UNIPROT:P02794 - FACTA Search

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Query: UNIPROT:P02794 (ferritin)
17,525 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Induction of Phase 2 enzymes is an effective and sufficient strategy for achieving protection against the toxic and neoplastic effects of many carcinogens. It is proposed that the concept of Phase 2 enzymes as being responsible only for the conjugation of functionalized xenobiotics with endogenous cellular ligands such as glutathione (glutathione S-transferases) and glucuronic acid (UDP-glucuronosyltransferases) be expanded to include proteins with the following common characteristics: (a) coordinate induction by a broad range of chemical agents that all have the capacity to react with sulfhydryl groups; (b) possible regulation by common promoter elements; and (c) catalysis of reactions that lead to comprehensive protection against electrophile and reactive oxygen toxicities, by a wide variety of mechanisms. These mechanisms include: conjugation with endogenous ligands, chemical modification of reactive features of molecules that can damage DNA and other macromolecules, and generation or augementation of cellular antioxidants. In addition to the above conjugating enzymes, a provisional and partial list of Phase 2 proteins might include: NAD(P)H:quinone reductase, epoxide hydrolase, dihydrodiol dehydrogenase, gamma-glutamylcysteine synthetase, heme oxygenase-1, leukotriene B4 dehydrogenase, aflatoxin B1 dehydrogenase, and ferritin.
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PMID:Chemoprotection against cancer by induction of phase 2 enzymes. 1121 5

Acute experimental iron loading causes iron to accumulate in the renal tissue. The accumulation of iron may play a role in enhancing oxidant-induced tubular injury by producing increased amounts of reactive oxygen species. From findings in cells from heme oxygenase-1 (HO-1)-deficient mice, HO-1 is postulated to prevent abnormal intracellular iron accumulation. Recently, it has been reported that HO-1 is induced in the renal tubular epithelial cells, in which iron is deposited after iron loading, and that this HO-1 induction may be involved in ameliorating iron-induced renal toxicity. We previously showed that chronic administration of angiotensin II to rats induces HO-1 expression in the tubular epithelial cells. These observations led us to investigate whether there is a link between iron deposition and HO-1 induction in renal tubular cells in rats undergoing angiotensin II infusion. In the present study, rats were given angiotensin II for continuously 7 days. Prussian blue staining revealed the distinct deposits of iron in the proximal tubular epithelial cells after angiotensin II administration. Electron microscopy demonstrated that iron particles were present in the lysosomes of these cells. Histologic and immunohistochemical analyses showed that stainable iron and immunoreactive ferritin and HO-1 were colocalized in the tubular epithelial cells. Treatment of angiotensin II-infused rats with an iron chelator, deferoxamine, blocked the abnormal iron deposition in kidneys and also the induced expression of HO-1 and ferritin expression. Furthermore, deferoxamine treatment suppressed the angiotensin II-induced increase in the urinary excretion of protein and N-acetyl-beta-D-glucosaminidase, a marker of tubular injury; however, deferoxamine did not affect the angiotensin II-induced decrease in glomerular filtration rate. These results suggest that angiotensin II causes renal injury, in part, by inducing the deposition of iron in the kidney.
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PMID:Abnormal iron deposition in renal cells in the rat with chronic angiotensin II administration. 1179 29

This article describes the first autopsy case of heme oxygenase (HO)-1 deficiency. A 6-year-old boy who presented with growth retardation; anemia; leukocytosis; thrombocytosis; coagulation abnormality; elevated levels of haptoglobin, ferritin, and heme in serum; a low serum bilirubin concentration; and hyperlipidemia was diagnosed as HO-1 deficient by gene analysis several months before death. Autopsy showed amyloid deposits in the liver and adrenal glands and mesangioproliferative glomerular changes in kidneys, in addition to an irregular distribution of foamy macrophages with iron pigments. Fatty streaks and fibrous plaques were noted in the aorta. Compared with HO-1--targeted mice, the present case seems to more severely involve endothelial cells and the reticuloendothelial system, resulting in intravascular hemolysis, disseminated intravascular coagulation, and amyloidosis with a short survival. This contrasts to the predominant iron metabolic disorders of HO-1--targeted mice with a long survival.
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PMID:Heme oxygenase-1 deficiency: the first autopsy case. 1182 83

