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)

Ionic iron at physiological pH hydrolyzes into insoluble aggregates, which disperse on slight acidification. Uncontrolled ionic iron promotes autoxidation, which crosslinks biomolecules and produces destructive activated oxygen. Defenses against autoxidative crosslinking include: 1. ferritin, the macromolecular scavenger of iron; 2. metabolic turnover, which prevents irreversible crosslinking through early catabolic degradation and replacement; and 3. enzymatic deactivation of oxygen. I am proposing that the anticrosslinking defenses are defeated by transient actions of metabolic perturbations, toxicants, oxidants and "foreign bodies", which cause oxidative crosslinking of proteins and lipids into irreversible tissue imprint: indigestible bodies containing porous limited-access spaces (LASs). The pores exclude the macromolecular ferritin and the digestive and antiautoxidation enzymes but admit ionic iron which, sheltered from ferritin, accumulates into decontrolled-iron pathogen (DIP). DIP utilizes the energy of ambient pH fluctuations to erupt from the LAS, swamp the available ferritin, poison the surroundings, catalyze autoxidation and crosslink cell components into additional LAS carriers. With time and sufficient promotion by pH fluctuations or metal-complexing agents, DIP and LAS expand. DIP injures through heavy-metal inhibition of life processes and catalysis of autoxidation. Typically, carcinogenic initiators are protein denaturants, cell poisons, "foreign bodies" and autoxidation catalysts. These are DIP-initiating properties, and DIP may be a preneoplastic stage of carcinogenesis. A DIP-model interpretation is given for the growth of asbestos bodies. DIP is an inorganic parasite. It may envelope and attack phagocytized particles.
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PMID:Biological autoxidation. I. Decontrolled iron: an ultimate carcinogen and toxicant: an hypothesis. 3 81

In the first part of this study we have shown how the serum levels of four selected tumour markers, namely tissue polypeptide antigen (TPA), carcino-embryonic antigen (CEA), hyaluronic acid (HA) and ferritin, display patterns characteristic of mesothelioma (M) or bronchogenic carcinoma (BC) in asbestos-exposed workers, and we hypothesize that the differences in marker patterns correspond to differences in carcinogenesis mechanisms. In a preliminary study, we found these specific marker patterns in 5/19 exposed workers of whom only one demonstrated any radiological signs of disease. Thus these specific marker patterns may be early events, occurring long (possibly years) before the classical radiological signs of exposure to asbestos. Accordingly they afford an optimal opportunity for prevention which should be adapted to the carcinogenesis mechanism as it is revealed by the marker pattern; it is aimed at antagonizing free radical carcinogenesis in all persons with TPA levels in excess of 100 U/l or Ferritin in excess of 400 ng/ml, and at inhibiting chemical carcinogenesis in those having elevated CEA levels (over 3 ng/ml). The mechanisms involved in these inhibitory processes are described and discussed, as well as the practical implementations that proceed from them. A prevention trial is now being started among 300 active and retired workers of an asbestos-cement works in northern France; the design of the study is presented. This prevention programme should be maintained over many years and holds a strong potential for reducing the untoward effects of exposure to asbestos.
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PMID:Biomarker assessments in asbestos-exposed workers as indicators for selective prevention of mesothelioma or bronchogenic carcinoma: rationale and practical implementations. 146 74

In this paper we describe an immunological method for the visualization of (+/-)7 beta, 8 alpha-dihydroxy-9 alpha, 10 alpha-epoxy-7,8,9,10- tetrahydrobenzo[a]pyrene (BPDE-I) adducts in DNA by electron microscopy (EM). The immunoglobulin fraction of rabbit antiserum specific for BPDE-I adducts was digested with papain, the Fab fragments were purified by affinity chromatography on protein A-Sepharose and cross-linked to ferritin. The reactivity of the Fab fragments coupled to ferritin was determined by using anti-ferritin antibodies to precipitate the complexes formed between ferritin-labeled Fab fragments and BPDE-I-modified DNA that had been uniformly labeled with [14C]thymidine. DNA from cells treated with BPDE-I in culture was reacted with ferritin-labeled Fab fragments, separated from unreacted Fab using a Sepharose CL-4B column, and examined by EM. An aliquot of the same DNA was used to determine the level of BPDE-I adduction using an enzyme-linked immunosorbent assay (ELISA). Close agreement was found between the levels of adduction determined by ELISA and EM. A good correlation was also found between the level of adduction measured by EM and scintillation spectrometry when DNA was modified with [3H]BPDE-I in vitro. The EM method presents the following advantages: (i) it avoids cross-linking of separate adducts by the same IgG molecule; and (ii) it requires only one antigen-antibody reaction and a single purification step, allowing analysis of very small amounts of DNA.
Carcinogenesis 1989 Jan
PMID:Ferritin-labeled rabbit Fab fragments for the single-step detection of benzo[a]pyrene-diol-epoxide adducts in DNA by electron microscopy. 249 69

