{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T01:20:48Z","timestamp":1784164848777,"version":"3.55.0"},"reference-count":40,"publisher":"American Physiological Society","issue":"6","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Endocrinology and Metabolism"],"published-print":{"date-parts":[[2007,12]]},"abstract":"<jats:p>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 [<jats:sup>13<\/jats:sup>C<jats:sup>18<\/jats:sup>O]urea, l-[<jats:sup>15<\/jats:sup>N<jats:sub>2<\/jats:sub>]arginine, l-[5,5 D<jats:sub>2<\/jats:sub>]ornithine, l-[6-<jats:sup>13<\/jats:sup>C, 4,4,5,5, D<jats:sub>4<\/jats:sub>]citrulline, and l-[ring-D<jats:sub>5<\/jats:sub>]phenylalanine to investigate the interaction between genetic background and spf-ash mutation on ureagenesis, arginine metabolism, and nitric oxide production. ICR<jats:sup>spf-ash<\/jats:sup>mice maintained ureagenesis (5.5 \u00b1 0.3 mmol\u00b7kg<jats:sup>\u22121<\/jats:sup>\u00b7h<jats:sup>\u22121<\/jats:sup>) and developed mild hyperammonemia (145 \u00b1 19 \u03bcmol\/l) when an unbalanced nitrogen load was imposed; however, B6<jats:sup>spf-ash<\/jats:sup>mice became hyperammonemic (671 \u00b1 15 \u03bcmol\/l) due to compromised ureagenesis (3.4 \u00b1 0.1 mmol\u00b7kg<jats:sup>\u22121<\/jats:sup>\u00b7h<jats:sup>\u22121<\/jats:sup>). 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 \u03bcmol\u00b7kg<jats:sup>\u22121<\/jats:sup>\u00b7h<jats:sup>\u22121<\/jats:sup>). Arginine entry rate was only reduced in B6<jats:sup>spf-ash<\/jats:sup>mice (B6<jats:sup>spf-ash<\/jats:sup>: 332, ICR<jats:sup>spf-ash<\/jats:sup>: 453; SE 20.6 \u03bcmol\u00b7kg<jats:sup>\u22121<\/jats:sup>\u00b7h<jats:sup>\u22121<\/jats:sup>). Genetic background and mutation had an effect on nitric oxide production (B6: 3.4, B6<jats:sup>spf-ash<\/jats:sup>: 2.8, ICR: 9.0, ICR<jats:sup>spf-ash<\/jats:sup>: 4.6, SE 0.7 \u03bcmol\u00b7kg<jats:sup>\u22121<\/jats:sup>\u00b7h<jats:sup>\u22121<\/jats:sup>). Protein breakdown was the main source of arginine during the postabsorptive state and was higher in ICR<jats:sup>spf-ash<\/jats:sup>than in B6<jats:sup>spf-ash<\/jats:sup>mice (phenylalanine entry rate 479 and 327, respectively; SE 18 \u03bcmol\u00b7kg<jats:sup>\u22121<\/jats:sup>\u00b7h<jats:sup>\u22121<\/jats:sup>). Our results highlight the importance of the interaction between mutation and genetic background on ureagenesis, arginine metabolism, and nitric oxide production. 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