Hematologic responses in pernicious anemia to orotic acid.

By R. WAYNE RUNDLES AND SPENCER S. BREwER, JR. OROTIC ACID has become a compound of considerable metabolic interest in recent years since it appears to be a key intermediate in the synthesis of pyrimidines. It was discovered in the whey of cow’s milk by Biscara and Belloni in 1905, but its correct chemical structure was not established unfil 1930 by Bachstez.’2 Orotic acid has been isolated from the milk of several mammals,3 and from yeast, liver, and (tried distiller’s solubles.”4 In fresh cow’s milk its average concentration is 50 to 100 y/ml. During the first one to three days after parturition, an amount four to five times as great is found.3 The first definite indication that orotic acid might be important in nucleic acid biosynthesis was the finding by Loring and Pierce and Rogers in 1944 that it could replace pyrimidines as a growth factor for a mutant of Neurospora and for certain streptococci.2’ Orotic acid was subsequently found to accumulate in large amounts in growing cultures of mutants of NeuroWora which required uridine, cytidine, or uracil.’ It was found to be a growth requirement for Lactohacillus hiilgarieiis 09. in this organism, equal concentrations of ureidosuccinic acid (carbamyl L-aspartate) were 10 to 20 per cent as effective. In young rats depleted of growth factors and maintained on a purified diet, the addition of orotic acid led to increased weight gain.4 Isotopically labeled orotic aci(l is readily incorporated into the pyrimidines of E. coli B, yeast, rat liver slices, rat tissues, animal and human tumors.2’7-9 In undertaking an investigation of the hematologic effect of some nucleic acid derivatives an(l precursors in p ttients with various types of impaired bone marrow function, orotic acid appeared to he a promising pyrimidine to study. That fairly complete and sustained remissions could be produced in