Ascorbate and Iron Overload

As discussed in Section 13.3.5, ascorbate enhances the intestinal absorption of inorgemic iron, and therefore it is frequently prescribed together with iron supplements. It is tilso used when it is desired to acidify the urine (e.g., in conjunction with some tmtibiotics). Supplements of viteimin C (often of the order of grams per day) tue widely consumed to protect ageiinst cancer, ctirdiovcis-cuIeu disease, and virtil infections, Edthough (tis discussed below) the evidence of efficacy is poor. 

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FIGURE 5. Ascorbic acid as an antioxidant. The free radical form of ascorbic acid, A , is the primary product of ascorbic acid oxidation, observed during catalytic, enzymatic, photooxidative, and free radical oxidation. It is relatively stable and, thus, can detected by electron spin resonance in ischemic reperfusion of the heart and iron overloaded blood plasma. Adapted from Bendich et al, (1986). 

Ascorbic acid also forms soluble chelate complexes with iron (142—145). It seems ascorbic acid has no effect on high iron levels found in people with iron overload (146). It is well known, in fact, that ascorbic acid in the presence of iron can exhibit either prooxidant or antioxidant effects, depending on the concentration used (147). The combination of citric acid and ascorbic acid may enhance the iron load in aging populations. Iron overload may be the most important common etiologic factor in the development of heart disease, cancer, diabetes, osteoporosis, arthritis, and possibly other disorders. The synergistic combination of citric acid and ascorbic acid needs further study, particularly because the iron overload produced may be correctable (147). 

In addition to the well-known iron effects on peroxidative processes, there are also other mechanisms of iron-initiated free radical damage, one of them, the effect of iron ions on calcium metabolism. It has been shown that an increase in free cytosolic calcium may affect cellular redox balance. Stoyanovsky and Cederbaum [174] showed that in the presence of NADPH or ascorbic acid iron ions induced calcium release from liver microsomes. Calcium release occurred only under aerobic conditions and was inhibited by antioxidants Trolox C, glutathione, and ascorbate. It was suggested that the activation of calcium releasing channels by the redox cycling of iron ions may be an important factor in the stimulation of various hepatic disorders in humans with iron overload. 

Iron overload, ascorbic acid and, 25 770 Iron(II) oxalate dihydrate, 14 547-548 Iron oxide(s), 14 541-542... 

It seems likely that the prooxidant actions of ascorbate are of relatively little importance in vivo. Except in cases of iron overload, there are almost no transition metal ions in free solution. They are all bound to proteins, and because the renal transport system is readily saturated, plasma and tissue concentrations of ascorbate are unlikely to rise to a sufficient extent to lead to radical formation (Halliwell, 1996 Carr and Frei, 1999a). 

Ascorbic acid promotes the absorption of iron, a reason for caution in giving high doses to patients with iron overload (SEDA-9, 324). In particular, patients with hemochromatosis, polycythemia, and leukemia who present with marked iron overload should keep their intake of ascorbic acid to a minimum (42). However, ascorbic acid can also interfere with the distribution of iron in the body in these patients. One consequence is that in patients with iron overload who also have scurvy, iron tends to be deposited in the reticuloendothelial system rather than the parenchymal cells, which may reduce the risks of damage to the liver, heart, or endocrine glands. It has conversely been noted that in beta-thalassemia major... 

Rowbotham B, Roeser HP. Iron overload associated with congenital pyruvate kinase deficiency and high dose ascorbic acid ingestion. Aust NZ J Med 1984 14(5) 667-9. 

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. 

Effects of Excess Tissue Iron on Ascorbic Acid Metabolism. Epidemiological observations among the Bantu of South Africa showed an apparent association of clinical scurvy in adult males with hemosiderosis common to this group. Both plasma clearance of ascorbic acid and urinary excretion of ascorbic acid were altered in severe iron overload plasma clearance was increased and urinary excretion was decreased in siderotic subjects (40,41), The evidence was interpreted as a demonstration of enhanced oxidative catabolism of ascorbic acid in the presence of excess tissue iron. 

As described in Section 3, iron can promote peroxidation of biological macromolecules due to its reactions with ROS and, thus, is of high toxic potential for cells, if it is not kept in a toxicologi-cally inactivated form bound to specific proteins. Only when iron is tightly bound to a chelator is its capacity for promoting LPO minimal. Amongst synthetic chelators of iron, fois-(2-aminoethyl)-amine-A, N,A, N -penta-acetic acid, desferrioxamine, o-phenanthroline and bathophenanthroline are able to complex Fe + and, thus, slow down reduction of Fe to Fe + by reductants like ascorbic acid or (O2) in vitro, but EDTA is ineffective. Desferrioxamine was originally developed for the treatment of iron overload disease because it binds Fe +... 

Ascorbate may also have detrimental effects related to its role in iron mobilization. Iron overload can occur as a result of high dietary iron, blood transfusion, or idiopathic hemochromatosis (Nienhuis, 1981 Murray, 1982 Halliwell, 1983 Hal-liwell and Gutteridge, 1989). 

Normally, most iron is stored as ferritin but with increasing iron overload hemosiderin increases. Hemosiderin is found in the parenchymal cells of the liver and this may result in hemosiderosis and even cirrhosis. Treatment is with the iron chelator desferrioxamine and small amounts of ascorbic acid. The effect of ascorbic acid upon iron transport has been reported for dietary iron overload and P-thalassemia. As a result of ascorbic acid administration, serum iron rapidly rises and its careful use in conjunction with the iron chelator desferrioxamine increases urinary iron excretion (O Brien, 1974 Nienuis et ai, 1976 Nienhuis, 1981 Murray, 1982). 

Neinuis, A. W., Delea, C., Aamodt, R., Bartter, F., and Anderson, W. F., 1976, Evaluation of desferoxamine and ascorbic acid for treatment of chronic iron overload. Birth Defects 12 177-185. 

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. 

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