Biliary excretion of plasma non-transferrin-bound iron in rats: pathogenetic importance in iron-overload disorders.
Plasma non-transferrin-bound iron (NTB-iron) is a potentially toxic form of iron, which is efficiently taken up by the normal, as well as the chronically iron-overloaded liver. In fact, NTB-iron may represent the major source of iron gaining access to hepatocytes in the iron-loaded state. We postulated that efficient biliary excretion of this form of iron could protect against iron-related hepatocellular injury. To characterize the biliary excretion of NTB-iron in intact normal and iron-loaded rats, the plasma disappearance and biliary excretion kinetics of plasma 55Fe-labeled NTB-iron were determined. In normal rats, prompt biliary excretion of plasma NTB-iron was evident, with peak radioactivity approximately 10 min after 55Fe injection (4.1% mean recovery at 3 h). In contrast, biliary iron excretion in iron-loaded rats was minimal (0.1%). In normal rats, a marked increase in biliary excretion of plasma NTB-iron was observed after intravenous desferrioxamine (mean recovery 20.9%) and the new oral iron chelator 1,2-dimethyl-3-hydroxypyrid-4-one administered intravenously (mean recovery 16.1%) or orally (11.4%). In iron-loaded rats, the cumulative recoveries of 55Fe in bile achieved by chelators were lower than in controls (7.6, 3.9, and 3.7%, respectively). Collectively, these findings demonstrate that 1) the normal liver rapidly excretes significant amounts of plasma NTB-iron in bile; 2) the iron-loaded liver exhibits a marked decrease in the capacity to excrete plasma NTB-iron into bile; and 3) chelating agents greatly enhance the biliary excretion of plasma NTB-iron, although the response in terms of cumulative recoveries is less pronounced in the iron-loaded state.(ABSTRACT TRUNCATED AT 250 WORDS)
Brissot
P
P
Gastroenterology Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
Zanninelli
G
G
Guyader
D
D
Zeind
J
J
Gollan
J
J
D000818:Animals; D001646:Bile / Q000378:metabolism*; D000077543:Deferiprone; D003676:Deferoxamine / Q000494:pharmacology; D007275:Injections, Intravenous; D007501:Iron / Q000097:blood* / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000494:pharmacology; D008297:Male; D011728:Pyridones / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D007502:Iron Chelating Agents; D011728:Pyridones; D000077543:Deferiprone; D007501:Iron; D003676:Deferoxamine