Intestinal changes caused by dl-α-difluoromethylornithine (DFMO), an inhibitor of ornithine decarboxylase

Abstract

Subacute (2 week) oral or intravenous administration of dl-α-difluoromethylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase (ODC), caused diarrhea and frequent emesis as early as 4 to 5 days in dogs (dose ⩾200 mg/kg/day). Diarrhea also occurred in monkeys after 1 week of treatment with an intravenous dose of 1000 mg/kg/day. Especially evident in the treated dogs with diarrhea were fluid loss, hemoconcentration, and decreased serum sodium and chloride which were findings totally reversible about 2 weeks after cessation of dosing. As a result of treatment with the highest intravenous dosage (1000 mg/kg/day), villous atrophy of the mucosa was observed by light and scanning electron microscopy in the canine small intestine. Transmission electron microscopy demonstrated that the most significant alterations of the canine intestinal tract involved the microvilli of epithelial cells which became shorter and were frequently less numerous or absent along focal areas of the plasma membrane. Intestinal mucosal levels of putrescine, especially in the duodenum and jejunum, were decreased as demonstrated in the monkeys following intravenous treatment with 100, 300, or 1000 mg/kg/day of DFMO. The results of this investigation are consistent with the hypothesis that the inhibition of ODC activity and subsequent altered polyamine metabolism may lead to delayed maturation of the intestinal epithelial cells and the impaired development of their microvilli, causing fluid loss due to reduced absorptive surface area.