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 concluded as negative, the ability of this compound to interact with DNA and elicit 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 administration by the oral route of 100 mg/kg, either as neutral (pH 7.0) suspension or as suspension acidified to pH 1.5, which favours its transformation into the active form of sulphenamide, did not induce DNA fragmentation in gastric mucosa and liver, as detected by the alkaline elution technique. In the same experimental conditions, a frequency of total 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 both tissues this higher frequency of nuclear anomalies was mostly due to pyknosis and karyorrhexis, which may be the outcome of a non-genotoxic effect, whereas there was no significant increase in the number of micronucleated cells, and this suggests the absence of clastogenic activity. 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-glutamyltranspeptidase positive foci, which is consistent with a potential promoting activity.(ABSTRACT TRUNCATED AT 250 WORDS)
Mereto
E
E
Institute of Pharmacology, University of Genoa, Italy.
Ghia
M
M
Martelli
A
A
Brambilla
G
G
D000818:Animals; D002467:Cell Nucleus / Q000187:drug effects; D016009:Chi-Square Distribution; D004249:DNA Damage; D004790:Enzyme Induction; D005260:Female; D005753:Gastric Mucosa / Q000187:drug effects*; D006965:Hyperplasia / Q000139:chemically induced; D007413:Intestinal Mucosa / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D015162:Micronucleus Tests; D009153:Mutagens / Q000633:toxicity*; D009853:Omeprazole / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D005723:gamma-Glutamyltransferase / Q000378:metabolism
D009153:Mutagens; D005723:gamma-Glutamyltransferase; D009853:Omeprazole