alexa Pathophysiology of iron overload.
Toxicology

Toxicology

Journal of Drug Metabolism & Toxicology

Author(s): Hershko C, Link G, Cabantchik I

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Abstract In thalassemia, iron overload is the joint outcome of excessive iron absorption and transfusional siderosis. While iron absorption is limited by a physiologic ceiling of about 3 mg/d, plasma iron turnover in thalassemia may be 10 to 15 times normal, caused by the wasteful, ineffective erythropoiesis of an enormously expanded erythroid marrow. This outpouring of catabolic iron exceeds the iron-binding capacity of transferrin and appears in plasma as non-transferrin-plasma iron (NTPI). The toxicity of NTPI is much higher than of transferrin-iron as judged by its ability to promote hydroxyl radical formation resulting in peroxidative damage to membrane lipids and proteins. In the heart, this results in impaired function of the mitochrondrial respiratory chain and abnormal energy metabolism manifested clinically in fatal hemosiderotic cardiomyopathy. Ascorbate increases the efficacy of iron chelators by expanding the intracellular chelatable iron pool, but, at suboptimal concentrations is a pro-oxidant, enhancing the catalytic effect of iron in free radical formation. NTPI is removed by i.v. DFO in a biphasic manner and reappears rapidly upon cessation of DFO, lending support to the continuous, rather than intermittent, use of chelators. Unlike DFO and other hexadentate chelators, bidentate chelators such as L1 may produce incomplete intermediate iron complexes at suboptimal drug concentrations.
This article was published in Ann N Y Acad Sci and referenced in Journal of Drug Metabolism & Toxicology

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