Acute Iron Research Articles

Effect of Deferasirox on Iron Absorption in a Randomized, Placebo-Controlled, Crossover Study in a Human Model of Acute Supratherapeutic Iron Ingestion

In 2005, the Food and Drug Administration approved deferasirox as an oral iron chelating agent for chronic iron overload. To determine usefulness in management of acute iron ingestion, we study the effect of orally administered deferasirox in healthy human adults. A double-blinded, placebo-controlled, randomized, crossover study of 8 healthy human volunteers was conducted. Subjects ingested 5 mg/kg of elemental iron in the form of ferrous sulfate. One hour after iron ingestion, subjects were randomized to receive 20 mg/kg of deferasirox or placebo. Serial iron levels were then obtained. A 2-week washout was used between study arms. The paired t test was used to compare area under time-concentration curves from baseline to both 12- and 24-hour iron levels between groups. Baseline serum iron levels were similar in the 2 groups. Deferasirox significantly reduced serum iron area under concentration-time curves compared with placebo during both 1 to 12 hours and 1 to 24 hours (12 hour=577 μmol-hour/L and 392 μmol-hour/L, 95% confidence interval for the difference 15.8 to 353.0 μmol-hour/L; 24 hour=808 μmol-hour/L and 598 μmol-hour/L, 95% confidence interval for difference 54.4 to 366.7 μmol-hour/L). Orally administered deferasirox significantly reduced serum iron levels when administered 1 hour after iron ingestion during the 12- and 24-hour periods after acute ingestion of 5 mg/kg of elemental iron in healthy human volunteers. Further study is required to determine optimal dosing, but deferasirox may be an important addition to current therapy for acute iron poisoning.

Valor diagnóstico de la resonancia magnética cardiaca en la insuficiencia cardiaca: estado actual

Chronic heart failure is a common disease placing significant burdens on patients and health-care services. Noninvasive imaging plays a key role in accurate diagnosis, determination of etiology and prognosis, and in monitoring of therapy. Cardiovascular magnetic resonance (CMR) allows both a valuable clinical and research toll for a comprehensive assessment of heart failure patients. Currently, CMR constitutes the gold standard imaging technique for accurate and reproducible measurement of myocardial anatomy, regional and global function, perfusion and viability. In addition, it allows evaluation of acute tissue damage (edema and necrosis), fibrosis, infiltration and iron overload. The information derived from CMR often reveals the underlying etiology of heart failure, and its high measurement accuracy makes it an ideal technique for monitoring disease evolution and the effects of therapy. Evidence on the prognostic value of CMR-derived parameters in heart failure is rapidly emerging.

Hyperbaric Oxygen Treatment Reduces Mortality in Acute Iron Intoxication in Rats

Acute iron intoxication is one of the leading causes of overdose morbidity and mortality in children. The toxicity of iron has been postulated to be related to free radical formation and subsequent lipid peroxidation. Hyperbaric oxygen treatment can result in a number of beneficial biochemical, cellular and physiological effects, and has recently been shown to induce cellular protection against ischaemia, and in some cases against free radical formation. In the current study, we aimed to investigate the effects of hyperbaric oxygen treatment on mortality in acute iron intoxication in rats. After iron administration, 57 animals were divided into two groups: a treatment group receiving hyperbaric oxygen treatment (n = 30) and a control group (n = 27), and followed for 48 hr for signs of severe intoxication. In the second part of the study, 21 animals were divided into a treatment group receiving hyperbaric oxygen treatment (n = 10) and a control group (n = 11), and markers of oxidative stress were evaluated. We showed a significant reduction in mortality in hyperbaric oxygen-treated animals from 17 of 27 (62.9%) among untreated rats to 6 of 30 (20%). Surprisingly, in the treatment group, levels of oxidative stress markers were higher. We postulate that hyperbaric oxygen has a potentially beneficial effect in acute iron intoxication.

