Attenuation of trophic response to gastrin after inhibition of ornithine decarboxylase.

The mechanism by which the hormone gastrin induces growth of the gastrointestinal mucosa is unknown. Many hormones are inducers of ornithine decarboxylase (ODC), the rate-limiting enzyme in the synthesis of the polyamines putrescine, spermidine, and spermine. Although the exact biochemical function of the polyamines is not completely understood, they appear to be required for normal cell growth and differentiation. Rats were maintained on a liquid diet for 5 days and treated with difluoromethylornithine (DFMO, 200 mg/kg ip, 3 times/day), a selective, irreversible inhibitor of ODC, for 5 days. Half of these animals also received pentagastrin (250 mg/kg ip) during the final 3 days of the treatment schedule. DFMO alone had no effect on body weight or mucosal growth. Pentagastrin increased total RNA, DNA, and protein in the oxyntic gland and duodenal and colonic mucosa. Concurrent treatment with DFMO completely inhibited the trophic response to pentagastrin in the oxyntic gland area of the stomach and the duodenal mucosa. In contrast, DFMO was without effect on response of the colonic mucosa to pentagastrin. Pentagastrin treatment did not induce the mucosal ODC activity of the oxyntic gland area of the stomach, the duodenum, the ileum, or the proximal colon of either animals fasted for 48 h or animals maintained on a liquid diet. ODC activity was measured at 4, 8, 12, and 24 h after administration of hormone. These results suggest that, in at least the proximal bowel, the stimulation by gastrin of nucleic acid and protein synthesis requires intact polyamine synthesis but that gastrin itself does not induce ODC.