A cell line, HuH-28, was established in vitro from a patient with cholangiocellular carcinoma (CCC). This cell line has grown slowly, revealing a doubling time of approximately 80 h, and the serial passages were carried out 20 times within 10 months. Light microscopy revealed spindle and polygonal morphology of the cells. Chromosome number of the cells were distributed near the hypotriploid region at passages 3 and 14. HuH-28 cells were not transplantable into nude mice, but secreted some tumor markers including alkaline phosphatase (ALP), gamma glutamyltranspeptidase (GGT), beta 2-microglobulin (BMG), ferritin, elastase-1, and tissue polypeptide antigen (TPA). This HuH-28 cell line will represent a good model for the investigation of carcinogenesis, histogenes, and diagnosis of CCC.
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PMID:Establishment and characterization of a cell line from a human cholangiocellular carcinoma. 285 88

A cell line, HuH-28 was established in vitro from a patient with cholangiocellular carcinoma (CCC). This cell line has been in continuous culture over 10 month period with slow growth potential. HuH-28 was composed of spindle-shaped cells as major population besides a small percentage of polygonal-shaped cells. Chromosome number of the cells were distributed near the hypotriploid region on the 3rd passage. HuH-28 cells were not transplantable into nude mice, but secreted some tumor markers including alkaline phosphatase (ALP), gamma glutamyltranspeptidase (GGT), beta 2-microglobulin (BMG), ferritin, elastase-1 and tissue polypeptide antigen (TPA). This HuH-28 cell line will represent a good model for the investigation of carcinogenesis, histogenesis+ and diagnosis of CCC.
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PMID:[Establishment and characterization of a human cholangiocellular carcinoma cell line]. 285 43

Highly specific antibodies bound to carcinogen adducts in DNA modified with (+/-)7 beta,8 alpha-dihydroxy-9 alpha, 10 alpha-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE I) were quantitated by electron microscopy (EM) visualization and these observations were compared with quantitation of adducts by enzyme-linked immunosorbent assay (ELISA). The antiserum, elicited in rabbits following inoculation with BPDE I-modified DNA, has been found to be highly specific in its recognition of BPDE I-deoxyguanosine moieties. Parallel DNA samples prepared for analysis by ELISA and EM quantitation were randomized, encoded, and analyzed to determine extents of carcinogen modification in double-blind studies. After levels of modification were determined by immunoassays, DNA samples were prepared for EM analysis by incubation with amounts of anti-BPdG-DNA serum in excess of that necessary for complete binding of antibody to antigenic sites. At equilibrium, samples were enzymatically digested with papain in order to cleave anti-BPdG-DNA IgG molecules into Fab fragments in situ. Following column exclusion chromatography, BPdG-DNA-Fab complexes were incubated with ferritin-labeled Fab' fragments of goat [anti-rabbit F(ab')2] IgG in amounts in excess of those necessary for complete binding. When DNA samples were modified to between 0 and 40 fmol adduct/micrograms DNA, excellent agreement was obtained between ELISA quantitation and visualization by EM of antibodies bound to adducts.
Carcinogenesis 1985 Feb
PMID:Quantitation by electron microscopy of the binding of highly specific antibodies to benzo[a]pyrene-DNA adducts. 391 1

Serum levels of retinol, beta-carotene, ascorbic acid, alpha-tocopherol, selenium, ferritin, copper, and zinc were assayed for approximately 600 adults aged 35 to 64 with pre-cancerous gastric lesions in an area of China with one of the world's highest rates of stomach cancer. Previous studies have shown that the cancers generally are preceded by chronic atropic gastritis (CAG), intestinal metaplasia (IM) and dysplasia. Concentrations of beta-carotene and ascorbic acid were significantly lower among individuals with IM than among those whose most severe lesion was superficial gastritis or CAG. The associations with IM for these nutrients were strong and independent. In combination, the odds of CAG progressing to IM were only 1/6 as high among those with upper tertile levels of beta-carotene and ascorbic acid as among those with lower tertile levels of both nutrients. The serum levels of beta-carotene and ascorbic acid were similar for individuals having IM with or without accompanying dysplasia. Risk of IM was also somewhat increased among those with low serum ferritin, but no significant effects were observed in multivariate analyses for the other nutrients assayed. The findings point to a major influence of specific nutrient deficits in the mechanisms of gastric carcinogenesis in this high-risk area.
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PMID:Serum micronutrients in relation to pre-cancerous gastric lesions. 831 41

