ascorbic-acid and Iron-Overload

Oxidative stress is a common denominator in the pathogenesis of many chronic diseases. Therefore, antioxidants are often used to protect cells and tissues and reverse oxidative damage. It is well known that iron metabolism underlies the dynamic interplay between oxidative stress and antioxidants in many pathophysiological processes. Both iron deficiency and iron overload can affect redox state, and these conditions can be restored to physiological conditions using iron supplementation and iron chelation, respectively. Similarly, the addition of antioxidants to these treatment regimens has been suggested as a viable therapeutic approach for attenuating tissue damage induced by oxidative stress. Notably, many bioactive plant-derived compounds have been shown to regulate both iron metabolism and redox state, possibly through interactive mechanisms. This review summarizes our current understanding of these mechanisms and discusses compelling preclinical evidence that bioactive plant-derived compounds can be both safe and effective for managing both iron deficiency and iron overload conditions.

Topics: Anemia, Iron-Deficiency; Animals; Antioxidants; Ascorbic Acid; Disease Models, Animal; Homeostasis; Humans; Iron; Iron Deficiencies; Iron Overload; Oxidative Stress; Plant Extracts; Polyphenols; Reactive Oxygen Species; Vitamin A

To determine the impact of adjuvant ascorbic acid therapy on erythropoietin-hyporesponsive, anemic patients undergoing hemodialysis.. The online databases of PubMed, Cochrane library, IPA, CINAHL, EMBASE, clinicaltrial.gov, WHO trial registry and PyschINFO were used.. Studies comparing ascorbic acid to a control, with participants receiving erythropoietin and hemodialysis, and reported outcomes for hemoglobin or transferring saturation.. Two independent researchers reviewed titles and abstracts to determine relevance and extracted study design, dose, duration, baseline values, and outcomes.. Five studies met all the criteria and were used for final analysis. The calculated weighted mean difference between hemoglobin in the ascorbic acid group versus the control group was 0.96 g/dL (95% CI, 0.78 to 1.14). The calculated weighted mean difference between transferrin saturation in the ascorbic acid treatment group versus the control was 8.26% (95% CI, 6.59 to 9.94).. Adjuvant ascorbic acid significantly raises hemoglobin levels in patients with erythropoietin hyporesponsiveness undergoing hemodialysis. The significant rise in transferrin saturation indicates that this positive effect on erythropoietin response may be due to increased iron utilization.

Topics: Adult; Anemia; Antioxidants; Ascorbic Acid; Erythropoietin; Female; Hemoglobins; Humans; Injections, Intravenous; Iron; Iron Overload; Kidney Failure, Chronic; Male; Middle Aged; Randomized Controlled Trials as Topic; Renal Dialysis

Iron is an essential nutrient for the growth, development, and long-term survival of most organisms. High tissue iron concentrations have been associated with the development and progression of several pathological conditions, including certain cancers, liver and heart disease, diabetes, hormonal abnormalities, and immune system dysfunctions. In this review we discuss the relevance of iron toxicity on free radical-mediated tissue damage, and how iron interactions with nutrient antioxidants and other metals can affect the extent of oxidative damage to different biomolecules. It can be concluded that the ingestion of antioxidant rich foods may prevent or delay primary and secondary effects associated with iron overload-related diseases.

Topics: Animals; Antioxidants; Ascorbic Acid; Flavonoids; Humans; Iron; Iron Chelating Agents; Iron Overload; Lead Poisoning; Oxidation-Reduction; Reactive Oxygen Species; Vitamin E; Zinc

Vitamin C, as antioxidant, increases the efficacy of deferoxamine (DFO).. To investigate the effects of vitamin C as an adjuvant therapy to the three used iron chelators in moderately iron-overloaded young vitamin C-deficient patients with β-thalassemia major (β-TM) in relation to tissue iron overload.. This randomized prospective trial that included 180 β-TM vitamin C-deficient patients were equally divided into three groups (n = 60) and received DFO, deferiprone (DFP), and deferasirox (DFX). Patients in each group were further randomized either to receive vitamin C supplementation (100 mg daily) or not (n = 30). All patients received vitamin C (group A) or no vitamin C (group B) were followed up for 1 yr with assessment of transfusion index, hemoglobin, iron profile, liver iron concentration (LIC) and cardiac magnetic resonance imaging (MRI) T2*.. Baseline vitamin C was negatively correlated with transfusion index, serum ferritin (SF), and LIC. After vitamin C therapy, transfusion index, serum iron, SF, transferrin saturation (Tsat), and LIC were significantly decreased in group A patients, while hemoglobin and cardiac MRI T2* were elevated compared with baseline levels or those in group B without vitamin C. The same improvement was found among DFO-treated patients post-vitamin C compared with baseline data. DFO-treated patients had the highest hemoglobin with the lowest iron, SF, and Tsat compared with DFP or DFX subgroups.. Vitamin C as an adjuvant therapy possibly potentiates the efficacy of DFO more than DFP and DFX in reducing iron burden in the moderately iron-overloaded vitamin C-deficient patients with β-TM, with no adverse events.

Topics: Ascorbic Acid; Ascorbic Acid Deficiency; beta-Thalassemia; Biomarkers; Dietary Supplements; Drug Therapy, Combination; Female; Humans; Iron; Iron Chelating Agents; Iron Overload; Liver; Magnetic Resonance Imaging; Male; Treatment Outcome

To assess the effects of iron removal on cytochrome P450 2E1 activity and oxidative stress in dysmetabolic iron overload syndrome.. Forty-eight patients were randomized to phlebotomy therapy consisting of removal of 300-500 mL of blood every 14 days until serum ferritin levels dropped under 100 microg/L or to follow-up without phlebotomy therapy. Cytochrome P450 2E1 activity was measured at baseline and at the end of treatment by using the 6-hydroxychlorzoxazone/chlorzoxazone blood metabolic ratio, 2 h after the intake of 500 mg of chlorzoxazone.. In the treatment group, a mean of 3.9 +/- 1.3 L of blood was removed and serum ferritin levels dropped from 715 +/- 397 to 74 +/- 34 microg/L. Variation of cytochrome P450 2E1 activity was not significantly different between the 2 groups (0.07 +/- 0.26 vs. 0.03 +/- 0.19, P = 0.36). In the treatment group, low-density lipoprotein cholesterol and vitamin E were lowered after treatment compared with control group (-0.15 +/- 0.51 vs. 0.24 +/- 0.58, P = 0.002 and -1.3 +/- 4.4 vs. 2.3 +/- 5.2, P = 0.03, respectively). Inversely, vitamin C was increased (0.5 +/- 3.5 vs. -1.8 +/- 3.9, P = 0.03).. In dysmetabolic iron overload syndrome, reduction of iron stores does not significantly influence cytochrome P450 2E1 activity but is associated with a significant decrease of low-density lipoprotein cholesterol, suggesting that venesection therapy may be a suitable option in these patients.

