EFFECT OF ANTIULCER DRUGS ON DNA-SYNTHESIS IN ADULT NORMAL HUMAN HEPATOCYTES IN CULTURE

The aim of this work was to investigate the effect of four H2 receptor antagonists, cimetidine, ranitidine, famotidine, nizatidine, and of t wo proton pump inhibitors, omeprazole and lansoprazole, on the mitotic response of human hepatocytes in primary culture. After plating at su bconfluent density, cells were exposed to 0.2 to 20 mu mol/L of these drugs for 48 hours, either in the absence or in the presence of epider mal growth factor (EGF). The rate of DNA synthesis was evaluated by [H -3]-thymidine incorporation into genomic DNA. Both the basal rate of D NA synthesis and the extent of stimulation by EGF exhibited a wide int erindividual variability, and were not correlated with the viability o f freshly prepared cells. In contrast, the effects of anti-ulcer drugs on the rate of DNA synthesis were clearly reproducible from one cultu re to another. H2 receptor antagonists had no significant effect (P >. 2) over the entire range of concentration tested, whereas omeprazole a nd lansoprazole significantly inhibited the rate of DNA synthesis by 6 0% to 90% at 20 mu mol/L (P =.016). This effect was concentration depe ndent between 2 and 20 mu mol/L. Neither of the drugs tested was cytot oxic under the conditions used in this work, as assessed by measuremen ts of the de novo protein synthesis. We conclude that, in contrast to H2 receptor antagonists, omeprazole and lansoprazole are able to inter fere with the replicative synthesis of DNA in human hepatocytes in cul ture, at suprapharmacological concentrations. Whether or not this effe ct is clinically significant remains to be established.