Induction of hepatic CYP enzymes by a subtoxic dose of acetaminophen in rats

Abstract

Acetaminophen (APAP) is activated by CYP enzymes to N‐acetyl‐benzoquinoneimine, which reacts with cellular macromolecules to initiate liver damage. Alteration of CYP enzyme system by a toxic dose of APAP is well known; however, its potential adverse effect at a lower dose has hardly been explored. Rats were treated with APAP (500 mg/kg, ip) 18 h before a challenge with CCl4. APAP treatment only did not alter serum AST, ALT, or SDH activities. But a prior dose of APAP increased the CCl4 hepatotoxicity significantly. In rats treated with APAP 18 h before, hepatic p‐nitrophenol hydroxylase, p‐nitroanisole O‐demethylase, and aminopyrine N‐demethylase activities were increased significantly. Protein levels of CYP2E1, 3A, 1A1/2, and NADPH CYP reductase were increased, but mRNA expressions of the CYP enzymes were reduced. Ubiquitinated protein expression was suppressed by a prior dose of APAP. The immunoprecipitated CYP proteins were analyzed using a specific Ab against ubiquitin. The ubiquitin‐conjugated proteins in the immunoprecipitated CYP enzymes were decreased, implying that protein stabilization would play an essential role in the induction of CYP enzymes by APAP. These results suggest that a subtoxic dose of APAP may induce CYP enzymes and their metabolizing capacities, thereby influencing the metabolic conversion of xenobiotics that are substrates for the same enzyme systems.