Topics: Ascorbic Acid; Biomarkers; Cholesterol, LDL; Cytochrome P-450 CYP2E1; Ferritins; Humans; Iron Overload; Male; Malondialdehyde; Oxidative Stress; Phlebotomy; Prospective Studies; Vitamin E

Ascorbic acid supplementation has been recommended to circumvent resistance to erythropoietin, which sometimes occurs in iron-overloaded uremic patients. In considering the pro-oxidant effect of ascorbic acid, the authors hypothesize that adjuvant therapy with larger doses of ascorbic acid in hemodialysis patients with iron overload may raise the risk of increasing free radical generation. The oxidative stress of intravenous ascorbic acid supplementation in hemodialysis patients was evaluated in this study.. Six healthy subjects and 29 hemodialysis patients were enrolled. Chemical scavenging activity of various compounds was measured by in vitro 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay. Free radical generation was determined in vitro by lucigenin-enhanced chemiluminescence (LucCL) assay on blood samples. Blood biochemistries were also measured simultaneously in hemodialysis patients 1 minute before and 5 minutes later in the presence or absence of intravenous injection of 300 mg ascorbic acid.. Ascorbic acid presented a strong antioxidant effect in DPPH chemical reaction. On the contrary, it exerted pro-oxidant effect when mixed with plasma or whole blood of healthy subjects and hemodialysis patients. The pro-oxidant effect of ascorbic acid detected by LucCL was attenuated by various iron chelators and superoxide dismutase. In hemodialysis patients, the changes of LucCL intensity were significantly higher in the ascorbic acid-treated group than those in the control group (1261.0 +/- 401.9 v 77.4 +/- 62.5 relative light unit [RLU]; P < 0.05). Adjuvant ascorbic acid therapy resulted in significantly higher LucCL intensity in hemodialysis patients with ferritin > or =600 ng/mL (1,348.2 pmol/L) than those with ferritin less than 600 ng/mL (2,296.0 +/- 763.8 v 414.3 +/- 88.0 RLU; P<0.05). The changes of LucCL intensity were positively correlated with serum ferritin level (R2=0.8673; P<0.05). However, there was no significant correlation between the responses of LucCL intensity to ascorbic acid administration and transferrin saturation (R2=0.195; P=0.0665).. Persons with excess ascorbic acid supplement in the blood or plasma generate iron-chelator-suppressible chemiluminescents suggestive of free radical formation. Whether the findings occur in vivo or that the free radicals generated in vitro lead to toxicity in patients is not known from this study. These results suggest that either lower parenteral dose or lower infusion rate of ascorbic acid may be more appropriate for adjuvant therapy in iron-overloaded uremic patients.

Topics: Aged; Antioxidants; Ascorbic Acid; Biphenyl Compounds; Female; Ferritins; Free Radical Scavengers; Free Radicals; Humans; Hydrazines; In Vitro Techniques; Injections, Intravenous; Iron; Iron Overload; Kidney Failure, Chronic; Luminescent Measurements; Male; Middle Aged; Oxidative Stress; Picrates; Renal Dialysis

Intravenous ascorbic acid administration (IVAA) could override recombinant human erythropoietin (rHuEPO) resistance in hemodialysis patients with iron overload. We investigated the hematopoietic response to IVAA in iron-overloaded hemodialysis patients. We included 36 patients whose ferritin levels were higher than 500 microg/L and who needed more than 100 U/kg/week of rHuEPO. The study included an initial phase (500 mg IVAA twice weekly was administered to all of the patients for 8 weeks) and a maintenance phase (patient groups were formed; Group 1 received IVAA 500 mg/week for 8 weeks and Group 2 received no therapy). We observed a significant increase in hematocrit and transferrin saturation and a decrease in the percentage of hypochromic red cells and ferritin levels at the end of the initial phase. The total weekly-required rHuEpo dose and rHuEpo/hemoglobin also fell significantly after the initial phase. The response remained stable in patient groups during the maintenance phase. In 6 nonresponders, the hypochromic red cells were <10%. In conclusion, IVAA effectively overrides rHuEPO resistance in iron-overloaded hemodialysis patients.

Topics: Adult; Anemia, Iron-Deficiency; Ascorbic Acid; Drug Resistance; Erythropoietin; Female; Hematopoiesis; Humans; Iron Overload; Male; Middle Aged; Recombinant Proteins; Renal Dialysis

Functional iron deficiency may develop and cause erythropoietin resistance in haemodialysis patients with iron overload. Controversy remains as to whether intravenous iron medication can improve this hyporesponsiveness due to decreased iron availability, or whether iron therapy will aggravate haemosiderosis. Intravenous administration of ascorbic acid has been shown to effectively circumvent resistant anaemia associated with iron overload in a small preliminary study. To elucidate further the possible mechanisms of this resistance, a parallel, comparative study was conducted to compare the effects of intravenous iron and ascorbate therapies in iron-overloaded haemodialysis patients.. Fifty haemodialysis patients with serum ferritin of > 500 microg/l were randomly divided into two protocols. They were further stratified into controls (Control I, n = 11) and intravenous iron group (IVFE, n = 15) in protocol I; and into controls (Control II, n = 12) and intravenous ascorbic acid group (IVAA, n = 12) in protocol II. Controls had a haematocrit of > 30% and did not receive any adjuvant therapy. IVFE and IVAA patients were hyporesponsive to erythropoietin and functionally iron deficient. Ferric saccharate (100 mg dose) was administered intravenously postdialysis on five consecutive dialysis sessions in the first 2 weeks; and ascorbic acid (300 mg dose) thrice a week for 8 weeks. Red cell and iron metabolism indices were examined before and following therapy.. Mean values of haematocrit and transferrin saturation were significantly lower, and erythropoietin dose was higher in IVFE and IVAA patients compared to controls. Intravenous iron therapy neither improved erythropoiesis nor reduced erythropoietin dose during 12 weeks. Iron metabolism indices significantly increased at 2 and 6 weeks, but decreased at 12 weeks returning to the baselines. In contrast, mean haematocrit significantly increased from 25.8+/-0.5 to 30.6+/-0.6% with a concomitant reduction of 20% in erythropoietin dose after 8 weeks of ascorbate therapy. Serum ferritin modestly fell but with no statistical significance. The enhanced erythropoiesis paralleled a rise in transferrin saturation from 27+/-3 to 48+/-6% and serum iron from 70+/-11 to 107+/-19 microg/dl (P<0.05).. Short term intravenous iron therapy cannot resolve the issue of functional iron deficiency in haemodialysis patients with iron overload. Intravenous administration of ascorbic acid not only facilitates iron release from storage sites, but also increases iron utilization in the erythron. Our study draws attention to a potential adjuvant therapy, intravenous ascorbic acid, to treat erythropoietin-hyporesponsive anaemia in iron-overloaded patients.

Topics: Anemia; Ascorbic Acid; Erythropoietin; Female; Follow-Up Studies; Humans; Injections, Intravenous; Iron; Iron Overload; Male; Middle Aged; Oxalic Acid; Recombinant Proteins; Renal Dialysis

Deferasirox is an orally active, lipophilic iron chelating drug used on thousands of patients worldwide for the treatment of transfusional iron overload. The essential transition metals iron and copper are the primary catalysts of reactive oxygen species and oxidative damage in biological systems. The redox effects of deferasirox and its metal complexes with iron, copper and other metals are of pharmacological, toxicological, biological and physiological importance. Several molecular model systems of oxidative damage caused by iron and copper catalysis including the oxidation of ascorbic acid, the peroxidation of linoleic acid micelles and the oxidation of dihydropyridine have been investigated in the presence of deferasirox using UV-visible and NMR spectroscopy. Deferasirox has shown antioxidant activity in all three model systems, causing substantial reduction in the rate of oxidation and oxidative damage. Deferasirox showed the greatest antioxidant activity in the oxidation of ascorbic acid with the participation of iron ions and reduced the reaction rate by about a 100 times. Overall, deferasirox appears to have lower affinity for copper in comparison to iron. Comparative studies of the antioxidant activity of deferasirox and the hydrophilic oral iron chelating drug deferiprone in the peroxidation of linoleic acid micelles showed lower efficiency of deferasirox in comparison to deferiprone.

