Effect of aspirin on metabolism of acetaminophen and benzidine by renal inner medulla prostaglandin hydroperoxidase.

The effect of in vivo and in vitro aspirin treatment on renal inner medullary prostaglandin hydroperoxidase-catalyzed metabolism of acetaminophen and benzidine was examined. Metabolism was assessed by the binding of [3H]acetaminophen and [14C]benzidine to TCA-precipitable material. Microsomes were prepared from control or aspirin-treated rabbits. Aspirin, whether administered in vivo (15 mg/kg i.v.) or added in vitro (2 mM), had no effect on peroxide-initiated metabolism. By contrast, arachidonic acid-initiated metabolism was completely prevented by both in vivo and in vitro aspirin. Salicylate did not inhibit either arachidonic acid- or peroxide-dependent metabolism. The antioxidant glutathione (1 mM) completely inhibited both peroxide- and arachidonic acid-initiated metabolism. Aspirin treatment completely inhibited metabolism of arachidonic acid by medullary microsomes. Thus aspirin does not inhibit the hydroperoxidase component of prostaglandin endoperoxide synthetase, and co-oxidation of acetaminophen and benzidine may proceed in the presence of aspirin. Co-oxidation may be involved in the genesis of the nephrotoxicity of mixed analgesic abuse.