Acetaminophen nephrotoxicity: studies on renal acetylation and deacetylation

Acetaminophen (N-acetyl-p-aminophenol; APAP) inhibits both the acetylation and uptake of p-aminohippurate (PAH) by slices of mouse kidney cortex; p-aminophenol (PAP) is more potent than APAP in inhibiting the acetylation of PAH, but has no effect on uptake of PAH. Since PAP itself is acetylated by the kidney, the action of PAP on the acetylation of PAH might be competitive. However, from kinetic analysis the inhibition is principally noncompetitive in nature. In studies on deacetylation, PAP was generated from APAP both in slices and homogenates of kidneys; acetylated PAH was relatively stable. PAP is a known nephrotoxin but has not been identified previously as a metabolite of APAP. The data indicate that the kidney has the capacity to generate a potent nephrotoxin, PAP, from a relatively benign precursor, APAP. This potentiality should be considered in further studies on the pathogenesis of analgesic nephropathy.