Ferritin formation

Table I. Stoichiometry Fe/02 in Ferritin Formation [Horse Spleen Apoferrltln, FedDUHitSOi ]...

As will become clear from the discussions below two quite different models have been advanced to explain the formation of ferritin. Historically the earliest demonstrations of ferritin formation by guinea pig... 

Fig. 11. Chelate model for ferritin formation see text for details...

Ferritin formation in mammalian tissues has been investigated in liver slices and homogenates. In liver slices, the incorporation of labeled plasma iron into ferritin is stimulated by adding a Krebs cycle substrate to the medium and is inhibited by iodoacetamide, cyanide, and anoxemia. These findings suggest that the conversion of apoferritin to ferritin is energy dependent. 

However, the postulated mechanism provides a simple explanation for the effect of anoxemia on iron uptake. The conversion of apoferritin to ferrritin is coupled with the reduction of ferric to ferrous iron. The rate of ferritin formation would be regulated by the redox levels of the cell. Whether this theory for the control of iron uptake will survive a concentrated tide of quantitatively well-controlled in vivo experiments remains to be seen. 

Immunohistochemical studies carried out in our laboratories have demonstrated the presence of xanthine oxidase in synovial endothelial cells (Stevens etal., 1991). As expected, the activity of this enzyme per unit weight of tissue is generally higher in synovia taken from RA patients due to their increased vascularity (Allen et al., 1987). In addition, it has also been shown that rheumatoid synoviocytes contain increased levels of iron-saturated ferritin (Morris et d., 1986). Xanthine oxidase (but not dehydrogenase) is able to mobilize iron from ferritin, supplying the necessary transition metal catalyst for the Haber-Weiss reaction and promoting OH formation (Biemond eta/., 1986). 

O Connell, M.J., Halliwell, B., Moothouse, C.P., Aruoma, O.I., Baum, H. and Peters, T.J. (1986). Formation of hydroxyl radicals in the presence of ferritin and haemosiderin. Is haemosiderin formation a biological protective mechanism Biochem. J. 234, 727-731. 

We can briefly conclude that the mineralization process of iron in ferritin cores is a difficult process to follow experimentally. While we believe that iron is delivered for storage within the protein cavity as Fe(II), and that an oxidation step occurs in the formation of the ferritin iron core, it is not clear what percentage of iron oxidation occurs on the growing surface of the mineral and what at the catalytic ferroxidase... 

The formation of nitric oxide in microsomes results in the inhibition of microsomal reductase activity. It has been found that the inhibitory effect of nitric oxide mainly depend on the interaction with cytochrome P-450. NO reversibly reacts with P-450 isoforms to form the P-450-NO complex, but at the same time it irreversibly inactivates the cytochrome P-450 via the modification of its thiol residues [64]. Incubation of microsomes with nitric oxide causes the inhibition of 20-HETE formation from arachidonic acid [65], the generation of reactive oxygen species [66], and the release of catalytically active iron from ferritin [67],... 

The mechanism of iron-initiated superoxide-dependent lipid peroxidation has been extensively studied by Aust and his coworkers [15-18]. It was found that superoxide produced by xanthine oxidase initiated lipid peroxidation, but this reaction was not inhibited by hydroxyl radical scavengers and, therefore the formation of hydroxyl radicals was unimportant. Lipid peroxidation depended on the Fe3+/Fe2+ ratio, with 50 50 as the optimal value [19]. Superoxide supposedly stimulated peroxidation both by reducing ferric ions and oxidizing ferrous ions. As superoxide is able to release iron from ferritin, superoxide-promoted lipid peroxidation can probably proceed under in vivo conditions [16,20]. 

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