The effect of mixed function oxidase induction and inhibition on salicylate-induced nephrotoxicity in male rats

Abstract

A previous study in this laboratory demonstrated that greater nephrotoxicity was induced by 500 mg/kg [ 14C]salicylate in 12-month-old male Sprague-Dawley rats than in 3-month-old animals, and the increased nephrotoxicity was correlated with greatly increased binding of radioactivity to the renal mitochondria in the older rats. To determine the role of reactive intermediate generation in salicylate-induced nephrotoxicity, male Sprague-Dawley rats were pretreated with piperonyl butoxide, phenobarbital, or Aroclor prior to the administration of 500 mg/kg [ 14C]salicylate. In the kidneys of rats pretreated with only corn oil, mitochondrial macromolecules contained 57% of the total covalently bound radioactivity while in the livers of these same animals, microsomes contained most (52%) of the bound radioactivity. Pretreatment with piperonyl butoxide, an inhibitor of mixed function oxidase activity, decreased (a) salicylate-induced nephrotoxicity; (b) the covalent binding of [ 14C]salicylate equivalents to renal mitochondria; and (c) the formation of the 2,3- and 2,5-dihydroxybenoic acid metabolites of salicylate. Pretreatment with phenobarbital and Aroclor, inducers of hepatic P-450, on the other hand, had no effect on salicylate-induced nephrotoxicity nor on the covalent binding of [ 14C]salicylate equivalents to renal mitochondria. These data are consistent with the hypothesis that salicylate is metabolized to reactive intermediates that irreversibly bind to renal mitochondria and lead to salicylate-induced nephrotoxicity.