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

Exposure of V79 Chinese hamster cells to non-cytotoxic concentrationsof paracetamol (4-hydroxyacetanilide, 4-HAA) increased sisterchromatid exchange (SCE) in the absence of an external activationsystem. Furthermore, a selective inhibition of DNA synthesiswas observed at low 4-HAA concentrations. The inhibition couldbe counteracted by the addition of ascorbate, indicating thatthe effect is caused by an oxidation product of 4-HAA. In attemptto clarify possible relationships between cytotoxicity, inhibitionof DNA synthesis and increased SCE, we studied the effect of4-HAA and some related structures on these parameters. The relativeposistion of the amino group and the hydroxyl group on the aromaticringappear to be important for the inhibition of DNA synthesis.Removal of either of the two groups, N-acetylation and/or alkylationof the aromatic ring or phenolic oxygen decreased the effectof the aromatic amine on DNA synthesis. A significant responseon SCE was observed with 4-aminophenol, 4-HAA, 2-HAA, 3, 5-dimethyl-4-HAA,3-HAA and 2, 6-dimethyl-4-HAA (none of the other compounds weretested). The increase in SCE frequency caused by 4-HAA and itsanalogs does not seem to be related to more general cytotoxiceffects. The relative potencies of the compounds for SCE inductionparalleled, for the most part, their effects on DNA synthesis.However, the induction of SCE and the inhibition of DNA synthesisdid not occur at comparable concentrations. Thus, the possibilitythat 4-HAA increases the frequency of SCE through some othermechanism cannot be excluded.