Transfusion of red blood cells after prolonged storage produces harmful effects that are mediated by iron and inflammation

Although red blood cell (RBC) transfusions can be lifesaving, they are not without risk. In critically ill patients, RBC transfusions are associated with increased morbidity and mortality, which may increase with prolonged RBC storage before transfusion. The mechanisms responsible remain unknown. We hypothesized that acute clearance of a subset of damaged, stored RBCs delivers large amounts of iron to the monocyte/macrophage system, inducing inflammation. To test this in a well-controlled setting, we used a murine RBC storage and transfusion model to show that the transfusion of stored RBCs, or washed stored RBCs, increases plasma nontransferrin bound iron (NTBI), produces acute tissue iron deposition, and initiates inflammation. In contrast, the transfusion of fresh RBCs, or the infusion of stored RBC-derived supernatant, ghosts, or stroma-free lysate, does not produce these effects. Furthermore, the insult induced by transfusion of stored RBC synergizes with subclinical endotoxinemia producing clinically overt signs and symptoms. The increased plasma NTBI also enhances bacterial growth in vitro. Taken together, these results suggest that, in a mouse model, the cellular component of leukoreduced, stored RBC units contributes to the harmful effects of RBC transfusion that occur after prolonged storage. Nonetheless, these findings must be confirmed by prospective human studies.

Suppression of hepatic hepcidin expression in response to acute iron deficiency is correlated with an increase of matripatase‐2 protein in the liver

Recent studies demonstrate a pivotal role of bone morphogenic protein‐6 (BMP6) and matriptase‐2, a protein encoded by the TMPRSS6 gene, in the induction and suppression of hepatic hepcidin expression, respectively. We examined their expression profiles in isolated liver cells and found an exclusive expression of TMPRSS6 mRNA in hepatocytes. In rats fed an iron deficient (ID) diet for 24 hrs, the rapid decrease of transferrin saturation from 71% to 24% (control versus ID diet) was associated with a marked decrease of hepatic hepcidin mRNA, by approximately 100‐fold in comparison with the corresponding controls. These results indicated a close correlation of low transferrin saturation with the decrease of hepcidin mRNA. The decrease of phosphorylated Smad1/5/8 detected in the ID rat livers suggests that the suppressed hepcidin expression resulted from the inhibition of BMP signaling. qRT‐PCR analysis revealed no significant change in either BMP6 or TMPRSS6 mRNA in the liver. However, an increase of matriptase‐2 protein in the liver from ID rats was detected, suggesting that suppression of hepcidin expression in response to acute iron deficiency is mediated by the increase of matriptase‐2 protein levels.

The Role of BMP6 in the Regulation of Hepcidin By Iron

Normally, hepcidin synthesis is increased in response to iron loading to limit further absorption of dietary iron and its release from stores. Mutations in HFE, TfR2 or HJV cause hepcidin insufficiency which results in the inability to downregulate the absorption of dietary iron, and eventually leads to iron overload. In order to understand the role each of these proteins plays in hepcidin regulation by iron, we analyzed hepcidin responsiveness to short and long‐term iron challenge in HFE, TfR2 and HJV mutant mouse models. While HFE mutants partially increased hepcidin expression after acute iron challenge, both TfR2 and HJV mutants showed no response. After chronic iron challenge, both HFE and TfR2 mutants increased hepcidin expression to near WT levels, but the hepcidin expression in HJV mutants remained severely impaired. We also analyzed BMP6 expression and show that BMP6 upregulation by iron is independent of HFE, TfR2 and HJV. Because of the different roles HFE, TfR2 and HJV play in the hepcidin response to short and long term iron challenges, we propose that there are two independent signals by which iron regulates hepcidin expression. The first is most likely mediated by iron‐transferrin and acts through HFE, TfR2 and HJV, while the long term signal may depend on intracellular iron concentration and requires HJV.

Changes in Rat Liver Proteome Following Acute In Vivo Iron Overload

The mammalian liver is a primary site for iron processing. Excess iron consumption or iron uptake/storage disorders alter hepatic gene expression and correlate with various liver diseases. The general patterns of change in the hepatic proteome following acute iron overload, however, are poorly understood. To address this, we injected rats with iron dextran to induce liver iron accumulation. After 24, 48, and 96 hours post‐injection, whole livers were isolated and flash‐frozen. Liver non‐heme iron levels increased 30‐fold at all post‐injection times. Liver proteins were solubilized from frozen liver powders with thiourea‐containing buffer and subjected to two‐dimensional gel electrophoresis. Digital spot quantitation of gel images and analysis of protein tryptic digests by MALDI‐TOF/TOF mass spectrometry identified 38 proteins whose expression changed ≥ 1.5 fold following acute iron overload. The majority of identified proteins increased during iron overload including urea cycle enzymes and various enzymes involved in anti‐oxidant defense, lipid metabolism, and mitochondrial ATP formation. Fewer proteins decreased during iron overloading and included specific lipid binding proteins. These results provide a foundation for more detailed analyses on the sequential patterns of changes in liver protein expression during acute iron overload. (Support: NIH DK‐61984)

