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Mutagenesis vol. 5 no. 5 pp. 475-480, 1990
© 1990 UK Environmental Mutagen Society/Oxford University Press

research-article

Paracetamol inhibits replicative DNA synthesis and induces sister chromatid exchange and chromosomal aberrations by inhibition of ribonucleotide reductase

Jan K. Hongslo, Christine Bjørge, Per E. Schwarze, Anton Brøgger1, Graham Mann2,3, Lars Thelander and Jørn A. Holme

Department of Toxicology, National Institute of Public Health Geitmyrsveien 75, N-0462 Oslo 4 1Department of Genetics, Institute of Cancer Research Montebello, N-0310 Oslo 3, Norway 2Department of Medical Biochemistry and Biophysics, University of Umeå S-90187 Umeå, Sweden

Effects of paracetamol have been studied in a hydroxyurea (HU)-resistant mouse mammary tumour cell line TA3H2, shown to overproduce the small subunit of ribonucleotide reductase. These TA3H2 cells were much more resistant than the TA3H (wild-type) cells towards the inhibitory effect of paracetamol on cell growth, IC5O 0.55 mM paracetamol for the wild-type compared to 2.7 mM for the HU-resistant cells. The reduced cell growth was due to an inhibition of replicative DNA synthesis, judged from an increased percentage of cells in S-phase measured by flow cytometry. Furthermore, in the wild-type cells, the increase in the number of cells in S phase was already observed at 0.1 mM while in the HU-resistant cell line this effect was first seen at 3.0 mM paracetamol. HU inhibits ribonucleotide reductase by destroying a tyrosyl free radical located on the small subunit of the enzyme. By electron paramagnetic resonance we demonstrate that paracetamol added to crude cell extracts of HU-resistant cells also immediately destroys this radical. These results show that paracetamol reduces DNA synthesis by a specific inhibition of ribonucleotide reductase. A concentration-dependent induction of sister chromatid exchanges was found both with paracetamol (1.0–10 mM) and HU (0.3–3 mM) in wild-type cells whereas no such increase was observed in HU-resistant cells. Paracetamol (1 mM for 2 h) also increased the number of chromosomal aberrations CAs in wild-type cells (i.e. chromatid breaks and chromatid exchanges). The frequency of CAs was not increased in HU-resistant cells at paracetamol concentrations up to 10 mM. These results indicate that induction of genotoxic effects by paracetamol is due to an inhibition of ribonucleotide reductase.

3Present address: Department of Medicine, University of Sydney, West Mead Hospital NSW 2145, Australia


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