Aberrations of ammonia metabolism in ornithine carbamoyltransferase-deficient spf-ash mice and their prevention by treatment with urea cycle intermediate amino acids and an ornithine aminotransferase inactivator

Sparse fur with abnormal skin and hair (spf-ash) mice are deficient in orni thine carbamoyltransferase (OCT) activity, but their OCT protein is kinetic ally normal, We administered ammonium chloride to spf-ash mice, in order to analyze ammonia metabolism and to find a rationale for the therapy of OCT deficiency. Ammonia concentration in the liver of spf-ash mice increased to a level much higher than in the control. Ammonium chloride injection cause d an increase in ornithine (Om) 5 min after injection and an increase in th e sum of Orn, citrulline (Cit) and arginine (Arg) for at least 15 min in th e liver of control mice, but no increase in Orn, Cit and Arg in the liver o f spf-ash mice. Treatment of spf-ash mice with Arg 5-20 min prior to the in jection of ammonium chloride kept the hepatic ammonia concentration at a le vel comparable to that without the load. A significant reciprocal relations hip between ammonia and Orn concentrations in the liver of spf-ash mice 5 m in after an ammonium chloride load with or without Arg strongly suggests th at ammonia disposal is dependent on the supply of Om. In spf-ash mice loade d with tryptone as a nitrogen source, Arg supplementation showed a dramatic decrease in urinary orotic acid excretion in a dose-dependent manner. Simi lar effects were observed with Cit and Orn at the same dose, and a long-las ting effect with an ornithine aminotransferase inactivator, 5-(fluoromethyl )ornithine, at a much lower dose. The rate of urea formation in liver perfu sed with ammonium chloride was lower in spf-ash mice than in controls, but with the addition of Orn to the medium it increased to a similar level in c ontrol and spf-ash mice. These results indicate that OCT is not saturated w ith Orn in vivo under physiological conditions and that the administration or enrichment of the urea cycle intermediate amino acids enhances the OCT r eaction so that the ammonia metabolism of OCT-deficient spf-ash mice is at least partially normalized. (C) 1999 Elsevier Science B.V. All rights reser ved.