Inhibition of ileal and colonic ornithine decarboxylase activity by alpha-difluoromethylornithine in rats: transient atrophic changes and loss of postresectional adaptive growth

Abstract

To determine the role of putrescine synthesis in adaptive hyperplasia of the ileum and colon, DL-alpha-difluoromethylornithine (DFMO), an enzyme-activated, irreversible inhibitor of ornithine decarboxylase (ODC), the enzyme controlling putrescine biosynthesis, was fed to rats after excision of the proximal half of the small bowel. A rise in ODC activity (280% in the proximal ileum, 62% in the proximal colon) and a rise in putrescine content (220% in the proximal ileum, 250% in the proximal colon) normally accompanied characteristic cytochemical adaptive increases in the ileum and colon at day 6. Inclusion of 1% DFMO (2.1 gm/kg/day) in drinking water for 12 hours before operation and for 14 days thereafter decreased ODC activity by 85% to 96%, reduced levels of putrescine and spermidine and measurements of the adaptive response by 50% in the ileum, and abolished the adaptive response in the colon. During the first 10 days of DFMO feeding, villous atrophy and other hypoplastic changes occurred in control rats, but by 14 days of DFMO feeding atrophy and hypoplasia were no longer present. Although DFMO inhibits adaptive hyperplasia occurring in the ileum and colon of rats after resection of the proximal half of the small bowel, spontaneous recovery of villous atrophy occurs during further DFMO feeding and may protect the host during chemotherapy.