Inhibition of Intestinal Epithelial DNA Synthesis and Adaptive Hyperplasia After Jejunectomy in the Rat by Suppression of Polyamine Biosynthesis

Transient increases in the activity of ornithine decarboxylase (ODC), the first and rate-limiting enzyme in polyamine biosynthesis, may be critical to initiation of cell growth. We previously reported such increases in ODC activity, and the polyamines, putrescine, and spermidine in rat ileal mucosa between days 1 and 4 after intestinal resection. During this time, there is initiation of mucosal cell hyperplasia, as measured morphologically and biochemically. Intestinal weight and mucosal thickness increase, as do mucosal DNA content and DNA synthesis. In the present study, we gave rats the specific irreversible ODC inhibitor, alpha-difluoromethyl ornithine (DFMO), beginning 3 d before jejunectomy. DFMO completely suppressed the increases in ODC activity and polyamine content in the intestinal mucosa. The suppression in ODC activity was associated with an 87% suppression of DNA synthesis, and resulted in a complete abolition of intestinal adaptation, as manifested by the absence of intestinal weight gain, increase in mucosal thickness, or increase in crypt cell production. Our results indicate that the increases in ODC activity and polyamine biosynthesis are critical for adaptive postresectional crypt cell proliferation in vivo, and that the critical step mediated by polyamines in this adaptive process is the onset of new DNA synthesis.