Reduced ornithine transcarbamylase activity does not impair ureagenesis in Otc(spf-ash) mice.
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 micromol/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.
Marini
Juan C
JC
Animal Science Department, University of Illinois, Urbana, IL 61801, USA. jcmarini@uiuc.edu
Lee
Brendan
B
Garlick
Peter J
PJ
D000596:Amino Acids / Q000008:administration & dosage; D000641:Ammonia / Q000097:blood / Q000378:metabolism; D000818:Animals; D004151:Dipeptides / Q000008:administration & dosage; D005508:Food Deprivation; D005838:Genotype; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D009954:Ornithine Carbamoyltransferase / Q000235:genetics / Q000378:metabolism; D020163:Ornithine Carbamoyltransferase Deficiency Disease; D012044:Regression Analysis; D014508:Urea / Q000097:blood / Q000378:metabolism*; D015431:Weight Loss
D000596:Amino Acids; D004151:Dipeptides; D000641:Ammonia; D014508:Urea; C065992:N-glycylalanine; D009954:Ornithine Carbamoyltransferase