Orotic acid, arginine, and hepatotoxicity

This communication presents evidence from the literature and recent experiments that describe circumstances wherein arginine may be a conditional dietary essential. Previous work has established that the synthesis of orotic acid (OA), the first pyrimidine formed in the de novo pathway of nucleic acid synthesis, becomes elevated whenever the ammonia load exceeds the capacity of the urea cycle. Under these circumstances, the common intermediate, carbamyl phosphate, leaks from the mitochondria and induces OA synthesis in the cytoplasm. This leads to increased OA excretion in the urine as pyrimidine synthesis escapes feedback control. A deficiency of urea cycle substrates such as arginine, and administration of certain drugs, ammonium salts, urease, or excess amino acids raises orotic acid excretion. Our recent experiments in rats show that OA excretion is also elevated after partial hepatectomy following galactosamine administration, exposure to carbon tetrachloride, or feeding 36% of calories as ethanol. The elevation in OA excretion was suppressed by dietary supplementation with arginine, implying that arginine is conditionally essential. Adult human male alcoholics showed elevated urinary orotic acid-to-creatinine ratios early after drinking episodes, which declined with time following abstinence. Such evidence shows that well studied hepatotoxins and surgical liver injury affect pathways of ammonia metabolism and suggests that urinary orotic acid can be an indicator of hepatotoxicity and increased needs for arginine. Arginine-deficient diets and alcohol feeding both enhance fatty deposition in the liver, which can be worsened by high fat intakes in rats. Alcoholism, various other diseases, and fasting and realimentation change orotic acid excretion. Such responses will have to be taken into account in establishing "normal values" for OA excretion.