Research on the effects of anti-ulcer drugs has focused on issues concerning potential risk from long term use. In particular, our studies have addressed whether short term treatment (ie 30 Days) of Tagamet (cimetidine), Zantac (ranitidine) or Prilosec (omeprazole) can induce sister chromatid exchanges (SCEs) or chromosomal aberrations (CA) in human lymphocytes and evaluate whether CYP1A1 is induced by omeprazole by either measuring the CYP1A1 dependent enzyme ethoxyresorufin-o- deethylase (EROD) in rodent and human tissues or cell lines or quantitating CYP1A1 mRNA levels in resting human lymphocytes. Previously we had shown that plasma gastrin was significantly elevated in 30% of the persons treated with Prilosec for 30 days. In comparison to rat studies, to elicit similar increases in gastrin in relation to dose, rats required 100 times more omeprazole than humans. Analysis of SCEs in human lymphocytes before and after 30 days of treatment showed baseline frequency (day 0) was similar for all groups, but after 30 days of treatment a significant increase was observed for the cimetidine (SCE=5.94 +/- 0.52, n=14 at p-O.002) and omeprazole (SCE = 6.15 +/- 0.53, n=15 at p=0.0002) groups. In contrast to SCEs, there was no apparent effect by any of the treatment groups on chromosomal aberrations, mitotic index or replicative index. published reports have demonstrated that humans treated with omeprazole for 5 days induces CYP1A1 activity. We have shown that EROD activity is increased approximately 10 fold in HEPG2 human hepatoma cell lines treated with omeprazole but is not induced appreciably in rodent hepatoma cell lines. Moreover, we have evidence that omeprazole may interact weakly with the aryl hydrocarbon receptor. Quantitative reverse transcriptase PCR has been applied to human lymphocytes to measure the level of mRNA for CYP1A1. We have been able to show that resting human lymphocytes have measurable levels of CYP1A1 mRNA in the range of 400 to 1200 molecules/100 ng RNA and that smoking seems to result in a 2-fold increase. This method is currently being applied to resting lymphocytes from the control and Prilosec treated individuals for both day 0 (baseline) and day 30 treatments.
