New mechanistic explanation for the localization of ulcers in the rat duodenum: role of iron and selective uptake of cysteamine.
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.
Diagnostic and Molecular Medicine, VA Long Beach Healthcare System, Long Beach, CA 90822, USA.
Tetyana
T
Khomenko
Joanna
J
Kolodney
John T
JT
Pinto
Gordon D
GD
McLaren
Xiaoming
X
Deng
Longchuan
L
Chen
Ganna
G
Tolstanova
Brankica
B
Paunovic
Boris F
BF
Krasnikov
Neil
N
Hoa
Arthur J L
AJ
Cooper
Sandor
S
Szabo
D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D018938:Caco-2 Cells; D003538:Cystamine / Q000378:metabolism; D003543:Cysteamine / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D003676:Deferoxamine / Q000494:pharmacology; D004381:Duodenal Ulcer / Q000378:metabolism* / Q000473:pathology; D004386:Duodenum / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D007501:Iron / Q000378:metabolism* / Q000494:pharmacology; D007502:Iron Chelating Agents / Q000494:pharmacology; D051379:Mice; D009928:Organ Specificity; D027701:Organic Cation Transport Proteins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D012964:Sodium / Q000378:metabolism
D007502:Iron Chelating Agents; D027701:Organic Cation Transport Proteins; D017382:Reactive Oxygen Species; D003543:Cysteamine; D012964:Sodium; D007501:Iron; D003676:Deferoxamine; D003538:Cystamine