Mismanagement of intracellular iron is a key pathological feature of many neurodegenerative diseases. Our long-term goal is to use animal models to investigate the mechanisms of iron neurotoxicity and its relationship to neurodegenerative pathologies. The immediate aim of this experiment was to determine regional distribution of iron and cellular distribution of iron storage proteins (L- and H-ferritin) and an oxidative stress marker (heme oxygenase-1) in brains of mice fed the lipophilic iron compound (3,5,5-trimethylhexanoyl) (TMH)-ferrocene. We fed male and female weanling BALB/cj mice diets either deficient in iron (0 mg Fe/kg diet), adequate in iron (35 mg Fe/kg diet; control mice), or adequate in iron and supplemented with 0.1 or 1.0 g TMH-ferrocene/kg diet for 8 wk. Iron concentrations in cerebrum were higher in mice fed 1.0 g TMH-ferrocene/kg diet than in control mice (p < 0.05). Liver iron concentrations were eightfold higher in mice fed 1.0 g TMH-ferrocene/kg diet than in control mice (p < 0.0001). L-Ferritin and heme oxygenase-1 expression were elevated in striatum in mice fed 1.0 g TMH-ferrocene/kg diet. We conclude that administration of the lipophilic iron compound TMH-ferrocene leads to subtle perturbations of cellular iron within the brain, potentially representing a model of iron accumulation similar to that seen in various neuropathological conditions.
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PMID:The lipophilic iron compound TMH-ferrocene [(3,5,5-trimethylhexanoyl)ferrocene] increases iron concentrations, neuronal L-ferritin, and heme oxygenase in brains of BALB/c mice. 1200 62

Numerous pathologies may involve toxic side effects of free heme and heme-derived iron. Deficiency of the heme-catabolizing enzyme, heme oxygenase-1 (HO-1), in both a human patient and transgenic knockout mice leads to an abundance of circulating heme and damage to vascular endothelium. Although heme can be directly cytotoxic, the present investigations examine the possibility that hemoglobin-derived heme and iron might be indirectly toxic through the generation of oxidized forms of low-density lipoprotein (LDL). In support, hemoglobin in plasma, when oxidized to methemoglobin by oxidants such as leukocyte-derived reactive oxygen, causes oxidative modification of LDL. Heme, released from methemoglobin, catalyzes the oxidation of LDL, which in turn induces endothelial cytolysis primarily caused by lipid hydroperoxides. Exposure of endothelium to sublethal concentrations of this oxidized LDL leads to induction of both HO-1 and ferritin. Similar endothelial cytotoxicity was caused by LDL isolated from plasma of an HO-1-deficient child. Spectral analysis of the child's plasma revealed a substantial oxidation of plasma hemoglobin to methemoglobin. Iron accumulated in the HO-1-deficient child's LDL and several independent assays revealed oxidative modification of the LDL. We conclude that hemoglobin, when oxidized in plasma, can be indirectly cytotoxic through the generation of oxidized LDL by released heme and that, in response, the intracellular defense-HO-1 and ferritin-is induced. These results may be relevant to a variety of disorders-such as renal failure associated with intravascular hemolysis, hemorrhagic injury to the central nervous system, and, perhaps, atherogenesis-in which hemoglobin-derived heme may promote the formation of fatty acid hydroperoxides.
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PMID:Pro-oxidant and cytotoxic effects of circulating heme. 1213 Apr 98

Much interest has recently been focused on the physiological/pathological role of the heme oxygenase (HO) system, the rate-limiting step in the conversion of heme, in inflammatory events. The HO system may be instrumental in mediating a number of cytoprotective effects, because of its end products, biliverdin, carbon monoxide (CO) and ferrous free iron (Fe2+). As each of the byproducts acts dependently and/or co-operatively with each other, their in vivo effects are complex. In general, the HO system is thought to exert three major functions in ischemia/reperfusion injury: (1) anti-oxidant effects; (2) maintenance of microcirculation; and (3) modulatory effects upon the cell cycle. The anti-oxidant functions depend on heme degradation, oxygen consumption and the production of biliverdin/ferritin via iron accumulation. On the other hand, the production of CO, which has vasodilatory and anti-platelet aggregative properties, can maintain tissue microcirculation. Strikingly, CO may also be instrumental in anti-apoptotic and cell arrest mechanisms. The HO system prevents early injury in the re-perfused organ, and inhibits the function of immune reactive cells, such as neutrophils, macrophages and lymphocytes. The role of the HO system as a novel strategy to mitigate an antigen-independent ischemia/reperfusion injury has been documented in a number of transplantation models.
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PMID:A novel strategy against ischemia and reperfusion injury: cytoprotection with heme oxygenase system. 1218 Aug 35

