Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P02794 (ferritin)
 17,525 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lipid peroxide formation was initiated by the addition of either ADP-complexed Fe3+ or cumene hydroperoxide to a suspension of isolated hepatocytes. The reaction was monitored by malonaldehyde measurements. Upon the addition of iron, malonaldehyde production in the cells started immediately but ceased within 30-60 min, and the response was dose-related with iron concentrations ranging from 19 to 187 muM. Malonaldehyde formation was associated with increased oxygen uptake and conjugated diene production. The addition in vitro of N,N,N',N'-tetramethyl-p-phenylenediamine, menadione or p-benzoquinone inhibited the iron-induced malonaldehyde production. It was also possible to demonstrate an apparent disappearance of malonaldehyde from fresh cells by addition of adequate amounts of N,N,N',N'-tetramethyl-p-phenylenediamine (100 muM). The attenuation of the iron-induced malonaldehyde production was found to be correlated with an increased binding of iron to an intracellular ferritin fraction. Further, malonaldehyde formation was also associated with a conversion of reduced glutathione to the oxidized form which, in turn, revealed a faster permeation out of the cells into the surrounding medium of the oxidized than of the reduced thiol. So, concomitant with the redox alterations, there was also an overall loss of glutathione from the cells. Cumene hydroperoxide-induced malonaldehyde production could be initiated by the addition of this peroxide in concentrations ranging from 150 muM to the liver cell incubate. With concentrations below 150 muM, a lag phase was present which seemed to be glutathione-dependent. It is concluded that iron enters the cell, then is probably reduced inside the cell by NADPH via the NADPH-cytochrome P-450 reductase, and in the reduced state initiates lipid peroxidation. The reaction is inhibited by intracellular mechanisms, the glutathione redox system being of principal importance, and possibly terminated by the iron-apoferritin complex formation.
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PMID:Further studies on lipid-peroxide formation in isolated hepatocytes. 0 Dec 55

Bovine heart microsomes have been found to contain a non-heme iron protein which serves as an electron acceptor for NADPH-cytochrome P-450 reductase and therefore stimulates NADPH oxidation. This protein, tentatively referred to as Microsomal Iron Protein (MIP), has been extracted with Triton N-101 and purified by ion exchange chromatography on CM- and DEAE-celluloses and gel filtration on Sepharose 6B. MIP is an Mr = 66,000 monomer with 17 atoms of Fe(III)/molecule. Incubation with dithionite removes iron from MIP and abolishes the stimulation of NADPH oxidation, but subsequent incubation with nitrilotriacetic-Fe(III) reincorporates iron and restores the stimulation of NADPH oxidation. Oxygen is the ultimate electron acceptor. In the presence of oxygen, the enzymatic reduction of MIP Fe(III) is followed by the reoxidation of Fe(II) at the expense of oxygen, generating superoxide anion and regenerating MIP Fe(III) for the continuous oxidation of NADPH. In the absence of oxygen, electron transfer from the reductase to MIP Fe(III) causes the release of Fe(II), which limits the ability of MIP to serve as an electron acceptor and stimulate NADPH oxidation. The--NH2-terminal of MIP has been sequenced, and no homology has been found with the sequence of other iron storage or transport proteins such as ferritin or transferrin.
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PMID:Bovine heart microsomes contain an Mr = 66,000 non-heme iron protein which stimulates NADPH oxidation. 193 64

Rat heart microsomes were found to contain nonheme iron and two lines of evidence suggested that this iron was involved in NADPH oxidation. As first evidence, pretreatment of rats with iron gluconate increased microsomal iron content and NADPH oxidation. As second evidence, treatment of microsomes with nonionic detergent Triton N-101 decreased membrane iron content and NADPH oxidation. Triton N-101-solubilized nonheme iron was nondialyzable and ammonium sulfate-precipitable, indicative of association with protein(s). This protein-bound iron per se did not oxidize NADPH but its addition to detergent-treated microsomes restored very high rates of NADPH oxidation, that were abolished by inhibiting NADPH-cytochrome P450 reductase with p-hydroxymercuribenzoate. Since heart microsomes did not contain cytochrome P450, these results suggested that stimulation of NADPH oxidation was mediated by direct electron transfer from reductase to iron. Purified rat heart ferritin and hemosiderin did not stimulate NADPH oxidation and the stimulation observed with detergent-solubilized microsomal iron was much higher than that observed with EDTA-Fe3+, a very effective electron acceptor for the reductase. This suggested that (i) microsomal iron was different from other intracellular iron-storage proteins, and (ii) microsomal iron was unusually permissive to one-electron transfer from reductase.
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PMID:Microsomal iron-dependent NADPH oxidation: evidence for the involvement of membrane-bound nonheme iron in NADPH oxidation by rat heart microsomes. 217 78