Topics: Antioxidants; Ascorbic Acid; Coordination Complexes; Deferasirox; Deferiprone; Humans; Iron; Iron Chelating Agents; Iron Overload; Linoleic Acid; Metals; Oxidation-Reduction; Oxidative Stress; Reactive Oxygen Species

Anemia prevalence in India remains high despite preventive iron supplementation programs. Consequently, concurrent national policies of iron fortification of staple foods have been initiated.. This study evaluated the relation between dietary iron intake and anemia (hemoglobin <12 g/dL) in women of reproductive age (WRA; 15-49 y) with respect to iron fortification in India.. Data from 2 national surveys were used. Data on hemoglobin in WRA were sourced from the National Family Health Survey-4, whereas dietary intakes were sourced from the National Sample Survey. Adjusted odds for anemia with increasing iron intake were estimated, along with the effect of modulating nutrients such as vitamins B-12 and C, from statistically matched household data from the 2 surveys. The risks of inadequate (less than the Estimated Average Requirement for WRA) and excess (more than the tolerable upper limit for WRA) intakes of iron were estimated by the probability approach.. The relation between iron intake and the odds of anemia was weak (OR: 0.992; 95% CI: 0.991, 0.994); increasing iron intake by 10 mg/d reduced the odds of anemia by 8%. Phytate and vitamin B-12 and C intakes modified this relation by reducing the odds by 1.5% when vitamin B-12 and C intakes were set at 2 μg/d and 40 mg/d, respectively. The additional intake of 10 mg/d of fortified iron reduced the risk of dietary iron inadequacy from 24-94% to 9-39% across states, with no risk of excess iron intake. Approximately doubling this additional iron intake reduced the risk of inadequacy to 2-12%, but the risk of excess intake reached 22%.. Providing fortified iron alone may not result in substantial anemia reduction among WRA in India and could have variable benefits and risks across states. Geographically nuanced dietary strategies that include limited fortification and the intake of other beneficial nutrients should be carefully considered.

Topics: Adolescent; Adult; Anemia; Anemia, Iron-Deficiency; Ascorbic Acid; Diet; Energy Intake; Female; Food, Fortified; Health Surveys; Hemoglobins; Humans; India; Iron; Iron Overload; Iron, Dietary; Middle Aged; Phytic Acid; Risk Factors; Vitamin B 12; Young Adult

Vitamin C, an excellent reducing agent, aids in increasing absorbable ferrous iron in iron deficiency anemia. As an efficient antioxidant, it is still unknown whether vitamin C exerts protective effects against liver damage caused by iron excess and whether mitochondria are the target effectors of the above effects. In this study, 48 mice were randomly divided into a control group, iron-overload group, TAU-treated + iron-overload group and vitamin C-treated + iron-overload group with 12 mice per group. The mice were fed 4 months on pellet diets supplemented with iron in the form of ferrocene. The iron ratio in the diet was maintained at 0.2% (w/w) for 90 days and then 0.4% (w/w) for the remaining 30 days. Furthermore, 2 g kg-1 vitamin C and 20 mg kg-1 TAU were administered daily by oral gavage prior to iron-overload administration at 6 weeks and throughout the course of the experiments. We investigated the protective effects of vitamin C against liver damage by assessing the liver weight to body weight ratio (LW/BW), serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities, and histological changes. In addition, enzymatic and non-enzymatic antioxidants, reactive oxygen species (ROS) generation, mitochondrial swelling, and mitochondrial membrane potential (MMP) were evaluated to clarify the antioxidant effects of vitamin C. We found that vitamin C significantly attenuated impaired liver function in mice induced by iron overload via antioxidation, whereas no significant effect on iron uptake was observed. Vitamin C targeted the mitochondria, preventing mitochondrial swelling, MMP dissipation, and ROS burst, thus inhibiting hepatic apoptosis. Collectively, our results suggest that vitamin C acts as a "double agent" in iron supplementation therapy for iron deficiency anemia, boosting iron absorption for preventing iron deficiency and preventing liver damage due to excessive iron intake during treatment.

Topics: Alanine Transaminase; Anemia, Iron-Deficiency; Animals; Antioxidants; Ascorbic Acid; Aspartate Aminotransferases; Dietary Supplements; Ferrous Compounds; Glutathione Peroxidase; Humans; Iron; Iron Overload; Liver; Liver Diseases; Male; Malondialdehyde; Membrane Potential, Mitochondrial; Metallocenes; Mice; Oxidative Stress; Reactive Oxygen Species

Globally, β-thalassemia major (β-TM) is one of the most common hereditary disorders. Multiple blood transfusions, that are a life-saving therapy in patients with β-TM, is a major source of iron overload. Iron overload can lead to significant morbidity and mortality. Research evidence indicates that oxidative stress induced by iron overload, is one of the major precipitating causes of vitamin C deficiency in β-TM patients. It has previously been shown that patients with β-TM have significantly lower levels of vitamin C as compared to healthy individuals. It is believed that vitamin C can reduce both ferric (Fe(3+)) and ferrous (Fe(2+)) ions, and also facilitate the accessibility of iron to chelators through increase of iron release from the reticuloendothelial system. Despite the potential benefits of vitamin C in patients with β-TM, several areas of concern exist that should be addressed by high quality research designs. Some recommendations have been provided through this study.

Topics: Ascorbic Acid; Ascorbic Acid Deficiency; beta-Thalassemia; Contraindications; Dietary Supplements; Humans; Iron Overload; Nutrition Policy; Oxidative Stress; Transfusion Reaction

Body iron disorders have been reported after myeloablative conditioning in patients undergoing hematopoietic stem cell transplantation (HSCT). There is a concern that labile plasma iron (LPI), the redox-active form of iron, can be involved in the occurrence of toxicity and other complications commonly observed in the early post-HSCT period. In order to better understand the LPI kinetics and its determinants and implications, we undertook sequential LPI determinations before and after conditioning until engraftment in 25 auto-HSCT patients. Increased LPI was present in only 5 patients before starting conditioning. Shortly after conditioning, LPI levels were increased in 23 patients, with peak at day 0, returning to normal range upon engraftment in 21 patients. Overall, LPI levels correlated weakly with serum ferritin and more strongly with transferrin saturation; however, both parameters were apparently not applicable as surrogate markers for increased LPI. Although this was a small cohort, logistic regression suggested that baseline LPI levels could predict occurrence of grade III or IV toxicity. In conclusion, LPI kinetics is influenced by aplasia following conditioning and engraftment. Measuring LPI before starting conditioning can offer an opportunity to predict toxicity and, perhaps, the need for chelation therapy.

Topics: Adult; Aged; Antioxidants; Ascorbic Acid; Cohort Studies; Deferiprone; Female; Fluorescent Dyes; Follow-Up Studies; Graft Survival; Hematopoietic Stem Cell Transplantation; Humans; Iron; Iron Chelating Agents; Iron Overload; Male; Middle Aged; Predictive Value of Tests; Pyridones; Rhodamines; Severity of Illness Index; Transplantation Conditioning; Young Adult

Iron is a component of several metalloproteins involved in crucial metabolic processes such as oxygen sensing and transport, energy metabolism, and DNA synthesis. This metal progressively accumulates in the pathogenesis of Alzheimer's (AD) and Parkinson's (PD) diseases. Naringenin (NGEN), a natural flavonoid compound, has been reported to possess neuroprotective effect against PD-related pathology, however, the mechanisms underlying its beneficial effects are poorly defined. Thus, the aim of this study is to investigate the potential mechanism involved in the cytoprotection of NGEN against iron-induced neurotoxicity in the cerebral cortex of Wistar rats. Animals that were given repetitive injections of iron dextran for a total of 4 weeks showed a significant increase in lipid and protein markers such as thiobarbituric reactive acid substances, protein carbonyl product content levels, and DNA apoptosis in the cerebral cortex. These changes were accompanied by a decrease of enzymatic antioxidants like superoxide dismutase and catalase and in the levels of nonenzymatic antioxidants like total thiols and ascorbic acid. The activity of glutathione peroxidase remained unchanged in rats. A significant decrease in acetylcholinesterase and Na(+)/K(+)-ATPase activities was also shown, with a substantial rise in the nitric oxide levels. Coadministration of NGEN to iron-treated rats significantly improved antioxidant enzyme activities and attenuated oxidative damages observed in the cerebral cortex. The potential effect of NGEN to prevent iron-induced neurotoxicity was also reflected by the microscopic study, indicative of its neuroprotective effects.