Oral N-acetylcysteine has a deleterious effect in acute iron intoxication in rats

Acute iron intoxication is associated with depletion of reduced glutathione in hepatocytes and changes in the glutathione system enzymes. We hypothesized that treatment with N-acetylcysteine (NAC), a glutathione reducing agent and an antioxidant, would reduce mortality in acute iron intoxication. We used a rat model to test this hypothesis. Male rats were assigned to 4 groups. Group 1 received 400 mg/kg elemental iron by oral gavage, group 2 received the same dose of iron followed by NAC, group 3 received NAC only, whereas group 4 received distilled water. Iron and liver transaminases in the blood, and glutathione system enzymes in the liver and erythrocytes were measured. Mortality in group 2 was significantly higher after 2, 6, and 24 hours compared with group 1 ( P < .001). No deaths were observed in groups 3 and 4. Serum iron levels were significantly higher in group 2 rats compared to group 1 rats ( P < .001). Hepatic and erythrocyte glutathione system enzymes were significantly lower among rats in group 2 compared to rats in group 1. The administration of NAC probably increased the absorption of iron through the gastrointestinal tract, causing higher serum iron levels with significant hepatic damage. These results indicate that in a rat model of acute iron intoxication, orally administered NAC may increase mortality.

Hepcidin Regulation by the BMP Pathway.

Abstract SCI-25Systemic iron balance is regulated by the key iron regulatory hormone hepcidin. Secreted by the liver, hepcidin inhibits iron absorption from the diet and iron mobilization from body stores by decreasing cell surface expression of the iron export protein ferroportin. Iron administration increases hepcidin expression, thereby providing a feedback mechanism to limit further iron absorption, while anemia and hypoxia inhibit hepcidin expression, thereby increasing iron availability for erythropoiesis. Hepcidin excess is thought to have a role in the anemia of inflammation, while hepcidin deficiency is thought to be the common pathogenic mechanism underlying the iron overload disorder hereditary hemochromatosis, due to mutations in the genes encoding hepcidin itself (HAMP), HFE, transferrin receptor 2 (TFR2), or hemojuvelin (HFE2). Notably the precise molecular mechanisms by which iron levels are “sensed” and how this iron “signal” is transduced to modulate hepcidin expression have remained elusive. We have recently discovered that hemojuvelin is a co-receptor for the bone morphogenetic protein (BMP) signaling pathway, and that hemojuvelin-mediated BMP signals increase hepcidin expression at the transcriptional level. In addition to patients with HFE2 mutations and Hfe2 knockout mice, other genetic mouse models associated with impaired hepatic BMP signaling through a global knockout of the ligand Bmp6, or selective hepatic knockout of an intracellular mediator of BMP signaling, Smad4, also cause inappropriately low hepcidin expression and iron overload. Exogenous BMP6 administration in mice increases hepatic hepcidin expression and reduces serum iron, while BMP6 antagonists inhibit hepatic hepcidin expression, mobilize reticuloendothelial cell iron stores and increase serum iron. Not only does the BMP6-hemojuvelin-SMAD pathway regulate hepcidin expression and thereby systemic iron homeostasis, but also the BMP6-SMAD pathway itself is regulated by iron. Acute iron administration in mice increases phosphorylation of Smad proteins in the liver, and chronic changes in dietary iron modulate hepatic Bmp6 mRNA expression and phosphorylation of Smad proteins concordantly with Hamp mRNA expression. Together, these data support the paramount role of the BMP6-hemojuvelin-SMAD signaling pathway in the iron-mediated regulation of hepcidin expression and systemic iron homeostasis, and suggest that modulators of this pathway may be an alternative therapeutic strategy for treating disorders of iron homeostasis. Recent work elucidating the role of the BMP signaling pathway in hepcidin regulation and systemic iron homeostasis will be presented. DisclosuresBabitt:Ferrumax Pharmaceuticals, Inc.: Equity Ownership.

Hepcidin in acute iron toxicity

Background Hepcidin regulates extracellular iron concentration by inhibiting iron release from macrophages and preventing iron absorption in the intestine. Our objective was to evaluate the expression of hepcidin in the liver in acute iron poisoning in a rat model. Methods Male Wistar rats were assigned to group 1, who received 750 mg/kg elemental iron (LD 50) by gavage, and group 2 (control), who received distilled water. Iron concentrations and liver transaminases were measured in the serum. Hepcidin messenger RNA levels were measured in the liver. Results Mean serum iron levels, aspartate aminotransferase, alanine aminotransferase, and uric acid were significantly higher in group 1 compared to group 2 ( P < .0001, P = .01, P < .0001, and P = 0.0001, respectively). Hepcidin messenger RNA levels in the liver were significantly higher in the study group ( P = .005). Conclusions In acute iron intoxication, hepcidin expression in the liver significantly increased. Further studies are needed to determine whether hepcidin levels correlate with the severity of the intoxication.

