Uptake of tritiated thymidine by cells of the rat gastric mucosa after exposure to loxtidine or omeprazole

Abstract

The H₂-antagonist loxtidine and the H⁺/K⁺ ATPase inhibitor omeprazole inhibit gastric acid secretion and both have been associated with the appearance of gastric tumours in rat cancer studies. Loxtidine is not genotoxic in a range of in vitro and in vivo assays. As false negative results can occur if the organotropic nature of the drug is not considered, both drugs were evaluated using an assay which estimates the uptake of tritiated thymidine by cells of the gastric mucosa (the target tissue) in comparison with the positive control, N-methl-N-nitro-nitrosoguanidine (MNNG), which others have shown to induce genetic damage in the stomach mucosa of rats. Such uptake may be, in part, indicative of unscheduled DNA synthesis (UDS) resultant from genotoxic damage. Serum gastrin levels were also determined at various times after either loxtidine or omeprazole treatment. Increased uptake of tritiated thy when this was estimated scintillometrically. The nature of the formulation of omeprazole was critical. The uptake of tritiated thymidine was greatest when omeprazole was administered in vehicle which has been buffered to pH 9. These effects were unlikely to be due to the trophic effects of gastrin since serum gastrin levels were similar after either loxtidine or omeprazole treatment. Autoradiographic analysis of stomach sections was also carried out and revealed a 2- to 3-fold increase in the number of labelled cells within the fund mucosa as compared to the control values after treatment with MNNG or Losec (enteric coated granules of omeprazole). Increased fundic labelling was also noted in a small proportion of animals treated with loxtidine but there was no consistent effect within any dose group. Control data from 135 animals show a low degree of variation in the uptake of radiolabelled thymidine and the total amount of DNA recovered per digest, indicating that inclusion of replicating cells within the samples was minimal. However, it has not proved possible to discriminate between a mitogenic or mutagenic effect of omeprazole on the gastric mucosa, since an enhancement of cell proliferation is likely to increase the chance of isolating cells undergoing normal replicative DNA synthesis (RDS). Further studies using an established gastric UDS assay in which hydroxyurea is used to block RDS, as well as using alternative end-points (e. g. DNA strand breakage), are required to definitively establish the extent of any genotoxic effect of this compound.