Research on the effects of anti-ulcer drugs on cellular processes has focused on three issues concerning potential risk from long-term use. These include determining, (1) the mechanism for carcinoid tumor formation in rodents by studying the relationships between inhibition of gastric acid secretion, serum gastrin levels and cell proliferation, (2) cytogenetic effects [SCEs and chromosomal aberrations (CA)] of Tagamet (cimetidine), Zantac (ranitidine) and Prilosec (omeprazole) in peripheral human lymphocytes and (3) whether omeprazole induces the CYP1A1 dependent enzyme ethoxyresorufin-o-deethylase (EROD) in rodent and human tissues and the mechanism involved. Omeprazole treatment of rats at a dose of 80 micromol/kg (100x the human dose) increases in plasma gastrin, induces EROD activity in rat small intestine but appears to inhibit this activity in liver. Treatment with ranitidine or cimetidine at the highest dose (100x human prescribed dose) caused transient increases in gastrin with no effect on EROD activity. We found that 30% of humans treated with omeprazole (100x lower dose than given rats) had elevated gastrin the magnitude of the increase similar to that seen in rodents. Analysis of SCEs in human lymphocytes before and after 30 days of treatment showed baseline SCE frequency (day 0) were similar for all groups, but after treatment for 30 days a significant increase was observed for the cimetidine (SCE = 5.94 0.52, n=14 at p=0.002) and omeprazole (SCE = 6.15 0.53, n=15 at p=0.0002) groups. The analysis of CAs is currently being performed, but preliminary data suggest a weak marginal effect of omeprazole on CAs. Published reports have demonstrated that humans treated with omeprazole for 5 days induces CYP1A1 activity. We have shown that EROD activity in the human hepatoma cell line HEPG2 is induced approximately 10-fold whereas not effect is seen in rodent derived hepatoma cell lines. We are currently determining if omeprazole can bind the Ah receptor and if there are differences in the interaction of omeprazole with receptor derived from human and rodent liver. Quantitative PCR to analyze CYP1A1 mRNA will be applied to human lymphocytes obtained from individuals that have taken omeprazole for 30 days.
