M W Gemborys

Nephrotoxicity of p-aminophenol, a metabolite of acetaminophen, in the Fischer 344 rat

Abstract Acetaminophen (APAP) produces proximal tubular necrosis in the Fischer 344 rat. APAP is deacetylated to p -aminophenol (PAP) in the hamster, and PAP has been reported to be a potent specific cortical nephrotoxicant in the rat. However, the role of PAP in APAP nephrotoxicity has not been defined. Therefore, it was of interest to quantify PAP formation after APAP administration and to correlate PAP formation with renal injury produced by APAP in the Fischer 344 rat. Urinary PAP excretion, measured as an index of PAP formation, increased with increasing doses of APAP. In addition, APAP was metabolized to PAP in isolated perfused kidneys. PAP at doses as low as 100 mg/kg produced significant renal toxicity (elevation in blood urea nitrogen and reduction in accumulation of p -aminohippurate by thin renal cortical slices). Ortho - and meta -aminophenol were not nephrotoxic. Pretreatment with polybrominated biphenyls or β-naphthoflavone, inducers of mixed function oxidases, protected against nephrotoxicity of PAP, possibly as a result of enhanced hepatic biotransformation of the parent compound. These studies indicate that PAP is a potent, selective nephrotoxicant that can be generated from APAP by the kidney and may be responsible for the renal necrosis subsequent to APAP administration.