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)

The hypothesis that the accumulation of uroporphyrin, characteristic of uroporphyria, arises at least in part from oxidation of uroporphyrinogen and the molecular basis for the potentiation of the disorder by iron have been investigated. The iron chelates of ethylenediaminetetraacetic acid (EDTA) and nitrilotriacetic acid were very active at promoting the hydrogen peroxide-dependent oxidation of porphyrinogens, and a similar role of iron was found for the NADPH-dependent oxidation of porphyrinogens by liver microsomes in vitro. In contrast, neither the iron chelate of desferrioxamine (DES) nor ferritin iron possessed prooxidant activity, but the latter could be mobilized in an active form by incubation with EDTA. Iron was also found to promote further modification of the porphyrin pigment, leading to marked loss of its Soret absorbance. This latter effect, which could also be inhibited by DES, suggested further oxidative conversion of the accumulating uroporphyrin, but further work is necessary to establish the relevance of this (or similar) reaction to the inhibitor of uroporphyrinogen decarboxylase which has recently been reported. These results suggest a possible mechanism for the exacerbation of uroporphyria by excess iron and also for its marked improvement when the iron stores are diminished, for example, by DES treatment.
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PMID:Role of iron in the hydrogen peroxide-dependent oxidation of hexahydroporphyrins (porphyrinogens): a possible mechanism for the exacerbation by iron of hepatic uroporphyria. 312 28

NADPH- and iron-dependent lipid peroxidation of rat heart and liver microsomes was measured in the presence and absence of adriamycin. Lipid peroxidation was enhanced by adriamycin when incubated in air and was increased as the pO2 was lowered, to a maximum of 3-4 times the aerobic level at a pO2 of approx. 4 mm Hg. Fe-ADP, Fe-ATP and ferritin were able to catalyse adriamycin-dependent peroxidation of microsomes under low pO2. Superoxide dismutase and catalase had minimal effect. These results indicate that adriamycin-dependent lipid peroxidation is favoured by the low O2 concentration that exist in active muscle cells and suggest that ferritin could provide the iron catalyst for the reaction.
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PMID:Adriamycin-dependent peroxidation of rat liver and heart microsomes catalysed by iron chelates and ferritin. Maximum peroxidation at low oxygen partial pressures. 339 66

In a comparative screening study of chelators intended for clinical use eleven iron chelators have been tested for their ability to mobilize (59Fe) iron from 59Fe-labelled ferritin and from hepatocytes of rats labelled with 59Fe-transferrin. The toxic effects of the chelators were also studied using microsomal lipid peroxidation induced by Fe3+/ADP and NADPH. From these tests it was shown that 1,2-dimethyl 3-hydroxypyrid-4-one (L1) and mimosine were the most effective iron chelators in iron mobilization and did not catalyse lipid peroxidation. In conclusion it can be stated that besides to investigate the iron binding capacity of new chelators also their ability to catalyse lipid peroxidation has to be ruled out.
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PMID:Free radical and cytotoxic effects of chelators and their iron complexes in the hepatocyte. 350 52

Nonheme iron is synergistic with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in producing hepatotoxicity in mice. Fe2+ rather than Fe3+ is the probable toxin and we speculated that TCDD, an inducer of microsomal electron transport, might favour reduction of iron. We have defined a system which will release Fe2+ from ferritin (Fe3+) under anaerobic conditions and in the presence of added flavin mononucleotide (FMN). The rate of reduction iron was proportional (a) to microsomal protein from 0.5 to greater than 3 mg/mL, (b) to the activity of NADPH-cytochrome c reductase over 0.1 U/mL, (c) to ferritin at concentrations exceeding iron concentrations greater than 200 mumol/L, and (d) to the concentration of FMN when it was less than 125 mumol/L. The system was approximately twice as active with NADPH as with NADH as electron donor. The linear phase of iron release did not commence immediately, but followed a delay (+/- 0.5 min) after adding FMN to an anaerobic mixture containing microsomes, ferritin, an NADPH-generating system, and an oxygen-scavenging system. When microsomes from untreated, phenobarbital-treated (3 days), or TCDD-treated (1 or 3 weeks) rats were compared, iron release correlated most closely with the cytochrome P-450 concentration. However, when the microsomal proteins were solubilized and the NADPH-cytochrome c reductase and cytochrome P-450 activities were separated, reduction of ferritin iron was shown to be a function only of the reductase fraction, except that the delay in initiating release of Fe2+ was increased with purified reductase and decreased when a monooxygenase system was reconstituted with cytochrome (phenobarbital or TCDD induced) and lipid.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Release of ferrous iron from ferritin by liver microsomes: a possible role in the toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin. 644 9