Hemin is released from hemoglobin after CNS hemorrhage and may contribute to its cytotoxic effect. In a prior study, we demonstrated that heme oxygenase-1 induction protected murine cortical astrocytes from hemoglobin toxicity. Since heme metabolism releases iron, this observation suggested that these cells are able to effectively sequester and detoxify free iron. In this study, we tested the hypotheses that astrocytes increased ferritin synthesis after exposure to heme-bound iron, and that this induction protected cells from subsequent exposure to toxic concentrations of hemin. Incubation with low micromolar concentrations of hemin, hemoglobin, or ferrous sulfate increased ferritin expression, as detected on immunoblots stained with a polyclonal antibody that was raised against horse spleen ferritin. Time course studies demonstrated an increase in ferritin levels within 2 h. Weak and scattered cellular staining was detected by immunohistochemistry in control, untreated cultures, while diffuse immunoreactivity was observed in cultures exposed to heme-bound iron. An enhanced ferritin band was detected on immunoblots from cultures that were treated with purified apoferritin, consistent with astrocytic ferritin uptake. Immunoreactivity after apoferritin treatment was not altered by concomitant treatment with cycloheximide. Pretreatment with apoferritin protected astrocytes from hemin toxicity in a concentration-dependent fashion between 1 and 4 mg/ml. At the highest concentration, cell death due to a 6-h exposure to 30 microM hemin was decreased by about 85%. A protective effect was also produced by induction of endogenous ferritin with nontoxic concentrations of ferrous sulfate, hemoglobin, or hemin. These results suggest that cortical astrocytes respond to exogenous heme-bound or free iron by rapidly increasing ferritin synthesis. The combined action of heme oxygenase-1 and ferritin may be a primary astrocytic defense against heme-mediated injury.
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PMID:Ferritin induction protects cortical astrocytes from heme-mediated oxidative injury. 1218 2

Atherosclerotic lesions preferentially develop in areas of the vasculature exposed to nonlaminar blood flow and low fluid shear stress, whereas laminar flow and high fluid shear stress are athero-protective. We have identified a set of genes including NAD(P)H:quinone oxidoreductase-1 (NQO1), heme oxygenase-1 (HO-1), ferritin (heavy and light chains), microsomal epoxide hydrolase, glutathione S-transferase, and gamma-glutamylcysteine synthase, whose expression is induced by exposure to prolonged physiological levels of steady laminar flow (shear stress = 20 dyn/cm(2)) in endothelial cells (EC). These genes contain an antioxidant response element (ARE) or ARE-like transcriptional regulatory sequence in their promoters and generally function to protect cells against oxidant stress. We demonstrate that exposure of EC to laminar flow activates ARE-mediated transcriptional activity. Mutation of the ARE from either the NQO1 or HO-1 promoter abolished laminar flow-induced NQO1 and HO-1 transcriptional activation. Expression of antisense Nrf2 (a transcriptional factor for ARE), a dominant negative Nrf2, or the cytoplasmic inhibitor of Nrf2 (Keap1/INrf2) inhibited laminar flow-induced NQO1 promoter activation in EC. In addition, expression of NQO1 or Nrf2 inhibited tumor necrosis factor-alpha-induced activation of VCAM-1 (vascular cell adhesion molecule-1) gene expression in EC. These data define the ARE as a novel endothelial shear stress response element. Furthermore, laminar flow activation of antioxidant genes via an ARE-dependent transcriptional mechanism may represent a novel athero-protective and anti-inflammatory mechanism in the vasculature.
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PMID:Laminar flow induction of antioxidant response element-mediated genes in endothelial cells. A novel anti-inflammatory mechanism. 1237 Jan 94

