Species Comparison of the Influence of Ammonia on Orotic Acid and Urea Biosynthesis in Liver

Abstract

Although orotic aciduria occurs in both male and female rats fed an arginine-deficient diet, only hepatocytes from male rats exhibited an enhanced rate of orotate biosynthesis to increasing ammonium compared to controls. Inhibition of incorporation [14C]NaHCO3 into urea by norvaline in the rat and mouse was accompanied by a 20 and 25% increase in orotate biosynthesis, respectively. Injection of ammonium chloride (2 mmol/kg) or consumption of a diet devoid of arginine resulted in an increased urinary orotate excretion in the rat. Injection of a similar quantity of ammonium chloride in mice did not result in an orotic aciduria. The influence of ammonia and arginine on the biosynthesis of orotic acid and urea in isolated liver slices from various mammals was also examined. In rat, mouse and pig liver, increasing quantities of ammonia stimulated the incorporation of [14C]NaHCO3 into orotic acid. In porcine, bovine and ovine liver the incorporation of [14C]NaHCO3 into orotic acid was low and was minimally effected by supplemental ammonia. Addition of arginine to the incubation medium diminished the incorporation of [14C]NaHCO3 into orotic acid in the liver of all species examined except the cow and sheep. This decrease was accompanied by a stimulation of urea biosynthesis in the rat, but a depression in the pig. Addition of ammonium (5.0 mM) markedly increased the incorporation of [14C]NaHCO3 into urea in all mammalian liver slices examined. These studies show that the liver of various mammals can respond to increasing ammonia by increasing orotic acid biosynthesis. However, species differences in the response to ammonia are evident.