Topics: Acetylcholinesterase; Animals; Apoptosis; Ascorbic Acid; Catalase; Cerebral Cortex; DNA Fragmentation; Flavanones; Iron Overload; Male; Neuroprotective Agents; Neurotoxicity Syndromes; Oxidative Stress; Protein Carbonylation; Rats, Wistar; Sodium-Potassium-Exchanging ATPase; Sulfhydryl Compounds; Superoxide Dismutase; Thiobarbituric Acid Reactive Substances

The view of scurvy being exclusively a nutritional disorder needs to be updated. Genetic polymorphisms of HFE and haptoglobin (Hp) may explain the geographic variability of mortality caused by the European famine of the mid-19th century. In this period, potatoes had fallen victim to the potato blight and Ireland was more severely hit than continental Europe. Hereditary hemochromatosis is a genetic disorder with mutations in the HFE gene, characterized by iron overload (with a reduced vitamin C stability) and with a predominance of affected men. The Irish have the world's highest frequency of the C282Y mutation and the particular iron metabolism of the Irish helps to understand the size of the catastrophe and the observed overrepresentation of male skeletons showing scurvy. Hp is a plasma α2-glycoprotein characterized by 3 common phenotypes (Hp 1-1, Hp 2-1 and Hp 2-2). When the antioxidant capacity of Hp is insufficient, its role is taken over by hemopexin and vitamin C. The relative number of scurvy victims corresponds with the Hp 2-2 frequency, which is associated with iron conservation and has an impact on vitamin C stability. As iron is more abundant in males, males are overrepresented in the group of skeletons showing scurvy signs.

Topics: Ascorbic Acid; Europe; Genotype; Haptoglobins; Hemochromatosis; Hemochromatosis Protein; Histocompatibility Antigens Class I; History, 19th Century; Humans; Iron; Iron Overload; Male; Membrane Proteins; Phenotype; Polymorphism, Genetic; Scurvy; Starvation; White People

An in vivo model in rat was developed by intraperitoneally administration of Fe-dextran to study oxidative stress triggered by Fe-overload in rat brain. Total Fe levels, as well as the labile iron pool (LIP) concentration, in brain from rats subjected to Fe-overload were markedly increased over control values, 6h after Fe administration. In this in vivo Fe overload model, the ascorbyl (A)/ascorbate (AH(-)) ratio, taken as oxidative stress index, was assessed. The A/AH(-) ratio in brain was significantly higher in Fe-dextran group, in relation to values in control rats. Brain lipid peroxidation indexes, thiobarbituric acid reactive substances (TBARS) generation rate and lipid radical (LR) content detected by Electron Paramagnetic Resonance (EPR), in Fe-dextran supplemented rats were similar to control values. However, values of nuclear factor-kappaB deoxyribonucleic acid (NFκB DNA) binding activity were significantly increased (30%) after 8h of Fe administration, and catalase (CAT) activity was significantly enhanced (62%) 21h after Fe administration. Significant enhancements in Fe content in cortex (2.4 fold), hippocampus (1.6 fold) and striatum (2.9 fold), were found at 6h after Fe administration. CAT activity was significantly increased after 8h of Fe administration in cortex, hippocampus and striatum (1.4 fold, 86, and 47%, respectively). Fe response in the whole brain seems to lead to enhanced NF-κB DNA binding activity, which may contribute to limit oxygen reactive species-dependent damage by effects on the antioxidant enzyme CAT activity. Moreover, data shown here clearly indicate that even though Fe increased in several isolated brain areas, this parameter was more drastically enhanced in striatum than in cortex and hippocampus. However, comparison among the net increase in LR generation rate, in different brain areas, showed enhancements in cortex lipid peroxidation, without changes in striatum and hippocampus LR generation rate after 6h of Fe overload. This information has potential clinical relevance, as it could be the key to understand specific brain damage occurring in conditions of Fe overload.

Topics: Animals; Antioxidants; Ascorbic Acid; Brain Chemistry; Catalase; DNA; Electron Spin Resonance Spectroscopy; Free Radicals; Iron; Iron Overload; Iron-Dextran Complex; Kinetics; Male; NF-kappa B; Oxidative Stress; Rats; Rats, Sprague-Dawley; Thiobarbituric Acid Reactive Substances

Iron chelation is essential to patients on chronic blood transfusions to prevent toxicity from iron overload and remove excess iron. Deferasirox (DFX) is the most commonly used iron chelator in the United States; however, some patients are relatively refractory to DFX therapy. We postulated that vitamin C supplementation would improve the availability of transfusional iron to DFX treatment by promoting iron's redox cycling, increasing its soluble ferrous form and promoting its release from reticuloendothelial cells. Osteogenic dystrophy rats (n = 54) were given iron dextran injections for 10 weeks. Cardiac and liver iron levels were measured after iron loading (n = 18), 12 weeks of sham chelation (n = 18), and 12 weeks of DFX chelation (n = 18) at 75 mg/kg/day. Ascorbate supplementation of 150 ppm, 900 ppm, and 2250 ppm was used in the chow to mimic a broad range of ascorbate status; plasma ascorbate levels were 5.4 ± 1.9, 8.2 ± 1.4, 23.6 ± 9.8 μM, respectively (p < 0.0001). The most severe ascorbate deficiency produced reticuloenthelial retention, lowering total hepatic iron by 29% at the end of iron loading (p < 0.05) and limiting iron redistribution from cardiac and hepatic macrophages during 12 weeks of sham chelation. Most importantly, ascorbate supplementation at 2250 ppm improved DFX efficiency, allowing DFX to remove 21% more hepatic iron than ascorbate supplementation with 900 ppm or 150 ppm (p < 0.05). We conclude that vitamin C status modulates the release of iron from the reticuloendothelial system and correlates positively with DFX chelation efficiency. Our findings suggest that ascorbate status should be probed in patients with unsatisfactory response to DFX.

Topics: Animals; Ascorbic Acid; Ascorbic Acid Deficiency; Benzoates; Deferasirox; Guinea Pigs; Humans; Iron; Iron Chelating Agents; Iron Overload; Liver; Mononuclear Phagocyte System; Myocardium; Rats; Rats, Mutant Strains; Triazoles

Alcoholic liver disease (ALD) is a major medical complication of drinking alcohol, and commonly accompanied with hepatic iron overload and liver injuries. Oxidative stress plays an important role in pathogenesis of ALD and also leads to iron-metabolic disorders. In this study, the effects of vitamin C (Vc) on iron metabolism-related genes expression and liver protection from drinking in mice were investigated. Twenty-four male kunming mice were divided into four groups (six mice per group): control (water drinking); alcohol group (20% alcohol drinking), alcohol + low Vc group (adding 50 mg/kg Vc daily) and alcohol + high Vc group (adding 100 mg/kg Vc daily). All these mice were sacrificed after 7 days. Vc can ameliorate the increase of sera alanine aminotransferase (ALT) activity and hepatic iron overload of drinking alcohol in mice. Vc increases the expression of the iron-regulated hormone hepcidin and decreases transferrin receptor 1 (TfR1) expression in liver. Vc also down-regulates the expression of ferroportin 1 (Fpn1) in the intestine and decreases the iron release to blood. In conclusion, Vc ameliorated the alcoholic liver injuries through regulating the iron metabolism-related genes expression.

