GENOTOXICITY STUDIES WITH PARACETAMOL

Paracetamol and its major ultimate reactive metabolite, N-acetyl-p-benzoquinone imine (NAPQI) were studied for their genotoxic potential. Neither paracetamol nor NAPQI caused mutations in Salmonella typhimurium, whereas NAPQI was severely cytotoxic to the bacteria. Radiolabeled paracetamol binds covalently to DNA added to mouse-liver microsmal incubations at a rate of 2.6 pmol/mg DNA/min. Paracetamol also bound covalently to hepatic DNA at a level of 15 pmol/mg DNA after a hepatotoxic dose of paracetamol to mice. NAPQI caused extensive DNA single-strand breaks as evidenced by alkaline elution of DNA from treated Reuber hepatoma cells. This effect occurrred at concentrations which later resulted in cytotoxicity. Paracetamol as shown to induce increased DNA-repair synthesis in isolated mouse-liver cells in monolayer culture, at concentrations where also cytotoxicity was evident. Increased DNA-repair synthesis occurred at lower paracetamol concentrations in cells isolated from mice pretreated with phenobarbital. Paracetamol can cause DNA interaction leading to damage at levels which are cytotoxic.