Abstract
Cysteamine (C) (HS-CH2-CH2-NH2) is a reducing aminothiol which may react with transition metals to generate H2O2. C specifically induces ulcers in rat proximal duodenum where most dietary iron absorption takes place. We hypothesized that iron may play a role in redox reactions involved in the pathogenesis of C-induced duodenal ulcers (DU). In rats, using oxygen and redox electrodes we detected a decrease in both oxygen concentration and redox potential in the proximal duodenum at 2 and 12 hr after administration of C (25 mg/100 g, p.o.). A detectable level of C was found by HPLC assay in duodenal mucosa (0.018 ug/mg wet weight) and 4 fold less in gastric mucosa but not in jejunum, colon or liver 2 hr after C administration. Rats fed an iron-deficient diet for 6 weeks had a 34% decrease in iron concentration in the duodenal mucosa, accompanied by a 6.6 fold decrease in C-induced DU size. Pretreatment of rats with Fe3+or Fe2+aggravated DU, whereas iron depletion by deferoxamine decreased DU by 38%. [C14]C uptake by isolated duodenal, gastric, jejunal and colonic enterocytes, and by IEC-6 and Caco-2 cells increased linearly with time (up to 15 min). [C14]C uptake was pH dependent, with higher uptake in more alkaline buffer. Unlabeled C (1 mM) markedly inhibited [C14]C uptake by all cells. Overloading IEC-6 with iron (100 uM for 1 hr) accelerated uptake of [C14]C by 40%, but incubation of cells with deferoxamine (100 or 200 uM for 24 hr) inhibited C uptake by 30% and 61%, respectively. These findings suggest a role for iron-catalyzed redox reactions in the pathogenesis of C-induced organ-specific tissue injury.
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