LACK OF EVIDENCE OF OMEPRAZOLE GENOTOXICITY IN SPRAGUE-DAWLEY RATS

Omeprazole is a proton pump inhibitor of increasingly wide use in the treatment of peptic ulcers. Although omeprazole has been subjected to an extensive range of genotoxicity tests, which have all been conclude d as negative, the ability of this compound to interact with DNA and e licit unscheduled DNA synthesis in the rat gastric mucosa has been the subject of debate. Therefore, we have examined omeprazole using other genotoxicity end-points. In female Sprague-Dawley rats, the administr ation by the oral route of 100 mg/kg, either as neutral (pH 7.0) suspe nsion or as suspension acidified to pH 1.5, which favours its transfor mation into the active form of sulphenamide, did not induce DNA fragme ntation in gastric mucosa and liver, as detected by the alkaline eluti on technique. In the same experimental conditions, a frequency of tota l nuclear anomalies (micronuclei, pyknosis and karyorrhexis) that was significantly higher than in controls was detected with both types of suspension in forestomach and descending colon mucosa. However, in bot h tissues this higher frequency of nuclear anomalies was mostly due to pyknosis and karyorrhexis, which may be the outcome of a non-genotoxi c effect, whereas there was no significant increase in the number of m icronucleated cells, and this suggests the absence of clastogenic acti vity. Finally, in rats initiated with N-nitrosodiethylamine, the oral administration of 100 mg/kg omeprazole for 14 successive days produced a modest but statistically significant increase of liver gamma-glutam yltranspeptidase positive foci, which is consistent with a potential p romoting activity. Taken as a whole and compared with previous finding s our results add further doubts about the undiscriminated capability of omeprazole to behave as a genotoxic carcinogen and provide evidence that the occurrence of a genotoxic effect, if it actually takes place , is limited to some strains of rats.