BILIARY-EXCRETION OF PLASMA NON-TRANSFERRIN-BOUND IRON IN RATS - PATHOGENETIC IMPORTANCE IN IRON-OVERLOAD DISORDERS

Plasma nontransferrin-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 Fe-55-labeled NTB-iron were determined. In normal rats, prompt biliary excretion of plasma NTB-iron was evident, with peak radioactivity similar to 10 min after Fe-55 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 Fe-55 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. These data extend the potential pathogenetic importance of plasma NTB-iron in chronic iron overload; thus this form of iron may present the liver with an obligatory load due not only to enhanced hepatic uptake but also to the relative absence of significant biliary excretion.