Urinary metabolites characteristic of urea-cycle amino acid deficiency

Experiments with 45-75-g male rats gave conclusive evidence that the simultaneous absence from the diet of arginine, ornithine, or citrulline caused an immediate and persistent elevation of orotic and citric acids in the urine. The experiments also demonstrated that a deficiency of no other individual amino acid increased urinary citrate and orotate. Elevated urinary excretion of orotic and citric acid occurred independently of the form of nonessential nitrogen. Replacement of arginine isonitrogenously with ornithine or citrulline prevented the rise in urinary orotic acid, but had different effects on growth, urinary citrate, and urinary urea. These differences were probably due to differential uptake of arginine, ornithine, and citrulline by tissues; In the reported experiments employing L-amino acids as sources of dietary nitrogen, a deficiency of any amino acid indispensable for growth and nitrogen balance or a deficiency of arginine, ornithine, or citrulline retarded growth, increased urinary urea, and decreased urinary ammonia. It is concluded that the severe loss of orotic acid during urea-cycle amino acid deficiency arises from a decreased capacity of the urea cycle to detoxify ammonia, thereby causing increased shunting of intramitochondrial carbamyl phosphate into pyrimidine synthesis. The similarities in metabolism during arginine deficiency and ammonia intoxication are discussed. The evidence shows that urinary orotic acid may be a valuable measure of arginine nutrition in mammals.