Topics: Alanine Transaminase; Animals; Antimicrobial Cationic Peptides; Antioxidants; Ascorbic Acid; Blotting, Western; Disease Models, Animal; Ethanol; Gene Expression Regulation; Hepcidins; Iron; Iron Overload; Liver; Liver Diseases, Alcoholic; Male; Mice; Mice, Inbred Strains; Receptors, Transferrin; RNA, Messenger

Pulmonary toxicity induced by asbestos is thought to be mediated through redox-cycling of fiber-bound and bioavailable iron (Fe). We hypothesized that Libby amphibole (LA)-induced cute lung injury will be exacerbated in rat models of cardiovascular disease (CVD)-associated Fe-overload and oxidative stress. Healthy male Wistar Kyoto (WKY), spontaneously hypertensive (SH) and SH heart failure (SHHF) rats were intratracheally instilled with 0.0, 0.25 or 1.0  mg/rat LA and examined at 1 day, 1 week or 1 month. Although histologically it was not possible to distinguish severity differences between strains in LA-induced initial inflammation and later fibrosis, quantitative assessment of biomarkers showed strain-related differences. LA-induced neutrophilic inflammation was reversible in WKY but persisted more in SH and SHHF. Lung MIP-2 mRNA increased only in WKY at 1 day in response to LA but not in SH and SHHF. Bronchoalveolar lavage fluid (BALF) protein increased in SH but not WKY at 1 week and 1 month, while γ-glutamyltransferase and N-acetyl-β-D-glucosaminidase activities increased in all strains (WKY>SH=SHHF). BALF ferritin levels were high at baseline and increased following LA exposure only in SH and SHHF. Ferritin heavy chain mRNA increased only in SHHF at 1 day. At 1 month ferritin light chain mRNA declined from already high baseline levels in SHHF but increased in WKY and SH suggesting its differential involvement in LA-induced injury in Fe-overload. Unlike WKY, both SHHF and SH failed to increase the lung lining antioxidant, ascorbate, in response to LA. We conclude that underlying CVD-associated Fe-overload is likely linked to persistent lung injury, inflammation and antioxidant decompensation following LA exposure in rats.

Topics: Animals; Asbestos, Amphibole; Asbestosis; Ascorbic Acid; Biomarkers; Bronchoalveolar Lavage Fluid; Cardiovascular Diseases; Chemokine CXCL2; Dose-Response Relationship, Drug; Ferritins; Gene Expression Regulation; Iron Overload; Lung; Male; Neutrophil Infiltration; Neutrophils; Oxidative Stress; Particulate Matter; Pneumonia; Rats; RNA, Messenger; Severity of Illness Index

Excess hepatic iron generates reactive oxygen species that result in oxidative stress and oxidative damage to the liver. Vitamins have hitherto been considered to be a possible remedy. The aim of this study was to determine if high doses of delta-alpha-tocopherol supplementation in iron overload would ameliorate the oxidative stress. Four groups of 20 male Wistar albino rats were studied: group 1 (control) was fed normal diet, group 2 (Fe) 0.75% Ferrocene iron, group 3 (FV gp) 0.75% Ferrocene/delta-alpha-tocopherol (10x RDA), group 4 (V gp) normal diet/delta-alpha-tocopherol. After 12 months, serum iron, reduced glutathione, catalase, vitamin C, Oxygen Radical Absorbance Capacity, lipid peroxidation, 8-hydroxy-2'-deoxyguanosine (8-OHdG), aspartate transaminase (AST), and alanine transaminase (ALT) were measured. Vitamin C levels were: F gp = 5.04 +/- 0.09; FV gp = 5.85 +/- 0.13 (micromol/l) (p < 0.05). 8-hydroxy-2'-deoxyguanosine levels were: F gp = 143.6 +/- 6.4; FV gp = 179.2 +/- 18.2 (ng/ml) (p < 0.05). Oxidative liver damage, as determined by serum AST and ALT levels, was not attenuated by alpha-tocopherol. A positive correlation existed between vitamin C and 8-OHdG, suggesting possible delta-alpha-tocopherol toxicity.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Administration, Oral; Alanine Transaminase; alpha-Tocopherol; Animals; Antioxidants; Ascorbic Acid; Aspartate Aminotransferases; Biomarkers; Catalase; Deoxyguanosine; Disease Models, Animal; Ferrous Compounds; Glutathione; Iron; Iron Overload; Lipid Peroxidation; Liver; Male; Metallocenes; Oxidative Stress; Rats; Rats, Wistar; Time Factors; Up-Regulation; Vitamins

Iron chelation therapy was initially designed to alleviate the toxic effects of excess iron evident in iron-overload diseases. However, some iron chelator-metal complexes have also gained interest due to their high redox activity and toxicological properties that have potential for cancer chemotherapy. This communication addresses the conflicting results published recently on the ability of the iron chelator, Dp44mT, to induce hydroxyl radical formation upon complexation with iron (B.B. Hasinoff and D. Patel, J Inorg. Biochem.103 (2009), 1093-1101). This previous study used EPR spin-trapping to show that Dp44mT-iron complexes were not able to generate hydroxyl radicals. Here, we demonstrate the opposite by using the same technique under very similar conditions to show the Dp44mT-iron complex is indeed redox-active and induces hydroxyl radical formation. This was studied directly in an iron(II)/H(2)O(2) reaction system or using a reducing iron(III)/ascorbate system implementing several different buffers at pH 7.4. The demonstration by EPR that the Dp44mT-iron complex is redox-active confirms our previous studies using cyclic voltammetry, ascorbate oxidation, benzoate hydroxylation and a plasmid DNA strand-break assay. We discuss the relevance of the redox activity to the biological effects of Dp44mT.

Topics: Ascorbic Acid; Buffers; DNA Damage; Electron Spin Resonance Spectroscopy; Hydrogen-Ion Concentration; Hydroxyl Radical; Iron; Iron Chelating Agents; Iron Overload; Iron, Dietary; Oxidation-Reduction; Thiosemicarbazones

The design of novel Fe chelators with high Fe mobilization efficacy and low toxicity remains an important priority for the treatment of Fe overload disease. We have designed and synthesized the novel methyl pyrazinylketone isonicotinoyl hydrazone (HMPIH) analogs based on previously investigated aroylhydrazone chelators. The HMPIH series demonstrated high Fe mobilization efficacy from cells and showed limited to moderate antiproliferative activity. Importantly, this novel series demonstrated irreversible electrochemistry, which was attributed to the electron-withdrawing effects of the noncoordinating pyrazine N-atom. The latter functionality played a major role in forming redox-inactive complexes that prevent reactive oxygen species generation. In fact, the Fe complexes of the HMPIH series prevented the oxidation of ascorbate and hydroxylation of benzoate. We determined that the incorporation of electron-withdrawing groups is an important feature in the design of N, N, O-aroylhydrazones as candidate drugs for the treatment of Fe overload disease.

Topics: Antineoplastic Agents; Ascorbic Acid; Benzoates; Cell Line, Tumor; Cell Proliferation; Crystallography, X-Ray; Humans; Hydrazones; Hydroxylation; Iron; Iron Chelating Agents; Iron Overload; Iron Radioisotopes; Isonicotinic Acids; Ketones; Ligands; Oxidation-Reduction; Pyrazines; Structure-Activity Relationship

Patients with iron overload frequently suffer from hemochromatosis of major organs, such as the heart and liver. Heart affection is the most common cause of death in patients with iron overload. Although the beneficial effects of deferoxamine (DFO) on iron-associated mortality are well documented, the role of deferiprone in the management of transfusional iron overload is controversial. The aim of this study was to compare the protective effect of iron chelators (DFO and deferiprone) individually and in combination with the anti-oxidant (vitamin C) in the prevention of myocardial damage. Sixty albino rats were divided into six groups: two control groups (noniron-loaded and iron-loaded) and four iron-loaded groups classified as follows: DFO group, DFO combined with vitamin C group, deferiprone group and deferiprone combined with vitamin C group. Heart tissue and blood samples were taken for histopathological examination of the heart, determination of total iron-binding capacity, 8-OH-deoxyguanosine (8-OH-dG), myocardial lipid peroxidation and glutathione (GSH) content. Less histopathological cardiac changes and a significant decrease in all biochemical parameters, except myocardial GSH, were observed in the deferiprone group. The addition of vitamin C improves the biochemical and histopathological changes in comparison to those rats administered DFO or deferiprone individually.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Antioxidants; Ascorbic Acid; Deferiprone; Deferoxamine; Deoxyguanosine; Glutathione; Heart; Heart Diseases; Iron; Iron Chelating Agents; Iron Overload; Male; Myocardium; Pyridones; Rats; Thiobarbituric Acid Reactive Substances

