Inhibition of replicative DNA synthesis by paracetamol in V79 Chinese hamster cells

Low concentrations of paracetamol (0.1 mm) inhibited DNA synthesis in V79 Chinese hamster cells within minutes of addition. RNA and protein synthesis were inhibited only after longer exposure (3 hr) to considerably higher concentrations of paracetamol (3-10 mm). Flow-cytometry studies showed that V79 cells exposed to paracetamol were blocked initially in the G(1)-phase and subsequently slowly passed through the S-phase. No metabolites were detected by high-performance liquid chromatography after exposure of V79 cells to paracetamol for 50 hr. Furthermore, metyrapon and SKF 525-A (inhibitors of cytochrome P-450), indomethacine (inhibitor of prostaglandin H synthetase), and paraoxon (inhibitor of deacetylase) did not prevent paracetamol-induced inhibition of DNA synthesis. On the other hand, low concentrations of ascorbate (2 mum) reduced the effect of paracetamol. No effect was observed with the non-reductive precursor of ascorbate, gulonolactone. Neither catalase nor superoxide dismutase reduced the effect of paracetamol on DNA synthesis. Ascorbate also partly reduced paracetamol-induced sister-chromatid exchange (SCE). The inhibition of DNA synthesis caused by hydroxyurea, an inhibitor of ribonucleotide reductase, was also counteracted by ascorbate. Both paracetamol and hydroxyurea caused increased frequencies of SCE in V79 cells. We suggest that a specific enzyme involved in the synthesis of DNA is inactivated by the oxidation of paracetamol.