Toxic effects of paracetamol and related structures in V79 Chinese hamster cells

Exposure of V79 Chinese hamster cells to non-cytotoxic concentrations of paracetamol (4-hydroxyacetanilide, 4-HAA) increased sister chromatid exchange (SCE) in the absence of an external activation system. Furthermore, a selective inhibition of DNA synthesis was observed at low 4-HAA concentrations. The inhibition could be counteracted by the addition of ascorbate, indicating that the effect is caused by an oxidation product of 4-HAA. In attempt to clarify possible relationships between cytotoxicity, inhibition of DNA synthesis and increased SCE, we studied the effect of 4-HAA and some related structures on these parameters. The relative position of the amino group and the hydroxyl group on the aromatic ring appear to be important for the inhibition of DNA synthesis. Removal of either of the two groups, N-acetylation and/or alkylation of the aromatic ring or phenolic oxygen decreased the effect of the aromatic amine on DNA synthesis. A significant response on SCE was observed with 4-amino-phenol, 4-HAA, 2-HAA, 3,5-dimethyl-4-HAA, 3-HAA and 2,6-dimethyl-4-HAA (none of the other compounds were tested). The increase in SCE frequency caused by 4-HAA and its analogs does not seem to be related to more general cytotoxic effects. The relative potencies of the compounds for SCE induction paralleled, for the most part, their effects on DNA synthesis. However, the induction of SCE and the inhibition of DNA synthesis did not occur at comparable concentrations. Thus, the possibility that 4-HAA increases the frequency of SCE through some other mechanism cannot be excluded.