Changes in serum hepcidin levels in acute iron intoxication in a rat model

Hepcidin is an important and recently discovered regulator of iron homeostasis. Acute iron intoxication is one of the leading causes of overdose mortality in children. It is difficult to estimate the degree of iron intoxication since iron serum levels do not correlate with the actual clinical severity. In the current study we aimed to investigate whether serum hepcidin levels are elevated in acute iron intoxication. Rats were divided into two iron dose groups and one control group. Each group was further subdivided into four time groups following the administration of iron. Levels of hepcidin, iron and liver enzymes were measured, and animals were followed for signs of toxicity. Serum hepcidin levels were significantly higher in the group treated with toxic doses of iron (p=0.005). No significant difference in serum iron levels was found between the groups. In acute iron intoxication serum hepcidin levels increase significantly and remain elevated for at least 6h. We postulate that beyond the first hour after iron administration, serum hepcidin levels provide a better estimate of the amount of iron intake than do serum iron levels.

TREATMENT OF ACUTE IRON INTOXICATION WITH DESFERRIOXAMINE.

Treatment of Acute Iron Intoxication with Desferrioxamine Get access Nutrition Reviews, Volume 23, Issue 3, March 1965, Pages 72–74, https://doi.org/10.1111/j.1753-4887.1965.tb02082.x Published: 01 March 1965

Iron medication-induced gastric mucosal injury

Severe gastrointestinal erosion, ulcer, necrosis and strictures after an acute iron overdose are well described. However, gastric mucosal injury in patients receiving therapeutic iron has received only scant recognition despite its wide use. We report a case of iron medication-induced gastric mucosal injury in a 76-year-old male who presented with iron deficiency anemia and had been taking ferrous sulfate tablet for 4 years. Esophagogastroduodenoscopy (EGD) revealed a pale, villous appearing flat lesion along the lesser curvature of gastric body. Histopathologic examination of EGD biopsies of the flat lesion showed brown crystalline materials deposited in the lamina propria of gastric mucosa, which was accompanied with fibrosis, chronic inflammation, and foreign body reaction. The crystalline materials were covered and admixed with gastric epithelium. Prussian blue iron stain confirmed that the brown crystalline materials were iron. The iron and hemosiderin accumulation was also seen in cytoplasm of epithelial cells and lumen of fundic gastric glands. The recognition and reporting by pathologists of iron-induced changes in EGD biopsies will alert clinicians to this underrecognized but easily correctable complication by alternative forms of iron therapy, such as liquid preparation.

Intestinal Hypoxia-Inducible Transcription Factors Are Essential for Iron Absorption following Iron Deficiency

Iron deficiency and iron overload are among the most prevalent nutritional disorders worldwide. Duodenal cytochrome b (DcytB) and divalent metal transporter 1 (DMT1) are regulators of iron absorption. Their expression is increased during high systemic requirements for iron, but the molecular mechanisms that regulate DcytB and DMT1 expression are undefined. Hypoxia-inducible factor (HIF) signaling was induced in the intestine following acute iron deficiency in the duodenum, resulting in activation of DcytB and DMT1 expression and an increase in iron uptake. DcytB and DMT1 were demonstrated as direct HIF-2alpha target genes. Genetic disruption of HIF signaling in the intestine abolished the adaptive induction of iron absorption following iron deficiency, resulting in low systemic iron and hematological defects. These results demonstrate that HIF signaling in the intestine is a critical regulator of systemic iron homeostasis.

Elevation of Serum Ferritin is Associated with the Outcome of Patients with Newly Diagnosed Multiple Myeloma

Background/AimsSerum ferritin is a marker of acute phase reactions and iron storage. In addition, hematologic malignancies are associated with elevated serum ferritin levels. Other studies have suggested that ferritin is a surrogate for advanced disease and has an impact on relapse, because elevated serum ferritin predicts overall survival (OS) and relapse-free survival following autologous stem cell transplantation for lymphomas.MethodsWe studied 89 consecutive patients with newly diagnosed multiple myeloma to determine the value of serum ferritin in comparison with known prognostic factors.ResultsThe OS in the elevated serum ferritin group (≥300 ng/mL) was shorter than that in the normal serum ferritin group (<300 ng/mL, p<0.001) after a median follow-up of 25 months. In univariate analysis, elevated ferritin was correlated with poor survival in the patients (relative risk [RR], 2.588; 95% confidence interval [CI], 1.536 to 4.358; p<0.001). Furthermore, multivariate analysis showed that elevated serum ferritin was an independent predictor of mortality in patients with multiple myeloma (RR, 2.594; 95% CI, 1.403 to 4.797; p=0.002).ConclusionsThe serum ferritin can a prognostic parameter of survival as well as disease activity in patients with multiple myeloma.

