Role of iron in the pathogenesis of cysteamine-induced duodenal ulceration in rats

Abstract

Cysteamine induces perforating duodenal ulcers in rats within 24-48 h. This reducing aminothiol generates hydrogen peroxide in the presence of transition metals (e.g., ferric iron), producing oxidative stress, which may contribute to organ-specific tissue damage. Since most intestinal iron absorption takes place in the proximal duodenum, we hypothesized that cysteamine may disrupt regulation of mucosal iron transport, and iron may facilitate cysteamine-induced duodenal ulceration. We show here that cysteamine-induced ulceration was aggravated by pretreatment of rats with Fe(3+) or Fe(2+) compounds, which elevated iron concentration in the duodenal mucosa. In contrast, feeding rats an iron-deficient diet was associated with a 4.6-fold decrease in ulcer formation, accompanied by a 34% decrease (P < 0.05) in the duodenal mucosal iron concentration. Administration of deferoxamine inhibited ulceration by 65%. We also observed that the antiulcer effect of H2 receptor antagonist cimetidine included a 35% decrease in iron concentration in the duodenal mucosa. Cysteamine-induced duodenal ulcers were also decreased in iron-deficient Belgrade rats (P < 0.05). In normal rats, cysteamine administration increased the iron concentration in the proximal duodenal mucosa by 33% in the preulcerogenic stage but at the same time decreased serum iron (P < 0.05). Cysteamine also enhanced activation of mucosal iron regulatory protein 1 and increased the expression of divalent metal transporter 1 mRNA and protein. Transferrin receptor 1 protein expression was also increased, although mucosal ferroportin and ferritin remained almost unchanged. These results indicate an expansion of the intracellular labile iron pool in the duodenal mucosa, increasing its susceptibility to oxidative stress, and suggest a role for iron in the pathogenesis of organ-specific tissue injury such as duodenal ulcers.

Hymenaea stigonocarpa Mart. ex Hayne: A Brazilian medicinal plant with gastric and duodenal anti-ulcer and antidiarrheal effects in experimental rodent models

“…This model has been considered the standard model for experimental duodenal ulcers and has been used for the biological efficacy assessment of new anti-ulcer drugs. According to Khomenko et al (2009), animals treated with cysteamine display a significant increase in duodenal lesions due to the generation of free radicals. Fig.…”

Byrsonima intermedia A. Juss.: Gastric and duodenal anti-ulcer, antimicrobial and antidiarrheal effects in experimental rodent models

“…Cysteamine hydrochloride inhibits alkaline mucus secretion from the Brunner's gland in the proximal duodenum and stimulates the rate of gastric acid secretion (Schwedes et al, 1977). According to Khomenko et al (2009) animals treated with cysteamine also display a significant increase in duodenal lesions due to the generation of free radicals. Fig.…”

Ghrelin accelerates the healing of cysteamine-induced duodenal ulcers in rats

“…Some studies have suggested that transcription factors such as hypoxia-inducible factor-1α and early growth response factor-1 and their target genes are involved in pathogenesis of cysteamine-induced ulcers [38,39]. Moreover, a recent study performed by Khomenko et al has produced strong evidence that cysteamine disrupts regulation of mucosal iron transport, leading to increased mucosal susceptibility to oxidative stress [40]. …”