Redox cycling is a characteristic of transition metals such as iron. Iron is hypothesized to have been actively involved in the birth of primitive life on earth through the generation of reducing equivalents in the presence of UV light. Iron is an essential metal in mammals for oxygen transport by hemoglobin and for the function of many enzymes including catalase and cytochromes. However, the "free" or "catalytic" form of iron mediates the production of reactive oxygen species via the Fenton reaction and induces oxidative stress. Serum "free" iron is observed in rare situations such as in severe hemochromatosis in which serum transferrin is saturated. However, it is known that superoxide can release "free" iron from ferritin and hemosiderin in the cell. "Free" iron is quite cytotoxic as well as mutagenic and carcinogenic. Iron compounds were first reported to induce sarcomas in rats by Richmond in 1959. Thereafter, several iron-induced carcinogenesis models were established, including the ferric nitrilotriacetate model by Okada and colleagues. Iron may have a role in the carcinogenic process of other transition metals such as copper and nickel, or other kinds of carcinogens such as nitrosamine and even virus-induced carcinogenesis. In humans, genetic hemochromatosis and asbestosis are two major diseases associated with iron-induced carcinogenesis. There is an increasing number of reports of an association between increased body iron stores and increased risk of cancer. Iron-induced oxidative stress results in two possible consequences: (1) redox regulation failure that leads to lipid peroxidation and oxidative DNA and protein damage; (2) redox regulation that activates a variety of reducing and oxystress-protective mechanisms via signal transduction. Both consequences appear to play a role in iron-induced carcinogenesis.
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PMID:Iron-induced carcinogenesis: the role of redox regulation. 890 96

Treatment of rats with the cancer chemopreventive agent 1,2-dithiole-3-thione (D3T) resulted in a significant increase in hepatic heme oxygenase (HO) activity, which corresponded to increased protein levels of HO-1. Upon further analysis of proteins related to heme metabolism, the level of ferritin, the major iron storage protein in liver, was also found to be elevated. Diminished levels of intracellular free iron were monitored by EPR spectroscopy at times after administration of D3T that suggested that increased ferritin content sequesters intracellular iron. The increased levels of protein were associated with increased levels of steady-state RNA of HO-1 and the light (FL) and heavy (FH) subunits of ferritin. A direct relationship between enhanced rates of gene transcription and elevated levels of HO-1 and ferritin RNA was found. The inductions of FL and FH, but not HO-1, were sensitive to cycloheximide, suggesting that in vivo these genes are regulated by distinct D3T-responsive transcriptional mechanisms. The known protective roles for induced HO-1 and ferritin in cellular stress have been suggested to include increased levels of the antioxidant bilirubin and enhanced sequestration of intracellular iron into ferritin, which can effectively reduce iron-mediated reactive oxygen generation. Thus, protective actions of D3T against the cytotoxic and carcinogenic consequences of chemicals that exert electrophilic or oxidative stresses may be mediated, in part, by the induction of HO-1, FL and FH.
Carcinogenesis 1996 Nov
PMID:Induction of hepatic heme oxygenase-1 and ferritin in rats by cancer chemopreventive dithiolethiones. 896 40

Dithiolethiones inhibit tumorigenicity elicited by many structurally diverse carcinogens in numerous target tissues. These protective actions are associated with the induction of several carcinogen detoxification enzymes, some of which have only recently been discovered. In order to identify additional novel inducible detoxification response genes, a cDNA library was prepared from liver of rats treated with 1,2-dithiole-3-thione (D3T) and was screened by a differential hybridization method. Complementary DNA clones for several known D3T-inducible genes were isolated, such as epoxide hydrolase, aflatoxin B1-aldehyde reductase, quinone reductase and multiple subunits of glutathione S-transferase. Clones representing genes not previously associated with detoxification were isolated, including those for ferritin heavy and light subunits, ribosomal proteins L18a and S16 and two novel genes, termed dithiolethione-inducible genes (or DIG-1 and DIG-2). Levels of mRNA recognized by each clone were increased from 2- to 31-fold, with maximum induction between 6 and 30 h after treatment with D3T. Except for epoxide hydrolase, the kinetics of induction of each mRNA was coordinate with increased rates of gene transcription. However, based on the time of response to D3T, at least two sets of responsive genes were identified. One set of genes, including glutathione S-transferase Yp, aflatoxin B1-aldehyde reductase, quinone reductase and DIG-1, had low constitutive and highly inducible expression (approximately 20-fold) and the other, including glutathione S-transferase Ya and Yb, epoxide hydrolase, ferritin heavy and light subunits, ribosomal proteins L18a and S16 and DIG-2, had relatively high constitutive and modestly inducible expression (approximately 5-fold). The simplest explanation for this differential expression of D3T-inducible genes is that multiple regulatory mechanisms govern their response. The transcriptional activation of ferritin, ribosomal protein, DIG-1 and DIG-2 genes in conjunction with those of carcinogen detoxification enzymes suggests that they participate in the pleiotropic cellular defense response to dithiolethiones that inhibits chemically produced tumorigenesis.
Carcinogenesis 1996 Nov
PMID:Isolation of cDNAs representing dithiolethione-responsive genes. 896 41


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