Does the haemosiderin iron core determine its potential for chelation and the development of iron-induced tissue damage?

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Abstract

Haemosiderin, the major iron storage protein in tissues of iron-loaded tissues shows heterogeneity with respect to both its iron mineralisation product and associated protein. Such mineralisation products have been characterised by a variety of physical techniques including Mössbauer spectroscopy, electron diffraction and EXAFS, and are closely related to the mineral ferrihydrite. A wide range of iron chelators are being developed for the treatment of abnormal haemoglobinopathies, predominantly β-thalassaemia, which may show greater chelator efficacy for particular mineralisation products of haemosiderin. Even though the tissue iron loadings achieved in different iron-loading syndromes are similar, e.g. naturally occurring iron loading, genetic haemochromatosis and thalassaemia, it is clear that the iron loading in thalassaemic causes extensive damage. The explanation for this could relate to the distribution of iron within different cell types, predominantly reticuloendothelial, its rate of deposition and the mineralisation product of its haemosiderin iron core, goethite.

Introduction

Excessive accumulation of iron occurs in many animal and bird species where its ability to initiate tissue toxicity appears to be limited. By contrast, iron-loading syndromes that occur in two major human conditions, genetic haemochromatosis and β-thalassaemia, are associated with extensive tissue damage, particularly with respect to the secondary iron overload. The explanation for this paradox remains unanswered but it could be related to a variety of factors which include the mineralisation product in the iron storage protein, haemosiderin, together with its associated protein, the distribution of such iron within various cells, i.e. parenchymal versus reticuloendothelial localisation, as well as the rate of iron deposition. Furthermore, such factors may also be important in dictating the efficacy of the chelation therapy.

Section snippets

Animal and bird species

In nature, many animals and birds are able to sustain high tissue iron content without showing any toxicity. Iron overload occurs naturally in many species, e.g. marmosets [1], lemurs [2], avian species [3], [4], [5], horse [6] and Svalbard reindeers [7], although in many cases the cause of the excessive iron accumulation has not been ascertained. In addition, in many of these early studies, excessive iron loading has been identified only by the observation of an increase in Perl staining

Biophysical studies of haemosiderin iron cores from different iron-loading syndromes

Although haemosiderin was identified over 100 years ago by Perl in 1867 [9], little was known until recently in biochemical terms of its composition, structure, biosynthesis and metabolism or indeed of its role in initiating or protecting the cell from iron-induced tissue damage. It is present in relatively small amounts in normal tissue but accumulates during iron overload [10]. Haemosiderin is a water-insoluble protein with a high iron to protein ratio and a molecular mass greater than 4000

Mössbauer spectroscopy

The spectra of each haemosiderin sample showed characteristic superparamagnetic behaviour of a magnetically ordered material in the form of small particles. This leads to a temperature dependence which is characterised by a superparamagnetic transition temperature or blocking temperature; a value between 20 and 30 K was determined for animal, bird and old-age haemosiderin, <10 K for genetic haemochromatosis haemosiderin, and between 63 and 70 K for thalassaemic haemosiderin. Such results

Chelation studies of ferritin and haemosiderin

Although the majority of experiments to test chelator efficacy have utilised in vivo animal models in which ferritin is the predominant iron storage protein present, or in vitro incubation with ferritin, it is clear that this iron storage protein should be investigated for its ability to release its iron to the various chelators, since the majority of the iron present in iron-loading syndromes is essentially haemosiderin (>80%).

Since haemosiderin cores have higher phosphate content than

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