Nocardamin Production by Streptomyces avermitilis

Desferrioxamine B (desferal®) is the only therapeutic agent for chronic iron overload and acute iron intoxication. Therefore, new drug candidates are required for more effective treatments. Recent genome analyses of microorganisms have enabled us to identify cryptic gene clusters of secondary metabolism. In a genomic analysis of Streptomyces avermitilis, we found the putative biosynthetic gene cluster for nocardamin and desferrioxamine derivatives, the production of which by S. avermitilis had been unknown. To determine the synthesis of nocardamin and discover new derivatives in S. avermitilis, we performed a comprehensive analysis and isolation of secondary metabolites of S. avermitilis. We obtained nocardamin and its related compounds, including a derivative that initially was isolated as a microbial product. The biosynthetic pathway of nocardamin and the substrate specificity of its biosynthesis enzymes were proposed based on the structures of the isolated nocardamin derivatives. The production of nocardamin by S. avermitilis was completely suppressed by the addition of more than 5 μM ferric ions. An iron-dependent regulatory protein (IdeR)-binding motif was located upstream of the sidABCD operon, using the profile hidden Markov model method. To determine the regulation of nocardamin synthesis by IdeR in S. avermitilis, we constructed ideR deletion mutants. The production of nocardamin by the deletion mutants was not suppressed by ferric ions (up to 100 μM).

Examining High Rates of Inadequate Bowel Preparation and Potential Causative Factors

Purpose: Inadequate bowel preparation (prep) is frequently observed during screening colonoscopy. Ramifications of poor prep include prolonged and incomplete procedures, increased costs, and the potential for missed lesions. We attempted to quantify the extent of inadequate prep at our institution and identify underlying causative factors. Methods: All colonoscopies performed at the Memphis Veterans Affairs Medical Center from January 1, 2006 through April 30, 2008 were retrospectively evaluated. Only screening colonoscopies that used sodium phosphate (NaP) or polyethylene glycol (PEG) were included in the review. Exclusion criteria included prior colonoscopy, inpatient status, nursing home residence, incomplete endoscopy report, and any colonoscopy performed for indications other than routine colorectal cancer screening (acute intestinal bleeding, iron deficiency, abdominal pain, constipation, diarrhea, and abnormal imaging findings). Prep adequacy was subjectively defined by the endoscopist at the time of the procedure as excellent, good, fair adequate, fair exam compromised, or poor. All patient data were obtained from the CORI and Computerized Patient Record System (CPRS) databases. Chi-squared tests were performed to determine statistical significance. Results: A total of 619 patients met all selection criteria and were included in the study. NaP prep was used in 83% and PEG in 17%. A strong correlation was seen between improved prep quality and the use of PEG (P= 0.06). No difference was seen between NaP and PEG in the number of adenomas detected. Overall prep adequacy was 11% excellent, 50% good, 29% fair adequate, 5% fair exam compromised, and 5% poor. Individual comorbidities such as diabetes mellitus, congestive heart failure, coronary artery disease, renal insufficiency, stroke and dementia were not significantly related to prep adequacy, but a strong correlation was seen between poorer prep quality and diabetes (P= 0.06). Improved prep quality was seen in procedures performed before 10 am (68% excellent/good) as compared to those performed after 10 am (52%) (P < 0.05). Patient attendance at a pre-colonoscopy educational class did not improve prep quality. Conclusion: At our institution 39% of patients undergoing screening colonoscopy had a prep adequacy that was less than good. Only colonoscopies performed after 10 am were significantly associated with poorer preps. These findings, coupled with our patient population's overall poor compliance with recommended follow up, indicate that a significant number of patients are not getting adequate colorectal cancer screening. Therefore, continued attempts to identify methods that improve bowel preparation, such as scheduling procedures earlier, should be made.

