Cellular uptake and release of two contrasting iron chelators

Desferrioxamine and CP94 (1,2diethyl-3 -hydroxypyridin-4-one) are metal che lators used or proposed for use in the clinical treatment of iron overload. Recent data on their capacity to deplete intracellular iron led to the con jecture that the differences observed arose from the different membrane-pen etration properties of the two compounds. The time-course of accumulation and subsequent release of [C-14]CP94 by the rat visceral yolk sac in-vitro was compared with that of [C-14]desferrioxa mine and for I-125- labelled poly(vinylpyrrolidone), a marker for fluid-pha se endocytosis. The results indicate that [C-14]CP94 crosses the plasma and lysosome membranes rapidly whereas [C-14]desferrioxamine and I-125-labelle d poly(vinylpyrrolidone) are effectively incapable of crossing these membra nes, entering cells only by endocytosis. It is concluded that although CP94 readily enters and leaves cells, desferr ioxamine has the potential to accumulate to high concentration in the lysos omes and complex with intralysosomal iron. The results support and extend t he proposed correlation between pharmacological activity and capacity for m embrane penetration.