METABOLISM OF ACETAMINOPHEN BY THE ISOLATED PERFUSED KIDNEY

  • 1 January 1982
    • journal article
    • research article
    • Vol. 221  (1) , 76-79
Abstract
Acetaminophen (APAP) produces proximal tubular necrosis in the Fisher 344 rat. This lesion may result from the covalent binding of reactive intermediates of APAP to cellular macromolecules when glutathione (GSH) is sufficiently depleted. Experiments were designed to evaluate the ability of the kidney to convert APAP to reactive electrophilic metabolites capable of depleting renal GSH by quantifying GSH concentrations in isolated perfused kidneys perfused with APAP. Perfusion without APAP reduced renal GSH in comparison to nonperfused controls. Addition of APAP (3 .times. 10-8-3 .times. 10-5 M) to the perfusion medium further reduced renal GSH content. Treatment of rats with polybrominated biphenyls enhanced the ability of 3 .times. 10-8 M APAP to deplete GSH. Treatment with piperonyl butoxide reduced the depletion of GSH produced by 3 .times. 10-5 M APAP. At 3 .times. 10-5 M APAP, the glucuronic acid, sulfate and the mercapturic acid excretion increased 4-fold, whereas the glucuronic acid and sulfate conjugate excretions were unaffected. Evidently the kidney can produce an electrophilic metabolite of APAP which can combine with and deplete renal GSH. An electrophilic metabolite of APAP produced by the kidney may initiate APAP-induced renal necrosis.