Interaction between murine spf-ash mutation and genetic background yields different metabolic phenotypes.
The spf-ash mutation in mice results in reduced hepatic and intestinal ornithine transcarbamylase. However, a reduction in enzyme activity only translates in reduced ureagenesis and hyperammonemia when an unbalanced nitrogen load is imposed. Six-week-old wild-type control and spf-ash mutant male mice from different genetic backgrounds (B6 and ICR) were infused intravenously with [(13)C(18)O]urea, l-[(15)N(2)]arginine, l-[5,5 D(2)]ornithine, l-[6-(13)C, 4,4,5,5, D(4)]citrulline, and l-[ring-D(5)]phenylalanine to investigate the interaction between genetic background and spf-ash mutation on ureagenesis, arginine metabolism, and nitric oxide production. ICR(spf-ash) mice maintained ureagenesis (5.5 +/- 0.3 mmol.kg(-1).h(-1)) and developed mild hyperammonemia (145 +/- 19 micromol/l) when an unbalanced nitrogen load was imposed; however, B6(spf-ash) mice became hyperammonemic (671 +/- 15 micromol/l) due to compromised ureagenesis (3.4 +/- 0.1 mmol.kg(-1).h(-1)). Ornithine supplementation restored ureagenesis and mitigated hyperammonemia. A reduction in citrulline entry rate was observed due to the mutation in both genetic backgrounds (wild-type: 128, spf-ash: 60; SE 4.0 micromol.kg(-1).h(-1)). Arginine entry rate was only reduced in B6(spf-ash) mice (B6(spf-ash): 332, ICR(spf-ash): 453; SE 20.6 micromol.kg(-1).h(-1)). Genetic background and mutation had an effect on nitric oxide production (B6: 3.4, B6(spf-ash): 2.8, ICR: 9.0, ICR(spf-ash): 4.6, SE 0.7 micromol.kg(-1).h(-1)). Protein breakdown was the main source of arginine during the postabsorptive state and was higher in ICR(spf-ash) than in B6(spf-ash) mice (phenylalanine entry rate 479 and 327, respectively; SE 18 micromol.kg(-1).h(-1)). Our results highlight the importance of the interaction between mutation and genetic background on ureagenesis, arginine metabolism, and nitric oxide production. These observations help explain the wide phenotypic variation of ornithine transcarbamylase deficiency in the human population.
Marini
Juan C
JC
USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA. marini@bcm.edu
Erez
Ayelet
A
Castillo
Leticia
L
Lee
Brendan
B
D000409:Alanine / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics; D000641:Ammonia / Q000097:blood / Q000378:metabolism; D000818:Animals; D001120:Arginine / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics; D002956:Citrulline / Q000097:blood / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005998:Glycine / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics; D007275:Injections, Intravenous; D007413:Intestinal Mucosa / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D008954:Models, Biological; D009154:Mutation; D009569:Nitric Oxide / Q000378:metabolism; D009952:Ornithine / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics; D009954:Ornithine Carbamoyltransferase / Q000235:genetics / Q000378:metabolism*; D020163:Ornithine Carbamoyltransferase Deficiency Disease / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D010649:Phenylalanine / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics; D014508:Urea / Q000097:blood / Q000378:metabolism
D002956:Citrulline; D009569:Nitric Oxide; D010649:Phenylalanine; D000641:Ammonia; D014508:Urea; D001120:Arginine; D009952:Ornithine; D009954:Ornithine Carbamoyltransferase; D000409:Alanine; D005998:Glycine