Effect of anti-ulcer drugs on DNA synthesis in adult normal human hepatocytes in culture

Abstract

The aim of this work was to investigate the effect of four H2 receptor antagonists, cimetidine, ranitidine, famotidine, nizatidine, and of two proton pump inhibitors, omeprazole and lansoprazole, on the mitotic response of human hepatocytes in primary culture. After plating at subconfluent density, cells were exposed to 0.2 to 20 μmol/L of these drugs for 48 hours, either in the absence or in the presence of epidermal growth factor (EGF). The rate of DNA synthesis was evaluated by [ 3h]-thymidine incorporation into genomic DNA. Both the basal rate of DNA synthesis and the extent of stimulation by EGF exhibited a wide interindividual variability, and were not correlated with the viability of freshly prepared cells. In contrast, the effects of anti-ulcer drugs on the rate of DNA synthesis were clearly reproducible from one culture to another. H2 receptor antagonists had no significant effect ( P > .2) over the entire range of concentration tested, whereas omeprazole and lansoprazole significantly inhibited the rate of DNA synthesis by 60% to 90% at 20 μmol/L ( P = .016). This effect was concentration dependent between 2 and 20 μmol/L. Neither of the drugs tested was cytotoxic under the conditions used in this work, as assessed by measurements of the de novo protein synthesis. We conclude that, in contrast to H2 receptor antagonists, omeprazole and lansoprazole are able to interfere with the replicative synthesis of DNA in human hepatocytes in culture, at suprapharmacological concentrations. Whether or not this effect is clinically significant remains to be established.