The Orotic Aciduria of Chemical Hepatotoxicity (Liver Disease, Alcohol, Galactosamine)

165 p.Thesis (Ph.D.)--University of Illinois at Urbana-Champaign, 1984.Increased urinary excretion of orotic acid has previously been shown to occur as a result of defects in the pathway of utilization of orotic acid or as a consequence of excessive demands on the urea cycle. Orotic acid is a precursor of nucleic acids which may depend on carbamyl phosphate, a product of the urea cycle, for synthesis under some physiological conditions. This thesis describes five previously unreported causes of orotic aciduria in rats: chemical damage to the liver by (1) carbon tetrachloride, (2) ethanol, (3) galactosamine, (4) partial removal of the liver, and (5) meal feeding by growing animals. Orotic acid excretion also depends upon: the dietary lysine/arginine ratio, and blood ammonia concentrations. Carbon tetrachloride exposure caused cirrhosis which was demonstrated histologically. The more severe lesions were shown to cause a defect in ammonia clearance during in vitro liver perfusion and an increase in portal ammonia concentration in the intact animals sufficient to account for the demonstrated increase in orotic acid excretion. Arginine supplementation as high as 2.1% of the diet did not prevent the orotic aciduria of carbon tetrachloride toxicity, although replacing casein with soy protein in the diets of growing cirrhotic rats significantly lowered orotate excretion. Cessation of carbon tetrachloride exposure allowed orotate excretion to return to normal within 7 days even in rats with advance cirrhosis. Ethanol ingestion as 36% of the calories in an all-liquid, 20% casein, 5% corn oil AIN-76A diet, did not result in hepatic steatosis after 8 or 10 weeks of consumption. However, orotic acid excretion correlated positively with hepatic lipid content, event when hepatic lipid was within the normal range. Lactulose, a disaccharide added to the ethanol-containing diet significantly lowered orotate excretion. Human patients undergoing acute alcohol detoxification were found to have increased orotic acid excretion compared to detoxified patients. In a collaborative starvation and refeeding study, orotic acid excretion of human subjects correlated highly with nitrogen intake. The toxicity of galactosamine in rats was prevented by dietary arginine deficiency or prior ammonia exposure, but was worsened by arginine supplementation. This argues that endogenous orotate production is the major factor in the previously known resistance of regenerating liver to galactosamine. Arginine supplementation, after removal of 68% of the liver, prevented orotic aciduria, but had no effect on the rate of liver regrowth.U of I OnlyRestricted to the U of I community idenfinitely during batch ingest of legacy ETD