The use of the extremely effective anthracycline antitumor drugs adriamycin and daunomycin is limited by a severe, dose-dependent cardiomyopathy. Anthracycline-induced toxicity has been proposed to involve iron-dependent oxidative damage to biological macromolecules yet little is known regarding the availability of physiologic iron. We now report that, in the presence of NADPH-cytochrome P-450 reductase, these drugs undergo redox cycling to generate superoxide which mediates a slow, reductive release of iron from ferritin, the major intracellular iron storage protein. Anaerobically, the semiquinone free radical forms of adriamycin and daunomycin catalyze a very rapid, extensive release of iron from ferritin. In contrast, diaziquone, an aziridinyl quinone antitumorigenic agent which is less cardiotoxic, is unable to release iron from ferritin. Thus, the present studies suggest that the cardiomyopathy observed with the anthracyclines, and perhaps their antineoplastic activity as well, may be related to their ability to delocalize tissue iron, thereby contributing to the formation of strong oxidants capable of damaging critical cellular constituents.
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PMID:Release of iron from ferritin by cardiotoxic anthracycline antibiotics. 301 16

NADPH-cytochrome P-450 reductase-catalyzed reduction of paraquat promoted the release of iron from ferritin. Aerobically, iron release was inhibited approximately 60% by superoxide dismutase, whereas xanthine oxidase-dependent iron release was inhibited nearly 100%. This suggests that both superoxide and the paraquat cation radical can catalyze the release of iron from ferritin. Accordingly, under anaerobic conditions, the paraquat radical mediated a very rapid, complete release of iron from ferritin. Similarly, the cation free radicals of the closely related chemicals, diquat and benzyl viologen, also promoted iron release. ESR studies demonstrated that electron transfer from the paraquat cation radical to ferritin accounts for the reductive release of iron. The ferritin structure was not altered by exposure to the paraquat radical and also retained its ability to re-incorporate iron. These studies indicate that release of iron from ferritin may be a common feature contributing to free radical-mediated toxicities.
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PMID:Reductive release of iron from ferritin by cation free radicals of paraquat and other bipyridyls. 302 22

We have investigated the degradation in rat liver of two typical endoplasmic reticulum (ER) membrane proteins, phenobarbital (PB)-inducible cytochrome P-450 (P-450[PB]) and NADPH-cytochrome P-450 reductase (FP2). Autolysosomes, almost completely free from contamination by the other organelles such as ER, were prepared from leupeptin-treated rat livers according to the method of Furuno et al. (Furuno, K., T. Ishikawa, and K. Kato, 1982, J. Biochem., 91:1943-1950). Quantitative immunoblot analysis showed that these two proteins were found in large amounts in the autolysosomes regardless of PB treatment. The specific content of P-450 (PB) in the autolysosomes changed along with that in the microsomes during and after PB treatment, whereas hardly any P-450(PB) was detected in the cytosol fraction throughout the experiment. We also found a marked increase in the autolysosomal proteins 3 d after cessation of PB treatment when microsomal proteins are degraded most rapidly. Ferritin immunoelectron microscopy revealed directly that when the limiting membranes of the premature autolysosomes were partially broken the smooth vesicles segregated within the autolysosomes were heavily stained with ferritin anti-P-450(PB) conjugates. Thus, for the first time, we could present convincing evidence that P-450(PB) and FP2 are segregated to be degraded in the autolysosomes.
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PMID:Cytochrome P-450 and NADPH-cytochrome P-450 reductase are degraded in the autolysosomes in rat liver. 310 62

A lipid peroxidation system consisting of phospholipid liposomes, paraquat, ADP, and NADPH-cytochrome P450 reductase was constituted using ferritin as the sole source of iron. Lipid peroxidation was completely inhibited by superoxide dismutase, essentially not affected by mannitol, but markedly stimulated by catalase. Similar effects of these scavenging agents were observed in incubations void of ADP. These data suggest that O2-, produced by the redox cycling of paraquat, can release iron from ferritin and thereby promote lipid peroxidation. The effects of catalase and mannitol suggest that the initiation of peroxidation, in either the presence or absence of ADP, is not significantly dependent upon the hydroxyl radical produced via an iron-catalyzed Haber-Weiss reaction.
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PMID:Paraquat and ferritin-dependent lipid peroxidation. 393 39

