Orotic Aciduria and Arginine Deficiency

Abstract

GROWING rats¹, guinea-pigs², rabbits³ and possibly human beings⁴ require dietary arginine for optimum nitrogen retention and normal growth. Adult men⁵, dogs⁶ and rats¹ do not require dietary arginine for nitrogen equilibrium and it is assumed that adults of other species also meet all of their arginine needs from synthesis within tissues. Kennan and Cohen⁷ have suggested, however, that the Krebs–Henseleit urea cycle, in which arginine is an intermediate, operates at near maximum capacity for ammonia (that is NH₃+NH₄⁺) detoxification in immature rats. Sperm, which contain a large concentration of arginine, decrease in numbers and motility when collected from mature men or rats fed arginine-deficient diets^8,9. Free orotic acid found normally in milk¹⁰ cannot be readily detected in normal tissues¹¹. It is barely detectable in normal urine¹² unless orotate is fed (our unpublished results). We have observed profound orotic aciduria in arginine-deficient growing rats¹³ and in ammonia-intoxicated rats (unpublished results). The accumulated evidence suggested that endogenous synthesis provides limited reserves of arginine for detoxifying ammonia in mature animals and that important metabolic consequences might ensue if their diet lacked arginine. We report here experiments with rats which clearly show that marked increases in orotate and urea excretion are sensitive indicators of dietary arginine deficiency, regardless of age and body size. The data also show that the usual methods of determining amino acid needs for adult mammals fail to reveal biochemical changes caused by diets lacking available arginine.