Vitamin iron overload

The efficiency of vitamin E in the suppression of free radical-mediated damage induced by iron overload has been studied in animals and humans. Galleano and Puntarulo [46] showed that iron overload increased lipid and protein peroxidation in rat liver. Vitamin E supplementation successfully suppressed these effects and led to an increase in a-tocopherol, ubiquinone-9, and ubiquinone-10 contents in liver. Important results were obtained by Roob et al. [47] who found that vitamin E supplementation attenuated lipid peroxidation (measured as plasma MDA and plasma lipid peroxides) in patients on hemodialysis after receiving iron hydroxide sucrose complex intravenously during hemodialysis session. These findings support the proposal that iron overload enhances free radical-mediated damage in humans. 

Chelators of iron, which are now widely applied for the treatment of patients with thalassemia and other pathologies associated with iron overload, are the intravenous chelator desferal (desferrioxamine) and oral chelator deferiprone (LI) (Figure 19.23, see also Chapter 31). Desferrioxamine (DFO) belongs to a class of natural compounds called siderophores produced by microorganisms. The antioxidant activity of DFO has been studied and compared with that of synthetic hydroxypyrid-4-nones (LI) and classic antioxidants (vitamin E). It is known that chronic iron overload in humans is associated with hepatocellular damage. Therefore, Morel et al. [370] studied the antioxidant effects of DFO, another siderophore pyoverdin, and hydroxypyrid-4-ones on lipid peroxidation in primary hepatocyte culture. These authors found that the efficacy of chelators to inhibit iron-stimulated lipid peroxidation in hepatocytes decreased in the range of DFO > hydroxypyrid-4-ones > pyoverdin. It seems that other siderophores are also less effective inhibitors of lipid peroxidation than DFO [371],... 

Overproduction of free radicals by erythrocytes and leukocytes and iron overload result in a sharp increase in free radical damage in T1 patients. Thus, Livrea et al. [385] found a twofold increase in the levels of conjugated dienes, MDA, and protein carbonyls with respect to control in serum from 42 (3-thalassemic patients. Simultaneously, there was a decrease in the content of antioxidant vitamins C (44%) and E (42%). It was suggested that the iron-induced liver damage in thalassemia may play a major role in the depletion of antioxidant vitamins. Plasma thiobarbituric acid-reactive substances (TBARS) and conjugated dienes were elevated in (3-thalassemic children compared to controls together with compensatory increase in SOD activity [386]. The development of lipid peroxidation in thalassemic erythrocytes probably depends on a decrease in reduced glutathione level and decreased catalase activity [387]. 

Ascorbate cataboUsm is increased in subjects with iron overload, probably as a result of nonenzymic reactions with bon that is not protein-bound. The transferrin polymorphisms that are associated with susceptibiUty to iron overload result in higher vitamin C requirements for those subjects with high iron status (Kasvosve et al., 2002). 

In rural sub-Saharan Africa, there is a kind of beer which is traditionally brewed in iron vats. The daily iron overload can amount to as much as 200 mg with markedly increased iron absorption (T.H. Bothwell et at, 1965). Such a condition is also observed in South Africa among the black population. Their diet consists of porridge fermented in iron pots with an acid pH value (V.R. Gordeuk et al., 1986). In both conditions, absorption of iron is facilitated by various factors, e. g. protein or vitamin C deficiency, alcohol abuse, acidic diet. It has been suggested that such iron overload is triggered by genetic factors. (437)... 

In the diet and at the tissue level, ascorbic acid can interact with mineral nutrients. In the intestine, ascorbic acid enhances the absorption of dietary iron and selenium reduces the absorption of copper, nickel, and manganese but apparently has little effect on zinc or cobalt. Ascorbic acid fails to affect the intestinal absorption of two toxic minerals studied, cadmium and mercury. At the tissue level, iron overload enhances the oxidative catabolism of ascorbic acid. Thus, the level of dietary vitamin C can have important nutritional consequences through a wide range of inhibitory and enhancing interactions with mineral nutrients. 

Vitamin C is given with iron chelators to patients with iron overload because it mobilises iron stores and thus promotes the excretion of iron. One study in 11 patients with thalassaemia noted that a striking deterioration in left ventricular function occurred when the patients were given 500 mg of vitamin C with intramuscular desferrioxamine. In most patients left ventricular function returned to normal when the vitamin C was stopped. For this reason it has been suggested that vitamin C should be used with desferrioxamine with caution, only where there is a demonstrated need, and in the lowest possible dose. The manufacturers of desferrioxamine recommend that a maximum daily dose of200 mg of vitamin C should be used in adults, that vitamin C should not be given within the first month of desferrioxamine treatment, and that it should not be given to those with cardiac failure. ... 

The combined use of deferoxamine with deferasrrox has been described in seven Asian patients with thalassemia and iron overload in a retrospective evaluation of alternating administration of deferoxamine (20-40 mg/ kg/day for 8-12 hours for 3 days, combined with vitamin C 100 mg/day) and deferasirox (20-30 mg/kg/day for 4 days) every week for 8-27 months [24 ]. There was a substantial reduction in serum ferritin concentrations and no adverse events were reported. 

Halliwell (22) suggests that the possible in vivo pro-oxidant effects of ascorbate are related to the availability of catalytic transition metal ions. The content of vitamin C in meals increases nonheme iron absorption (24). In patients with iron accumulation diseases such as hemochromatosis or thalassemia, this might lead to increased iron overload and deleterious clinical effects (22). Non-protein-bound iron, as far as it exists in the human body, can induce lipid peroxidation especially if it is present together with the pro-oxidative ascorbic acid (reactions 3 and 5). According to previous reviews (6,24), vitamin C ingestion enhances the iron absorption also in individuals with iron deficiency, but may have a rather small effect in individuals with normal iron status. 

To enhance iron excretion, intensive chelation therapy is used. The most successful drug is desferrioxamine B, a powerful Fe3+-chelator produced by the microbe Streptomyces pilosus,6 The formation constant for the Fe(III) complex, called ferrioxamine B, is 103afi. Used in conjunction with ascorbic acid—vitamin C, a reducing agent that reduces Fe3+ to the more soluble Fe2+— desferrioxamine clears several grams of iron per year from an overloaded patient. The ferrioxamine complex is excreted in the urine. 

Abnormal accumulation in tissues and overloading of normal metabolic pathways, leading to signs of toxicity and possibly irreversible lesions. Iron (section 11.15.2.3), selenium (section 11.15.2.5), niacin (section 11.8.5.2) and vitamins A (section 11.2.5.2), D (section 11.3.5.1) and (section 11.9.6.1) are all known to be toxic in excess. 

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