New mechanistic explanation for the localization of ulcers in the rat duodenum: Role of iron and selective uptake of cysteamine
| Autor: | Arthur J.L. Cooper, Xiaoming Deng, Neil Hoa, John T. Pinto, Brankica Paunovic, Ganna Tolstanova, Joanna Kolodney, Longchuan Chen, Gordon D. McLaren, Tetyana Khomenko, Boris F. Krasnikov, Sandor Szabo |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
medicine.medical_specialty
Organic Cation Transport Proteins Duodenum Cysteamine Iron Cystamine Intracellular Space Biophysics Deferoxamine Iron Chelating Agents Biochemistry Mice chemistry.chemical_compound Internal medicine medicine Animals Humans Intestinal Mucosa Receptor Molecular Biology chemistry.chemical_classification Reactive oxygen species Gastrointestinal tract Organic cation transport proteins biology Chemistry Sodium Biological Transport Iron deficiency medicine.disease In vitro Rats Endocrinology Gene Expression Regulation Intestinal Absorption Organ Specificity Duodenal Ulcer biology.protein Female Caco-2 Cells Reactive Oxygen Species Intracellular |
| Zdroj: | Archives of Biochemistry and Biophysics. 525:60-70 |
| ISSN: | 0003-9861 |
| DOI: | 10.1016/j.abb.2012.05.013 |
| Popis: | Cysteamine, a coenzyme A metabolite, induces duodenal ulcers in rodents. Our recent studies showed that ulcer formation was aggravated by iron overload and diminished in iron deficiency. We hypothesized that cysteamine is selectively taken up in the duodenal mucosa, where iron absorption primarily occurs, and is transported by a carrier-mediated process. Here we report that cysteamine administration in rats leads to cysteamine accumulation in the proximal duodenum, where the highest concentration of iron in the gastrointestinal tract is found. In vitro, iron loading of intestinal epithelial cells (IEC-6) accelerated reactive oxygen species (ROS) production and increased [(14)C]cysteamine uptake. [(14)C]Cysteamine uptake by isolated gastrointestinal mucosal cells and by IEC-6 was pH-dependent and inhibited by unlabeled cysteamine. The uptake of [(14)C]cysteamine by IEC-6 was Na(+)-independent, saturable, inhibited by structural analogs, H(2)-histamine receptor antagonists, and organic cation transporter (OCT) inhibitors. OCT1 mRNA was markedly expressed in the rat duodenum and in IEC-6, and transfection of IEC-6 with OCT1 siRNA decreased OCT1 mRNA expression and inhibited [(14)C]cysteamine uptake. Cysteamine-induced duodenal ulcers were decreased in OCT1/2 knockout mice. These studies provide new insights into the mechanism of cysteamine absorption and demonstrate that intracellular iron plays a critical role in cysteamine uptake and in experimental duodenal ulcerogenesis. |
| Databáze: | OpenAIRE |
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