The cardiotoxicity of doxorubicin (DOX) and other quinone-containing antitumor anthracyclines has been tentatively attributed to the formation of drug semiquinones which generate superoxide anion and reduce ferritin-bound Fe(III), favoring the release of Fe(II) and its subsequent involvement in free radical reactions. In the present study NADPH- and DOX-supplemented cytosolic fractions from human myocardial biopsies are shown to support a two-step reaction favoring an alternative mechanism of Fe(II) mobilization. The first step is an enzymatic two-electron reduction of the C-13 carbonyl group in the side chain of DOX, yielding a secondary alcohol metabolite which is called doxorubicinol (3.9 +/- 0.4 nmoles/mg protein per 4 h, mean +/- SEM). The second step is a nonenzymatic and superoxide anion-independent redox coupling of a large fraction of doxorubicinol (3.2 +/- 0.4 nmol/mg protein per 4 h) with Fe(III)-binding proteins distinct from ferritin, regenerating stoichiometric amounts of DOX, and mobilizing a twofold excess of Fe(II) ions (6.1 +/- 0.7 nmol/mg protein per 4 h). The formation of secondary alcohol metabolites decreases significantly (Pi < 0.01) when DOX is replaced by less cardiotoxic anthracyclines such as daunorubicin, 4'-epi DOX, and 4-demethoxy daunorubicin (2.1 +/- 0.1, 1.2 +/- 0.2, and 0.6 +/- 0.2 nmol/mg protein per 4 h, respectively). Therefore, daunorubicin, 4'-epi DOX, and 4-demethoxy daunorubicin are significantly (P < 0.01) less effective than DOX in mobilizing Fe(II) (3.5 +/- 0.1, 1.8 +/- 0.2, and 0.9 +/- 0.3 nmol/mg protein per 4 h, respectively). These results highlight the formation of secondary alcohol metabolites and the availability of nonferritin sources of Fe(III) as novel and critical determinants of Fe(II) delocalization and cardiac damage by structurally distinct anthracyclines, thus providing alternative routes to the design of cardioprotectants for anthracycline-treated patients.
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PMID:Secondary alcohol metabolites mediate iron delocalization in cytosolic fractions of myocardial biopsies exposed to anticancer anthracyclines. Novel linkage between anthracycline metabolism and iron-induced cardiotoxicity. 770 66

Chromium(VI) reduction was studied in a system composed of reduced nicotinamide adenine dinucleotide phosphate-cytochrome P450 oxidoreductase (NADPH-P450 reductase) and different iron chelators and iron sources. In an aerobic phosphate buffer containing iron(II), chromium(VI) was not reduced by the Fe2+ probably because of spontaneous autoxidation of Fe2+, but freshly made Fe2+, added directly to a CrVI-containing buffer, reduced CrVI. Under anaerobic conditions, iron(II) reduced chromium(VI) stoichiometrically. A systemic containing ethylenediaminetetraacetic acid (EDTA)-Fe3+, NADPH-P450 reductase and NADPH effectively reduced chromium(VI) anaerobically. Under aerobic conditions this reaction was inhibited by about 45%. Adenosine diphosphate (ADP)-Fe3+, which is a poor acceptor of electrons from NADPH-P450 reductase, reduced chromium(VI) only marginally, Mannitol slightly increased the aerobic CrVI reduction. Addition of superoxide dismutase and catalase, which both regenerate some O2, led to inhibition of CrVI reduction. Ferritin, NADPH-P450 reductase and the iron chelators, EDTA and citrate, reduced CrVI, indicating mobilization of Fe2+ from ferritin. Low levels of EDTA (55 mumol l-1) and citrate (100 mumol l-1) in contrast to high levels (5 mmol l-1) did not increase CrVI reduction in microsomes. Using 4-(2-hydroxyethyl)-1-piperazineethane sulfonic acid buffer instead of phosphate buffer, the CrVI-reducing activity was increased.
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PMID:The role of iron chelators and oxygen in the reduced nicotinamide adenine dinucleotide phosphate-cytochrome P450 oxidoreductase-dependent chromium(VI) reduction. 774 Dec 58