Hyperbaric oxygen (HBO) treatment of cell cultures is a well suited model for studying genetic and cellular consequences of oxidative stress. We have previously shown that exposure of isolated human lymphocytes to HBO induces DNA damage and leads to the development of an adaptive response which protects lymphocytes from oxidative DNA damage induced by a repeated HBO exposure or by treatment with H(2)O(2). Our earlier studies also provided evidence for a functional involvement of the inducible enzyme heme oxygenase-1 (HO-1) in this adaptive protection. In contrast, V79 Chinese hamster cells did neither show a comparable adaptive protection nor an induction of HO-1 after HBO exposure. We now investigated possible mechanism(s) by which HO-1 contributes to an enhanced resistance of lymphocytes against oxidative stress. HO-1 catalyzes the rate-limiting step in heme degradation to form carbon monoxide (CO), biliverdin and free iron. We can now show that supplementation with exogenous CO does not protect V79 cells from HBO-induced oxidative DNA damage suggesting that increased generation of CO cannot account for the observed adaptive protection. On the other hand, HBO-exposed lymphocytes showed a small but reproducible increase in cellular ferritin levels, which might indicate that the underlying protective mechanism is based on an induction of ferritin, which may act antioxidatively by preventing the generation of the DNA-damaging hydroxyl radical via Fenton reaction. Our results further show that isolated lymphocytes also induce HO-1 and develop an adaptive protection when the first HBO exposure does not induce DNA damage, indicating that DNA damage is not the trigger for the development of the adaptive protection.
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PMID:Investigations on the mechanism of hyperbaric oxygen (HBO)-induced adaptive protection against oxidative stress. 1237 71

Iron is a vitally important element in mammalian metabolism because of its unsurpassed versatility as a biologic catalyst. However, when not appropriately shielded or when present in excess, iron plays a key role in the formation of extremely toxic oxygen radicals, which ultimately cause peroxidative damage to vital cell structures. Organisms are equipped with specific proteins designed for iron acquisition, export, transport, and storage as well as with sophisticated mechanisms that maintain the intracellular labile iron pool at an appropriate level. These systems normally tightly control iron homeostasis but their failure can lead to iron deficiency or iron overload and their clinical consequences. This review describes several rare iron loading conditions caused by genetic defects in some of the proteins involved in iron metabolism. A dramatic decrease in the synthesis of the plasma iron transport protein, transferrin, leads to a massive accumulation of iron in nonhematopoietic tissues but virtually no iron is available for erythropoiesis. Humans and mice with hypotransferrinemia have a remarkably similar phenotype. Homozygous defects in a recently identified gene encoding transferrin receptor 2 lead to iron overload (hemochromatosis type 3) with symptoms similar to those seen in patients with HFE-associated hereditary hemochromatosis (hemochromatosis type 1). Transferrin receptor 2 is primarily expressed in the liver but it is unclear how mutant forms cause iron overload. Mutations in the gene encoding the iron exporter, ferroportin 1, cause iron overload characterized by iron accumulation in macrophages yet normal plasma iron levels. Plasma iron, together with dominant inheritance, discriminates iron overload due to ferroportin mutations (hemochromatosis type 4) from hemochromatosis type 1. Heme oxygenase 1 is essential for the catabolism of heme and in the recycling of hemoglobin iron in macrophages. Homozygous heme oxygenase 1 deletion in mice leads to a paradoxical accumulation of nonheme iron in macrophages, hepatocytes, and many other cells and is associated with low plasma iron levels, anemia, endothelial cell damage, and decreased resistance to oxidative stress. A similar phenotype occurred in a child with severe heme oxygenase 1 deficiency. Recently, a mutation in the L-subunit of ferritin has been described that causes the formation of aberrant L-ferritin with an altered C-terminus. Individuals with this mutation in one allele of L-ferritin have abnormal aggregates of ferritin and iron in the brain, primarily in the globus pallidus. Patients with this dominantly inherited late-onset disease present with symptoms of extrapyramidal dysfunction. Mice with a targeted disruption of a gene for iron regulatory protein 2 (IRP2), a translational repressor of ferritin, misregulate iron metabolism in the intestinal mucosa and the central nervous system. Significant amounts of ferritin and iron accumulate in white matter tracts and nuclei, and adult IRP2-deficient mice develop a movement disorder consisting of ataxia, bradykinesia, and tremor. Mutations in the frataxin gene are responsible for Friedreich ataxia, the most common of the inherited ataxias. Frataxin appears to regulate mitochondrial iron (or iron-sulfur cluster) export and the neurologic and cardiac manifestations of Friedreich ataxia are due to iron-mediated mitochondrial toxicity. Finally, patients with Hallervorden-Spatz syndrome, an autosomal recessive, progressive neurodegenerative disorder, have mutations in a novel pantothenate kinase gene (PANK2). The cardinal feature of this extrapyramidal disease is pathologic iron accumulation in the globus pallidus. The defect in PANK2 is predicted to cause the accumulation of cysteine, which binds iron and causes oxidative stress in the iron-rich globus pallidus.
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PMID:Rare causes of hereditary iron overload. 1238

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