Inhibition of DNA synthesis by paracetamol in different tissues of the rat in vivo

DNA synthesis in the spleen, testis, thymus, stomach, small intestine and bone marrow was inhibited by 70-90% at 1 h following an oral dose of paracetamol (1 g/kg). This inhibitory effect was still apparent using a lower dose of 125 mg/kg paracetamol, but not when the dose was reduced to 60 mg/kg. In contrast, the liver was resistant to the inhibitory action of paracetamol on DNA synthesis, there being no significant inhibition of DNA synthesis at 500 mg/kg or 1 g/kg paracetamol. These doses and the associated plasma levels are in the range found in human overdose. Tissue levels of paracetamol in the liver, spleen, thymus, kidney and testis were essentially the same as the plasma level. However the apparent paracetamol tissue levels in the stomach wall and duodenum were orders of a magnitude higher than the plasma level. The tissue levels of paracetamol did not explain the differences between tissues in the degree of inhibition of DNA synthesis, in particular the high levels of paracetamol in the tissue of the stomach and duodenum did not result in higher levels of inhibition in these tissues. This study also shows that the inhibitory effect of paracetamol on DNA synthesis is transient. All the tissues, except the spleen, no longer showed inhibition of DNA synthesis by 4 h post paracetamol dosing.