Glucose-6-phosphatase (G6Pase) is a microsomal enzyme which is very sensitive to inactivation by lipid peroxidation. Experiments were carried out to evaluate whether ferritin, which is the major storage form of iron within cells, could catalyze inactivation of G6Pase and to determine the mechanism responsible for this effect of ferritin. Incubation of microsomes with NADPH in the absence of ferritin led to decreased activity of G6Pase. Ferritin stimulated this inactivation of G6Pase in a time- and concentration-dependent manner. Ferritin did not stimulate G6Pase inactivation when NADH replaced NADPH as the microsomal reductant. Superoxide dismutase but not catalase or DMSO prevented the ferritin-stimulated inactivation of G6Pase suggesting a role for superoxide, but not H2O2 or hydroxyl radical, in the overall mechanism. Trolox, at concentrations which prevent lipid peroxidation, also prevented the ferritin-catalyzed inactivation of G6Pase. Inhibition of G6Pase by ferritin was further enhanced in the presence of ATP but was inhibited in the presence of EDTA or desferrioxamine; ferric-ATP stimulates, whereas ferric-EDTA inhibits microsomal lipid peroxidation. The redox cycling agent paraquat increased the ability of ferritin to inactivate G6Pase by a reaction prevented by superoxide dismutase, trolox, EDTA, and desferrioxamine, but not by catalase or DMSO. Ferritin stimulated microsomal light emission, a reaction reflecting lipid peroxidation, with time and concentration dependence, and sensitivity to scavengers (trolox, superoxide dismutase), iron chelators and paraquat, identical to the inactivation of G6Pase. These results indicate that one possible toxicological consequence of ferritin-catalyzed lipid peroxidation is inhibition of microsomal enzymes such as G6Pase.
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PMID:Ferritin-dependent inactivation of microsomal glucose-6-phosphatase. 818 31

Iron mobilized from ferritin has been shown to catalyze production of potent reactive oxygen intermediates. Experiments were carried out to evaluate the ability of ferritin to catalyze nuclear generation of hydroxyl radical in the presence of either NADPH or NADH. In the absence of redox cycling agents, ferritin did not catalyze nuclear oxidation of hydroxyl radical scavenging agents (2-keto-4-thiomethylbutyric acid, dimethylsulfoxide, ethanol) even if EDTA was added to chelate any released iron. The addition of menadione or paraquat resulted in a ferritin-dependent oxidation of chemical scavengers; menadione promoted the catalysis by ferritin with either NADPH or NADH, whereas paraquat was much more reactive with NADPH as the nuclear reductant. The presence of an externally added iron chelator was required for elevated rates of scavenger oxidation, with EDTA and DTPA being more reactive than ATP or citrate and desferrioxamine being inhibitory. The ferritin-catalyzed hydroxyl radical scavenger oxidation was sensitive to superoxide dismutase, catalase, and competitive scavengers. In the absence or presence of ferritin, rates of NADPH- or NADH-dependent H2O2 production were low; menadione increased H2O2 production with both NADPH and NADH, whereas paraquat was mostly effective with NADPH. Depending on the nature of the added chelating agent (e.g., EDTA, ATP) and the reductant, rates of nuclear production of .OH in the presence of redox cycling agent plus ferritin were 10 to 70% as high as rates found with redox cycling agent plus ferric-chelate (e.g., ferric-EDTA, ferric-ATP). Since reactive oxygen intermediates such as the hydroxyl radical can alter the structural integrity of the nucleus and interact with DNA, the ability of ferritin to promote nuclear generation of hydroxyl radical may play a role in the toxicity associated with iron as well as redox cycling agents.
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PMID:Ferritin stimulation of hydroxyl radical production by rat liver nuclei. 831 76