Osteoporosis and femoral neck fractures (FNF) are uncommon in black Africans although osteoporosis accompanying iron overload (from traditional beer brewed in iron containers) associated with ascorbic acid deficiency (oxidative catabolism by iron) has been described from sub-Saharan Africa. This study describes histomorphometric findings of iliac crest bone biopsies and serum biochemical markers of iron overload and of alcohol abuse and ascorbic acid levels in 50 black patients with FNFs (29 M, 21 F), age 62 years (40-95) years (median [min-max]), and in age- and gender-matched black controls. We found evidence of iron overload in 88% of patients and elevated markers of alcohol abuse in 72%. Significant correlations between markers of iron overload and of alcohol abuse reflect a close association between the two toxins. Patients had higher levels of iron markers, i.e., siderin deposits in bone marrow (P < 0.0001), chemical non-heme bone iron (P = 0.012), and serum ferritin (P = 0.017) than controls did. Leukocyte ascorbic acid levels were lower (P = 0.0008) than in controls. The alcohol marker mean red blood cell volume was elevated (P = 0.002) but not liver enzymes or uric acid. Bone volume, trabecular thickness, and trabecular number were lower, and trabecular separation was greater in patients than in controls, all at P < 0.0005; volume, surface, and thickness of osteoid were lower and eroded surface was greater, all at P < 0.0001. There was no osteomalacia. Ascorbic acid deficiency accounted significantly for decrease in bone volume and trabecular number, and increase in trabecular separation, osteoid surface, and eroded surface; iron overload accounted for a reduction in mineral apposition rate. Alcohol markers correlated negatively with osteoblast surface and positively with eroded surface. Relative to reported data in white FNF patients, the osteoporosis was more severe, showed lower osteoid variables and greater eroded surface; FNFs occurred 12 years earlier and were more common among men. We conclude that the osteoporosis underlying FNFs in black Africans is severe, with marked uncoupling of resorption and formation in favor of resorption. All three factors--ascorbic acid deficiency, iron overload, and alcohol abuse--contributed to the osteoporosis, in that order.

Topics: Adult; Aged; Aged, 80 and over; Alcoholism; Ascorbic Acid; Ascorbic Acid Deficiency; Biomarkers; Black People; Bone Marrow; Female; Femoral Neck Fractures; Humans; Ilium; Iron Overload; Leukocytes; Male; Middle Aged; Osteoporosis; Siderosis

Topics: Ascorbic Acid; Dietary Supplements; Female; Ferrous Compounds; Humans; Iron Overload; Middle Aged; Self Medication

The oxidant properties of iron-overload and simultaneous ethanol consumption have received much interest, due to evidence reporting from hereditary hemochromatosis (HC). The full form of this disease is often associated with chronic alcoholism. An additive effect of toxicity of iron and ethanol was assumed. In this study, we examined nutritively iron-loaded Wistar rats (n = 59) (TMH-Ferrocene) additionally fed with ethanol up to 8% in drinking water for 36 wk.. By reverse-phase HPLC we measured the concentration of ascorbic acid, tocopherole and retinol in serum and liver homogenates as well as transaminases in the serum. Lipid peroxidation was assessed utilizing the ethane-exhalation method. Iron concentration in the liver was measured with the Bathophenanthrolin-method. Liver histology was performed to investigate the iron deposits and the organ damage (H.E., Azan and Berlin-blue-stainings).. 1. Vitamin C: A linear decrease of the concentration of vitamin C in serum and liver was found independent of alcohol and iron uptake. 2. Vitamin E: Animals fed iron and alcohol showed elevated vitamin E concentrations in the serum but not in the liver. 3. Vitamin A: Elevated levels in serum but strongly decreasing levels in liver could be measured. 4.. All iron-fed animals showed massive deposits of iron in the liver. Iron diet caused liver cirrhosis, while an additional administration of ethanol could prevent this. 5. Lipid peroxidation increased in animals fed ethanol and iron, but was significantly lower in animals only receiving an iron diet.. Evidence indicates that the additional exposition to ethanol in iron-loaded animals could modulate the organ damage and oxidative stress. The biochemical findings are positively correlated to the histology.

Topics: Alanine Transaminase; Alkaline Phosphatase; Animals; Ascorbic Acid; Aspartate Aminotransferases; Chromatography, High Pressure Liquid; Ethanol; Female; Iron; Iron Overload; Lipid Peroxidation; Liver; Liver Diseases; Rats; Rats, Wistar; Tocopherols; Vitamin A

The impact of altering the octanol-water partition properties (log P) of analogues of desazadesferrithiocin, (S)-4,5-dihydro-2-(2-hydroxyphenyl)-4-methyl-4-thiazolecarboxylic acid, on the ligands' iron clearing properties is described. Increasing chelator lipophilicity can both substantially augment iron clearing efficiency in Cebus apella primates as well as alter the mode of iron excretion, favoring fecal over urinary output. The complications of iron overload are often associated with the metal's interaction with hydrogen peroxide, generating hydroxyl radicals (Fenton chemistry) and, ultimately, other related deleterious species. In fact, some iron chelators actually promote this chemistry. All of the compounds synthesized and tested in the current study are shown to be both inhibitors of the iron-mediated oxidation of ascorbate, thus removing the metal from the Fenton cycle, and effective radical scavengers.

Topics: 1-Octanol; Animals; Ascorbic Acid; Cebus; Feces; Free Radical Scavengers; Iron; Iron Chelating Agents; Iron Overload; Ligands; Oxidation-Reduction; Pyridines; Solubility; Solvents; Structure-Activity Relationship; Thiazoles; Urine; Water

Recent report demonstrates that inadequate iron mobilization and defective iron utilization may cause recombinant erythropoieitin (rEPO) hyporesponsiveness in hemodialysis (HD) patients with iron overload. The effect of intravenous ascorbic acid (IVAA) in HD patients selected on the basis of iron overload and EPO resistance also has been proven. However, it is uncertain whether IVAA still works in diabetic ESRD patients with hyperferritinemia. Therefore, the aim of this study focusing on diabetic ESRD patients was to analyze the potential effect of low dose IVAA on improvement of anemia and erythropoiesis-related parameters when compared with control period.. This study consisted of 22 chronic hemodialysis patients with type II diabetes in a single dialysis unit. In studies of this type, all eligible patients are followed up, but the primary comparison is still between different sequentially treatment including control period and post-IVAA period in same patients. IVAA patients received ascorbic acid, 100 mg each administered intravenously three times per week for eight weeks of treatment and four months of post-treatment follow-up.. The demographic characteristics of 22 diabetic uremic patients show that mean age is 63.6 +/- 10.2 years old. The ratio of sex (M/F) = 10/12. Mean duration of HD is 46.7 +/- 33.2 months. As for the urea kinetic study between these two periods including KT/V, nPCR, and URR, there is no significantly different. As for anemia-related parameters, Hb and Hct increased significantly in post-IVAA period after 3 months compared with control period, while MCV did not increase significantly. Serum ferritin significantly decreased at study completion. The same situation is for iron. As for TS, it significantly increased at one month and further markedly increased at subsequent three months.. This study has demonstrated that short-term low dose IVAA therapy can facilitate iron release from reticuloendothelial system but also increase iron utilization in diabetic hemodialysis patients with iron overload. Therefore, IVAA is a potential adjuvant therapy to treat erythropoeitin-hyporesponsive anemia in iron-overloaded patients.