Assessing Variability in Surveillance Recommendations for Fair Adequate Bowel Preparations

Purpose: The Clinical Outcomes Research Initiative (CORI) system defines a fair adequate bowel preparation (prep) as one having “enough feces or liquid to prevent a completely reliable exam”. Prior studies have defined an acceptable prep quality as one that is considered excellent, good, or fair adequate. In addition, firm guidelines do not exist regarding appropriate surveillance intervals after fair adequate preps. The aim of this study is to determine if fair adequate preps are truly acceptable and if there is a consensus among endoscopists regarding recommended surveillance intervals for these preps. Methods: All colonoscopies performed at the Memphis Veterans Affairs Medical Center from January 1, 2006 through April 30, 2008 were retrospectively evaluated. Only outpatient screening colonoscopies were included in the review. Exclusion criteria included prior colonoscopy, inpatient status, nursing home residence, incomplete endoscopy report, and any colonoscopy performed for indications other than routine colorectal cancer screening (acute intestinal bleeding, iron deficiency, abdominal pain, constipation, diarrhea, and abnormal imaging findings). Bowel preparation adequacy was subjectively defined by the endoscopist at the time of the procedure as excellent, good, fair adequate, fair exam compromised, or poor. All patient data were obtained from the CORI and the Computerized Patient Record System (CPRS) databases. Chi-squared tests were performed to determine statistical significance. Results: A total of 623 patients met all selection criteria and were included in the study. Of these, 29% had a fair adequate prep. No significant difference was seen in the percentage of patients having fair adequate preps with adenoma (30%) as compared to patients with good (25%) and excellent (30%) preps. Interestingly, no clear consensus was seen in terms of recommended follow for fair adequate preps with or without adenomas (see Table).Table: Recommended Follow Up Intervals for Fair Adequate Bowel Preparations.Conclusion: A significant number of patients undergoing colonoscopy have fair adequate preps. These preps can potentially be considered acceptable since there is no difference in the percentage of patients having fair adequate preps that detect adenomas as compared to patients with good and excellent preps. However, a consensus does not exist regarding recommended surveillance intervals for fair preps. This lack of consensus may be due to the fact that a fair adequate prep is defined as not being “a completely reliable exam”. Therefore, formal guidelines need to be developed for surveillance intervals in patients with fair adequate bowel preparations.

Influence of iron chelation on R1 and R2 calibration curves in gerbil liver and heart

MRI is gaining increasing importance for the noninvasive quantification of organ iron burden. Since transverse relaxation rates depend on iron distribution as well as iron concentration, physiologic and pharmacologic processes that alter iron distribution could change MRI calibration curves. This article compares the effect of three iron chelators, deferoxamine, deferiprone, and deferasirox, on R1 and R2 calibration curves according to two iron loading and chelation strategies. Thirty-three Mongolian gerbils underwent iron loading (iron dextran 500 mg/kg/wk) for 3 weeks followed by 4 weeks of chelation. An additional 56 animals received less aggressive loading (200 mg/kg/week) for 10 weeks, followed by 12 weeks of chelation. R1 and R2 calibration curves were compared to results from 23 iron-loaded animals that had not received chelation. Acute iron loading and chelation-biased R1 and R2 from the unchelated reference calibration curves but chelator-specific changes were not observed, suggesting physiologic rather than pharmacologic differences in iron distribution. Long-term chelation deferiprone treatment increased liver R1 50% (P < 0.01), while long-term deferasirox lowered liver R2 30.9% (P < 0.0001). The relationship between R1 and R2 and organ iron concentration may depend on the acuity of iron loading and unloading as well as the iron chelator administered.

Uncoupling and oxidative stress in liver mitochondria isolated from rats with acute iron overload

One hypothesis for the etiology of cell damage arising from iron overload is that its excess selectively affects mitochondria. Here we tested the effects of acute iron overload on liver mitochondria isolated from rats subjected to a single dose of i.p. 500 mg/kg iron-dextran. The treatment increased the levels of iron in mitochondria (from 21 +/- 4 to 130 +/- 7 nmol/mg protein) and caused both lipid peroxidation and glutathione oxidation. The mitochondria of iron-treated rats showed lower respiratory control ratio in association with higher resting respiration. The mitochondrial uncoupling elicited by iron-treatment did not affect the phosphorylation efficiency or the ATP levels, suggesting that uncoupling is a mitochondrial protective mechanism against acute iron overload. Therefore, the reactive oxygen species (ROS)/H+ leak couple, functioning as a mitochondrial redox homeostatic mechanism could play a protective role in the acutely iron-loaded mitochondria.