The ability of ferritin to catalyze rat liver microsomal chemiluminescence was determined in the absence and presence of the redox cycling agent paraquat, and with either NADPH or NADH as reductant. Microsomal chemiluminescence was used as a index of lipid peroxidation. In the absence of added ferritin, NADPH-dependent microsomal light emission was 4-fold greater than the NADH-dependent reaction, and was not sensitive to superoxide dismutase, catalase or DMSO. Ferritin stimulated NADPH-, but not NADH-dependent chemiluminescence in a time- and concentration-dependent manner. The stimulation by ferritin was completely sensitive to superoxide dismutase, but not to catalase or DMSO, suggesting the requirement for superoxide to mobilize iron from ferritin. An iron ligand was not required for the stimulation by ferritin; the addition of certain ligands such as EDTA, DETAPAC or desferrioxamine resulted in inhibition of the stimulation by ferritin. Paraquat potentiated the effect of ferritin on microsomal chemiluminescence with NADPH as cofactor and was weakly stimulatory with NADH. The potentiation by paraquat plus ferritin was prevented by superoxide dismutase and was further elevated by ligands such as ATP. Chemiluminescence proved to be a more sensitive parameter than production of thiobarbituric acid-reactive components to evaluate the stimulation of oxygen radical production by iron released from ferritin, in the absence or in the presence of paraquat.
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PMID:Stimulation of microsomal chemiluminescence by ferritin. 849 75

Microsomes can remove iron from ferritin by a superoxide-dependent reaction. The released iron can then catalyse formation of a variety of reactive oxygen species. Experiments were carried out to evaluate the role of cytochrome P-450 in the release of iron from ferritin, and whether induction of certain P-450 isoforms alters ferritin-dependent reactive oxygen radical production. Rats were treated with phenobarbital, 3-methylcholanthrene, 4-methylpyrazole, or saline to produce microsomes with varying P-450 content and composition. Oxidation of 2,7'-dichlorofluorescein diacetate to a fluorescent product and chemiluminescence were used as indices of production of reactive oxygen species. The extreme sensitivity of these reactions to trolox, a potent chain-breaking oxidant, indicates the involvement of lipid peroxidation products in these reactions. In the absence of ferritin, formation of reactive oxygen species was higher in microsomes from the treated rats compared to saline controls when results were expressed on a per mg protein basis but not per nmol P-450, suggesting that the increased content of total P-450 (2-fold increases) rather than the population of isoforms was responsible for the increase. Superoxide dismutase had no effect on the non-ferritin catalyzed reactions. Ferritin increased production of reactive oxygen species with all the microsomal preparations; the increase by ferritin was completely prevented by superoxide dismutase. The net increase by ferritin was higher in microsomes from the treated rats compared to saline controls, but this, again, largely reflected the increased content, rather than the type of isoforms of P-450 present. Similar results were obtained with either NADPH or NADH as microsomal reductants, although NADPH was much more effective in supporting ferritin-dependent reactive oxygen formation. In microsomes from phenobarbital-treated rats, anti-CYP2B1/B2 IgG completely prevented the NADPH- and NADH-dependent increases in reactive oxygen formation produced by ferritin. Anti-cytochrome b5 IgG produced partial inhibition of the ferritin-stimulation. These results indicate that P-450, and to a lesser extent, cytochrome b5, play a role in the ferritin-dependent increase in formation of reactive oxygen species with either NADPH or NADH, most likely reflecting the requirement of these enzymes for microsomal production of superoxide anion.
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PMID:Role of cytochrome P-450 in the stimulation of microsomal production of reactive oxygen species by ferritin. 860 Sep 80


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