Uptake of tritiated thymidine by cells of the rat gastric mucosa after exposure to loxtidine or omeprazole.
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-methyl-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 thymidine was only obtained after omeprazole or MNNG treatment, 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 had 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 fundic mucosa as compared to the control values after treatment with MNNG or Losec (enteric coated granules of omeprazole).(ABSTRACT TRUNCATED AT 250 WORDS)
Burlinson
B
B
Genetic and Reproductive Toxicology Department, Glaxo Group Research Ltd., Ware, Hertfordshire.
Morriss
S
S
Gatehouse
D G
DG
Tweats
D J
DJ
Jackson
M R
MR
D000284:Administration, Oral; D000818:Animals; D001345:Autoradiography; D002469:Cell Separation; D004247:DNA / Q000096:biosynthesis*; D004261:DNA Replication / Q000187:drug effects*; D005753:Gastric Mucosa / Q000166:cytology / Q000378:metabolism*; D005755:Gastrins / Q000097:blood; D008297:Male; D008769:Methylnitronitrosoguanidine / Q000494:pharmacology; D009152:Mutagenicity Tests; D009853:Omeprazole / Q000494:pharmacology*; D011402:Pronase / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013936:Thymidine / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology*
D005755:Gastrins; D014230:Triazoles; D008769:Methylnitronitrosoguanidine; C039993:loxtidine; D004247:DNA; D011402:Pronase; D009853:Omeprazole; D013936:Thymidine