Vestigial ornithine transcarbamylase activity does not impair ureagenesis in Otc spf‐ash mice

Abstract

Mouse models for urea cycle (UC) disorders have been available for the past 30 years; however, until now no measurements of urea entry rate (UER) in vivo have been conducted. The purpose of this research was the study of urea metabolism in conscious Otcspf-ash mice, a model of ornithine transcarbamylase deficiency, under defined nitrogen load conditions. UER was determined in mutant and littermate controls by a primed-continuous infusion of 15N15N urea. A saline infusion control, a complete mixture of amino acids (AA) or a Glycine-Alanine (GA) mixture were infused at 0 (Saline), 86 (AA1, GA1) and 172 mg N kg−1 h−1 (AA2, GA2) to impose a defined nitrogen load on the UC. UER and plasma urea concentration (PU) increased (P < 0.001) as a consequence of the increase in level of infusion of the complete mixture of amino acids, but no difference (P = 0.96, P = 0.44, respectively) between the two genotypes was detected. The infusion of the GA mixture, however, decreased the PU (P < 0.001) and UER in Otcspf-ash compared to controls. At the higher level (GA2) UER was further depressed (P < 0.001) and Otcspf-ash mice became hyperammonemic (1701±150 μM). An acute hepatic enlargement (P < 0.001) was also evident in Otcspf-ash mice infused with GA2. The present results show that despite very low OTC activity, Otcspf-ash mice were able to maintain UER at the same rate as control animals, if arginine or UC intermediates were provided. This implies that there is a hepatic requirement for these UC intermediates to sustain ammonia detoxification and urea production in Otcspf-as mice.