Topics: Aged; Anemia; Ascorbic Acid; Biomarkers; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dose-Response Relationship, Drug; Erythrocyte Indices; Erythropoietin; Female; Ferritins; Follow-Up Studies; Free Radical Scavengers; Hematocrit; Hemoglobins; Humans; Infusions, Intravenous; Iron; Iron Overload; Kidney Failure, Chronic; Male; Middle Aged; Parathyroid Hormone; Phosphates; Prospective Studies; Recombinant Proteins; Renal Dialysis; Serum Albumin; Taiwan; Time Factors; Treatment Outcome

Plasma non-transferrin-bound-iron (NTBI) is believed to be responsible for catalyzing the formation of reactive radicals in the circulation of iron overloaded subjects, resulting in accumulation of oxidation products. We assessed the redox active component of NTBI in the plasma of healthy and beta-thalassemic patients. The labile plasma iron (LPI) was determined with the fluorogenic dihydrorhodamine 123 by monitoring the generation of reactive radicals prompted by ascorbate but blocked by iron chelators. The assay was LPI specific since it was generated by physiologic concentrations of ascorbate, involved no sample manipulation, and was blocked by iron chelators that bind iron selectively. LPI, essentially absent from sera of healthy individuals, was present in those of beta-thalassemia patients at levels (1-16 microM) that correlated significantly with those of NTBI measured as mobilizer-dependent chelatable iron or desferrioxamine chelatable iron. Oral treatment of patients with deferiprone (L1) raised plasma NTBI due to iron mobilization but did not lead to LPI appearance, indicating that L1-chelated iron in plasma was not redox active. Moreover, oral L1 treatment eliminated LPI in patients. The approach enabled the assessment of LPI susceptibility to in vivo or in vitro chelation and the potential of LPI to cause tissue damage, as found in iron overload conditions.

Topics: Ascorbic Acid; Cohort Studies; Humans; Iron; Iron Chelating Agents; Iron Overload; Oxidation-Reduction; Rhodamines; Thalassemia; Transferrin

Topics: Ascorbic Acid; Dietary Supplements; Female; Ferrous Compounds; Humans; Iron Overload; Middle Aged; Self Medication

Oxidative stress has been developed using dietary carbonyl-iron and iron-dextran parenteral administration as models of in vivo iron overload in rats. Carbonyl-iron led to a 2-fold increase in plasma iron content, a significant decrease (34%) in ascorbate plasma content and non-significant changes in plasma ascorbyl radical content. Iron-dextran produced a dramatic increase (6.7-fold) in plasma iron content, overwhelming the plasma total iron binding capacity. The ascorbyl radical content increased significantly in iron-dextran treatment (2.6-fold) and plasma ascorbate level was not affected. Ascorbyl radical/ascorbate ratio was significantly higher in both iron treated groups as compared with the control group (4 x 10(-4)+/-1 x 10(-4)). Data reported here indicate that the ascorbyl radical/ascorbate ratio is an appropriate in vivo indicator of oxidative stress under conditions of iron overload. The overall mechanism that describes the ascorbate status in plasma seems to be strongly dependent on the way the excess of iron is stored and thus, to the availability of the catalytically active iron for interacting with the plasma components. On this regard, evaluation of A*/AH(-) ratio did not help to discriminate between the possible involved mechanisms.

Topics: Animals; Antioxidants; Ascorbic Acid; Biomarkers; Electron Spin Resonance Spectroscopy; Free Radicals; Iron; Iron Overload; Male; Oxidative Stress; Rats; Rats, Wistar; Thiobarbituric Acid Reactive Substances

Transferrin is the major iron binding protein in human plasma. In black persons, the transferrin CD phenotype has been associated with alterations in certain markers of iron status.. We studied vitamin C status in a Zimbabwean population according to transferrin phenotype because vitamin C metabolism is influenced by iron-driven oxidative stress.. The study population consisted of 150 black African adults, 90 of whom were at risk of iron overload on the basis of high dietary iron content in the form of traditional beer. Transferrin phenotypes, indirect measures of iron status, and leukocyte ascorbic acid concentrations were determined. The in vitro rate of L-ascorbic acid depletion in sera from different transferrin phenotypes was investigated.. The transferrin phenotype frequencies of transferrin CC and CD were 0.893 and 0.107, respectively. The iron status of transferrin CC and CD subjects was similar. After adjustment for traditional beer consumption, baseline leukocyte vitamin C concentrations were significantly higher in 16 transferrin CD subjects ( +/- SE: 2.10 +/- 0.34 and 2.61 +/- 0.28 fmol/leukocyte in men and women, respectively) than in 134 transferrin CC subjects ( +/- SE: 1.65 +/- 0.11 and 1.99 +/- 0.11 fmol/leukocyte in men and women, respectively; P = 0.024). Oral administration of ascorbic acid (2.0 g every 24 h for 48 h) led to slower rises in leukocyte vitamin C concentrations in subjects with the transferrin CD phenotype than in subjects with the transferrin CC phenotype (P = 0.028). After in vitro supplementation of serum with 570 micromol vitamin C/L, the rate of L-ascorbic acid depletion was significantly lower in subjects of a transferrin CD phenotype than in subjects with the transferrin CC phenotype.. Transferrin polymorphism may affect vitamin C status in blacks.

Topics: Administration, Oral; Adult; Ascorbic Acid; Beer; Black People; Female; Humans; Iron Overload; Iron, Dietary; Male; Phenotype; Polymorphism, Genetic; Transferrin; Zimbabwe

Ascorbate is a strong antioxidant; however, it can also act as a prooxidant in vitro by reducing transition metals. To investigate the in vivo relevance of this prooxidant activity, we performed a study using guinea pigs fed high or low ascorbate doses with or without prior loading with iron dextran. Iron-loaded animals gained less weight and exhibited increased plasma beta-N-acetyl-D-glucosaminidase activity, a marker of tissue lysosomal membrane damage, compared with control animals. The iron-loaded animals fed the low ascorbate dose had decreased plasma alpha-tocopherol levels and increased plasma levels of triglycerides and F(2)-isoprostanes, specific and sensitive markers of in vivo lipid peroxidation. In contrast, the two groups of animals fed the high ascorbate dose had significantly lower hepatic F(2)-isoprostane levels than the groups fed the low ascorbate dose, irrespective of iron load. These data indicate that 1) ascorbate acts as an antioxidant toward lipids in vivo, even in the presence of iron overload; 2) iron loading per se does not cause oxidative lipid damage but is associated with growth retardation and tissue damage, both of which are not affected by vitamin C; and 3) the combination of iron loading with a low ascorbate status causes additional pathophysiological changes, in particular, increased plasma triglycerides.

Topics: Animals; Antioxidants; Ascorbic Acid; Dinoprost; F2-Isoprostanes; Female; Guinea Pigs; Iron Overload; Iron-Dextran Complex; Lipid Peroxidation; Liver; Oxidative Stress

Concern has been raised that high levels of ascorbic acid consumption may lead to potential adverse effects, such as vitamin B12 deficiency, iron overload, and kidney stones.. To examine the relation of serum ascorbic acid level, which reflects intake, to serum vitamin B12 level, serum ferritin level, and kidney stones.. We analyzed data collected on a random sample of the US population enrolled in the Second National Health and Nutrition Examination Survey, 1976-1980. We analyzed data using linear and logistic regression models. Serum ascorbic acid, serum vitamin B12, hemoglobin, red blood cell mean corpuscular volume (MCV), and serum ferritin levels were measured using standardized protocols. History of kidney stones was determined by self-report.. After multivariate adjustment, serum ascorbic acid level was associated with higher serum vitamin B12 levels among women in regression models that assumed a linear relationship; each 57-pmol/L (1.0-mg/dL) increase in serum ascorbic acid level (range, 6-153 micromol/L [0.1 to 2.7 mg/dL]) was independently associated with a serum vitamin B12 level increase of 60 pmol/L (81 pg/ mL) (P<.001). Among men, serum ascorbic acid level was marginally associated with higher serum vitamin B12 levels: each 57-micromol/L (1.0-mg/dL) increase in serum ascorbic acid level was associated with a serum vitamin B12 level increase of 27 pmol/L (36 pg/mL) (P = .10). In addition, serum ascorbic acid level was not associated with correlates of vitamin B12 deficiency, such as higher MCV levels, macrocytosis (MCV >100), or lower hemoglobin concentrations. Serum ascorbic acid level was not independently associated with serum ferritin levels. However, among women only, serum ascorbic acid levels were associated in a nonlinear fashion with prevalence of elevated serum ferritin levels (P = .02). We found no association between serum ascorbic acid level and prevalence of kidney stones in women or men (both P>.05).. Serum ascorbic acid levels were not associated with decreased serum vitamin B12 levels (or indicators of vitamin B12 deficiency), prevalence of kidney stones, serum ferritin levels, or-among men-prevalence of elevated serum ferritin levels. Serum ascorbic acid levels were associated with prevalence of elevated serum ferritin levels among women. Although the clinical relevance of these findings is uncertain, it seems prudent to suggest that women with a genetic susceptibility to iron overload should consider moderating their intake of ascorbic acid.

