Acetaminophen nephrotoxicity in the rat. II. Strain differences in nephrotoxicity and metabolism of p-aminophenol, a metabolite of acetaminophen

Acetaminophen (APAP) produces renal necrosis restricted to the straight segment of the proximal tubule in Fischer 344 (F344) rats. On the other hand, Sprague-Dawley (SD) rats are extremely resistant to the nephrotoxic effects of APAP. Such strain differences may be due to different susceptibilities to the nephrotoxic metabolite, p-aminophenol (PAP). PAP administration in both strains of rats resulted in a renal lesion indistinguishable from the APAP-induced renal lesion in F344 rats. The PAP-induced renal lesions in F344 rats, however, were generally more severe than those in SD rats. PAP-induced renal functional changes (elevation in blood urea nitrogen and reduction in the accumulation of p-aminohippurate by renal cortical slices) correlated with strain-dependent histopathological changes. Analysis of urinary metabolites over a 24-hr period following PAP administration (200 and 400 mg/kg) indicated that more PAP was excreted as APAP in SD than in F344 rats. Covalent binding of PAP to renal microsomes in vitro was much greater in F344 rats than in SD rats at substrate concentrations less than 5 mM. These results suggest that strain differences in PAP-induced nephrotoxicity may be related to differences in the intrarenal activation of PAP. Furthermore, strain differences in APAP-induced nephrotoxicity may be related to strain differences in the activation of the nephrotoxic metabolite, PAP.