Strain-related Susceptibility to Nephrotoxicity Induced by Aspirin and Phenylbutazone in Rats

Abstract

Single doses of aspirin induce scattered foci of necrosis of proximal tubules in some strains of rats, whereas acute or sub-acute administration of phenylbutazone causes renal papillary necrosis. Initially, using Sprague-Dawley rats of CFY and CD strains, it became clear that these rats were not as susceptible to these drugs as the literature suggested. Aspirin-induced necrosis was apparently sex-related, being seen in females but could be induced by hormone treatment in males. Male Wistar and Sprague-Dawley rats had reacted differently to administration of phenylbutazone for two weeks. Two experiments were performed with four rat strains: Wistar, Lister-Hooded, Sprague-Dawley, and Fischer-344. The rats were six weeks old at the start of the experiments. Five males and five females of each strain were gavaged with either a single dose of 1,000 mg/kg of aspirin or 200 mg/kg phenylbutazone once daily for four weeks. The drugs were suspended in methylcellulose, which was given to equal numbers of control male and female rats in each experiment. The rats were maintained under standard conditions. Blood and 18-hour overnight urine samples were collected prior to sacrifice. There were no strain-related differences in the types of renal lesions seen, however there were differences in the degrees of responses to the two drugs. With aspirin the female Fischer-344 rats were the most susceptible showing necrosis of proximal tubules of both kidneys and markedly elevated urinary protein concentration and gamma-GT activity. Other females showed less change. Male rats were affected only slightly and males of the Wistar strain were not. Thus, the greater susceptibility of female rats to aspirin-induced nephrotoxicity was confirmed. Phenylbutazone killed two female and one male Wistar rats with gastrointestinal ulceration after three doses. Fischer-344 rats also showed reaction to the drug. For these two strains the dosage was reduced to 50 mg/kg/day for the remainder of the study. At the end of the dosing period one or more rats from each strain showed renal papillary necrosis. Thus, strain differences occurred in the susceptibility of the rats to phenylbutazone but this was not seen in the nephrotoxicity profiles.