma urea concentration increased (P < 0.001) as a consequence of the increase in the infusion rate of the complete mixture of amino acids, but the 2 genotypes did not differ (P = 0.96 and P = 0.44, respectively). The infusion of the GA mixture, however, decreased (P < 0.001) the plasma urea concentration and urea entry rate in Otc^spf-ash mice compared with controls. At the highest level (GA₂), urea entry rate was further depressed (P < 0.001), Otc^spf-ash mice became hyperammonemic (1701 ± 150 µmol/L), and hyperammonemic symptoms were evident. An acute hepatic enlargement (P < 0.001) was also evident in Otc^spf-ash mice infused with GA₂. These results show that despite vestigial OTC activity, Otc^spf-ash mice were able to maintain ureagenesis at the same rate of control animals when a complete mixture of amino acids was infused. This implies that Otc^spf-ash mice are able to dispose of ammonia, without apparent adverse effects, when a balance mixture of amino acids is provided, despite reduced enzyme activity.

KEY WORDS: • mouse models • spf-ash mouse • ornithine transcarbamylase deficiency • urea cycle disorders • urea kinetics

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