The incubation of lambda DNA in the reaction system of alloxan plus NADPH-cytochrome P450 reductase (fp2) in the presence of ferritin caused strand breaks after a lag time of about 5 min. Addition of ferritin to the reaction system at concentrations below 50 micrograms/ml caused the strand breaks of DNA in a concentration-dependent fashion. Catalase, scavengers of hydroxyl radicals (HO.) and iron-chelators almost completely inhibited the DNA strand breaks, but superoxide dismutase (SOD) did not, suggesting that the strand breaks are induced by the generation of HO. via the reaction of H2O2 and Fe(II), namely, the Fenton reaction. When the ferritin was incubated in the reaction system of alloxan plus fp2, the iron release from ferritin increased with incubation time depending on the amount of fp2. The addition of increasing concentrations of ferritin to the reaction system resulted in progressive increase in the iron release and a decrease in the electron spin resonance signal intensity of alloxan radical (HA.), the one electron reduced form of alloxan, suggesting that HA. generated in the reaction system is capable of releasing iron from ferritin. These results support the possibility that the iron released from ferritin may be involved in the diabetogenic action of alloxan.
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PMID:Effect of ferritin on lambda DNA strand breaks in the reaction system of alloxan plus NADPH-cytochrome P450 reductase: ferritin's role in diabetogenic action of alloxan. 774 95

Heme oxygenase (HO) proteins are members of the HSP30 family and consist of 2 isozymes identified to date, termed HO-1 and HO-2. Separate genes encode the isozymes and protein products which are immunochemically distinct, share less than 50% similarity at the amino acid sequence level. Each form, however, shows greater than 90% similarity among species, including human and the rat (reviewed in ref.). Furthermore, these isozymes function in a well-defined role to carry out oxidation of the heme molecule (Fe-protoporphyrin IX) in concert with NADPH-cytochrome P450 reductase. The oxidation of heme is isomer specific and results in the formation of bile pigments, carbon monoxide, and iron. The heme molecule constitutes the prosthetic moiety of hemoproteins, such as hemoglobin, myoglobin, catalase, soluble guanylate cyclase, cytochrome b5, cytochromes P450 and NO synthase. HO-1 also known as heat shock protein (HSP) 32 is encoded by a gene which is exquisitely stress-responsive and a host of stimuli that mediate oxidative stress cause induction of the protein both in vivo and in vitro. The HO-2 form shows a unique pattern of regulation from that of HO-1. HO-2 is a constitutive protein and its expression is not affected by the inducers of HO-1 tested to date; rather, the only known regulator of HO-2 yet identified is adrenal glucocorticoids. The two isozymes display vast differences in tissue distribution and under normal conditions HO-1 is present in the whole brain at the limit of immunodetection and is discreetly localized in select neuronal populations. HO-1 protein (approximately 32 kDa) and its approximately 1.8 kb transcript are increased, however, in response to stressful stimuli primarily in non-neuronal cell populations. The heme oxygenase system serves in both a catabolic and anabolic capacity in the cell. In the former capacity, it down-regulates cellular heme and hemoprotein levels. And, as such it inactivates the most effective catalyst for formation of free radicals, the heme molecule. In its anabolic role, as noted above, heme oxygenase produces bile pigments, carbon monoxide, and iron, all of which are biologically active: bile pigments function as antioxidants; the carbon monoxide generated by HO activity has been correlated with the generation of cGMP; and iron regulates expression of various genes, including that of HO-1 itself, as well as transferrin receptors, ferritin, and NO synthase. We used rabbit anti-rat HO-2 polyclonal antibody and HO-2 cDNA to localize HO-2 immunoreactive protein and the 1.3- and 1.9 kb homologous transcripts, respectively, in rodent brain as visualized by histochemical staining procedures. These protocols provide the first detailed description of methodologies successfully used to define the pattern of HO-2 expression at the transcriptional and translational levels in the adult rat brain and glucocorticoid-treated newborn rats. The procedures described herein have the virtue of being non-radioactive, as well as applicability to the systemic organs, such as the cardiovascular system and the male reproductive organs. Visualization of cellular HO-2 expression aids in assessment of potential sites of carbon monoxide, iron, and bilirubin production within the nervous system.
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PMID:Histochemical localization of heme oxygenase-2 protein and mRNA expression in rat brain. 938 81