NEPHROTOXICITY OF PARA-AMINOPHENOL .2. EFFECT OF METABOLIC-INHIBITORS AND INDUCERS

Inducers and inhibitors of the microsomal mixed function oxidase system have no consistent effect upon the nephrotoxicity of p-aminophenol [an analgesic metabolite], or on binding of the compound in vivo to cell protein. p-[ring-3H]Aminophenol was bound in vitro to [rat] kidney microsomal protein and to a lesser extent to liver. The binding was enhanced by preincubation of the p-aminophenol in air and inhibited by ascorbate, reduced glutathione, N2 and NADPH. In contrast to paracetamol hepatoxicity which is dependent upon the mixed function oxidase system, nephrotoxicity of p-aminophenol is dependent upon oxidation to a toxic metabolite by some other pathway. A similar metabolite may be responsible for the nephrotoxic action of phenacetin.