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.