The long range objective of this study is to evaluate the effects of anti-ulcer drugs on cellular processes of the stomach, liver and lymphocytes using animal models, primary and established liver cell lines and human epidemiologic approaches. Research has focused on three issues concerning potential risk from long term use of antiulcer medications. These include: (1) mechanism for carcinoid tumor formation using animal models, by studying the quantitative relationships between inhibition of gastric acid secretion (achlorhydria), gastrin levels and cell proliferation of enterochromaffin-like (ECL) cells of the glandular stomach, (2) cytogenetic effects of Tagamet (cimetidine), Zantac (ranitidine) and Losec (omeprazole) by measuring SCEs and chromosomal aberrations in human lymphocytes following 30 days of drug use by volunteers and (3) induction of cytochrome P450s and the mechanism for this induction by omeprazole (Losec) using both rodent and human hepatoma cell lines as well as in vivo treatment of rats. We have shown that omeprazole treatment of rats for either 12 or 30 days significantly increases serum gastrin in a dose dependent manner and are currently measuring cell proliferation in the forestomach, glandular stomach and liver. Moreover, it appears that omeprazole induces P-450c in rat small intestine by 10 fold following 30 day treatment at both doses tested (8 and 80 micro-mol/kg body weight), whereas in liver there is a marginal inductive effect at 8 micro- mol/kg and a decrease at 80 micro-mol/kg. Using mouse, rat and human derived hepatoma cell lines, there was an approximate 2-fold induction after 48 hr incubation with 50 micro-M omeprazole, but only in the human Hep-G2 cell line. Studies are currently underway to determine whether the induction is through the Ah receptor. We have enrolled 60 healthy adults in a single blind study to determine whether antiulcer drugs cause cytogenetic damage. Serum gastrin levels have been measured for all individuals at the beginning of the study (baseline), after 30 days of treatment and 30 days post-treatment. We have detected significant interindividual variation in the serum gastrin response and we are investigating the mechanism responsible for this variation. SCE and chromosomal aberration frequencies are currently being measured.