Topics: Adult; Aged; Ascorbic Acid; Female; Ferritins; Humans; Iron Overload; Kidney Calculi; Linear Models; Logistic Models; Male; Middle Aged; Prevalence; Sex Factors; United States; Vitamin B 12; Vitamin B 12 Deficiency

Iron overload in Africa was previously regarded as purely due to excessive iron in traditional beer, but we recently found evidence that transferrin saturation and unsaturated iron binding capacity may be influenced by an interaction between dietary iron content and a gene distinct from any HLA-linked locus. To determine if serum ferritin follows a genetic pattern and to confirm our previous observations, we studied an additional 351 Zimbabweans and South Africans from 45 families ranging in size from two to 54 members. Iron status was characterized with repeated morning measurements of serum ferritin, transferrin saturation, and unsaturated iron binding capacity after supplementation with vitamin C. For each measure of iron status, segregation analysis was consistent with an interaction between a postulated iron-loading gene and dietary iron content (P < .01). In the most likely model, transferrin saturation is 75% and serum ferritin is 985 micrograms/L in a 40-year-old male heterozygote with an estimated beer consumption of 10,000 L, whereas the saturation is 36% and serum ferritin is 233 micrograms/L in an unaffected individual with identical age, sex, and beer consumption. This segregation analysis provides further evidence for a genetic influence on iron overload in Africans.

Topics: Adult; Africa; Aged; Alleles; Ascorbic Acid; Beer; Diet; Female; Ferritins; Gene Frequency; Heterozygote; Humans; Iron; Iron Overload; Male; Middle Aged; Pedigree; Protein Binding; South Africa; Transferrin; Zimbabwe

Topics: Ascorbic Acid; Eswatini; Ferritins; Humans; Iron; Iron Overload; Leukocytes; Receptors, Transferrin; Time Factors; Zimbabwe

Vitamin C (ascorbic acid, AA) can act as an antioxidant or a pro-oxidant in vitro, depending on the absence or the presence, respectively, of redox-active metal ions. Some adults with iron-overload and some premature infants have potentially redox-active, bleomycin-detectable iron (BDI) in their plasma. Thus, it has been hypothesized that the combination of AA and BDI causes oxidative damage in vivo. We found that plasma of preterm infants contains high levels of AA and F2-isoprostanes, stable lipid peroxidation end products. However, F2-isoprostane levels were not different between those infants with BDI (138 +/- 51 pg/ml, n = 19) and those without (126 +/- 41 pg/ml, n = 10), and the same was true for protein carbonyls, a marker of protein oxidation (0.77 +/- 0.31 and 0.68 +/- 0.13 nmol/mg protein, respectively). Incubation of BDI-containing plasma from preterm infants did not result in detectable lipid hydroperoxide formation (10% of its initial concentration. Finally, when iron was added to plasma devoid of AA, lipid hydroperoxides were formed immediately, whereas endogenous and exogenous AA delayed the onset of iron-induced lipid peroxidation in a dose-dependent manner. These findings demonstrate that in iron-overloaded plasma, AA acts an antioxidant toward lipids. Furthermore, our data do not support the hypothesis that the combination of high plasma concentrations of AA and BDI, or BDI alone, causes oxidative damage to lipids and proteins in vivo.

Topics: Adult; Antioxidants; Ascorbic Acid; Bleomycin; Blood Proteins; Cholesterol Esters; Chromatography, High Pressure Liquid; Humans; Infant; Infant, Newborn; Infant, Premature; Iron; Iron Overload; Lipids; Oxidation-Reduction

It is well-documented that iron chelation by desferrioxamine protects/improves the cardiac function in blood transfusion-dependent children suffering from beta-thalassaemia. In patients who do not become dependent upon blood transfusion until adulthood (ANT-patients), iron chelation by desferrioxamine may affect the cardiac function in unknown ways, presumably because age-related changes in the heart may cause iron chelation to affect the cardiac function in different ways. We therefore followed the left ventricular ejection fraction (LVEF) by multigated radionuclide angiography in 16 iron-loaded ANT-patients during iron chelation alone and after increasing the efficacy of chelation by vitamin C supplementation. During 12 months of iron chelation the mean LVEF fell significantly from 63.3% to 58.0% (p=0.04). Individual changes in LVEF did not correlate significantly with age but with the pretreatment liver iron concentration. After initiation of vitamin C supplementation, the mean LVEF increased from 55.9% to 65.3% (p=0.01). Our data suggest that in ANT-patients prolonged desferrioxamine treatment without vitamin C supplementation may be associated with reduced LVEF, whereas vitamin C supplementation seems to benefit the cardiac function. Similar findings have not been described in beta-thalassaemia and may hence be specific for ANT-patients. However, our findings have to be confirmed by controlled studies.

Topics: Adolescent; Adult; Aged; Aging; Antidotes; Ascorbic Acid; beta-Thalassemia; Chelating Agents; Coronary Angiography; Deferoxamine; Female; Humans; Injections, Subcutaneous; Iron Overload; Male; Middle Aged; Transfusion Reaction; Ventricular Function, Left

It has been suggested that iron plays an important role in the pathogenesis of atherosclerosis, primarily by acting as a catalyst for the atherogenic modification of LDL. Although some epidemiological data suggest that high stored iron levels are an independent risk factor for coronary artery disease and that iron has been detected in both early and advanced atherosclerotic lesions, the evidence is often contradictory and inconclusive. We used the New Zealand White rabbit to investigate the effects of iron overload (FeO) and iron deficiency (FeD) on atherosclerosis. Groups of 7 rabbits were either iron loaded by injections of iron dextran (FeO group), iron depleted by phlebotomy (FeD group), or given injections of saline (control group) for a total of 9 weeks. All rabbits were fed a chow diet containing 1% (wt/wt) cholesterol for the last 6 weeks of the study. Iron and antioxidant status and cholesterol levels were assayed in plasma before cholesterol feeding (week 3) and at the time that the rabbits were killed (week 9). In addition, the susceptibility of LDL to oxidation was measured and pathological examination of the aortic arch and thoracic aorta performed at the end of the study. FeD significantly decreased the levels of blood hemoglobin, serum iron, and transferrin saturation compared with controls. Conversely, FeO significantly increased transferrin Fe saturation. FeO but not FeD decreased plasma cholesterol levels compared with control animals both before (P < .05) and after (P = .055) cholesterol feeding. Neither FeO nor FeD had a significant effect on the levels of antioxidants and lipid peroxidation products in plasma and aortic tissue or on the susceptibility of LDL to ex-vivo oxidation. FeO significantly decreased aortic arch lesion formation by 56% compared with controls (P < .05), whereas FeD had no significant effect. These results indicate that in this animal model, FeO decreases rather than increases atherosclerosis, likely because iron dextran exerts a hypocholesterolemic effect. Our data do not support the hypotheses that elevation of Fe stores increases or that a reduction of Fe stores by phlebotomy decreases the risk of coronary artery disease.

Topics: Animals; Antioxidants; Aorta; Aortic Diseases; Arteriosclerosis; Ascorbic Acid; Diet, Atherogenic; Hypercholesterolemia; Iron; Iron Deficiencies; Iron Overload; Lipid Peroxidation; Lipids; Lipoproteins, LDL; Male; Phlebotomy; Prostaglandins F; Rabbits; Risk Factors; Vitamin E