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PubMed1986

Enhancement of hepatic gallium-67 uptake by asialo-transferrin.

A significant fraction of intravenously injected 67Ga localizes in the liver. The mechanism of 67Ga uptake by the liver is not clear. Hepatocyte membranes contain galactose-specific receptors which selectively remove asialo-glycoproteins from the circulation by way of endocytosis. In this investigation, we examined whether endocytic uptake of asialo-transferrin would involve 67Ga transport into hepatocytes. We demonstrated that asialo-transferrin bound 67Ga as effectively as apotransferrin. Human asialo-transferrin markedly enhanced 67Ga uptake by isolated, perfused rat livers. Human asialo-orosomucoid, but not orosomucoid competitively inhibited hepatic uptake of the 67Ga asialo-transferrin complex, indicating that hepatic 67Ga uptake in the presence of asialo-transferrin occurred by way of galactose-specific receptors. Our results point to a novel pathway for metal ion transport into hepatocytes by way of galactose receptor mediated endocytosis.

Animals↗
PubMed1987

The reaction of superoxide, formate radical, and hydrated electron with transferrin and its model compound, Fe(III)-ethylenediamine-N,N'-bis[2-(2-hydroxyphenyl)acetic acid] as studied by pulse radiolysis.

Transferrin and the transferrin model compound Fe(III)-EHPG (Fe(III)-ethylenediamine-N,N'-bis[2-(2-hydroxyphenyl)acetic acid] were found not to react with superoxide, as pulse radiolysis and kinetic spectroscopy revealed no transient species and no bleaching of the 465-nm absorption. However, transferrin was found to react with the formate radical, CO-.2, and the hydrated electron, e-aq, with second-order rate constants of 3.8 X 10(8) and 1.1 X 10(10) M-1 S-1, respectively. These reactions produced a transient species (lambda max = 420 nm) which subsequently decayed by a second-order process. However, no reduction of the Fe(III) in transferrin was detected. Fe(III)-EHPG was also found to react with CO-.2 and e-aq, k = 7.3 X 10(6) and 1.1 X 10(9) M-1 S-1, respectively. The reactions of CO-.2 and e-aq with Fe(III)-EHPG resulted in no transient species but rather in reduction of the iron. These results are consistent with the inability of transferrin and Fe(III)-EHPG to catalyze the Haber-Weiss reaction.

Chemical Phenomena↗
PubMed1988

High-performance liquid affinity chromatography: rapid immunoanalysis of transferrin in serum.

We describe a new method for quantitatively measuring substances of clinical interest by high-performance liquid affinity chromatography (HPLAC). As a model system we selected analysis for transferrin in human serum with immobilized antibodies in a high-performance liquid chromatographic system. SelectiSpher-10 Activated Tresyl columns (5 or 10 x 0.5 cm) were used for in situ coupling of polyclonal antibodies to transferrin. The amount of transferrin eluted was determined by integrating the eluted peak at 280 nm. The whole analytical procedure--including injection of sample, washing, elution, and analysis of data--takes only 7 min. We characterized the HPLAC system for analysis of transferrin in several ways: intra-assay CV approximately 3%; inter-assay CV 2-9%; linear response up to 1 mg/mL column volume; detection limit approximately 3 micrograms; analytical recovery 98% +/- 2%; purity of eluted sample greater than 95% (SDS-PAGE). The HPLAC method was compared with "rocket" immunoelectrophoresis, a commonly used method of analysis for transferrin, and there was excellent correlation between the two methods (r = 0.96, n = 60). Benefits of this HPLAC technique include high precision, rapid analysis, and simplified sample handling.

Chromatography, High Pressure Liquid↗
PubMed1988

The use of serum transferrin in the evaluation of protein-calorie malnutrition in cancer patients.

Forty-five patients with various malignancies of the gastrointestinal tract had their nutritional status assessed pre-operatively to determine the prevalence of malnutrition and to establish the correlation of malnutrition with post-operative outcome. Ten nutritional parameters were assessed. Based on these markers, we found a significant degree of malnutrition. Half of the study population developed some form of post-operative complication and nearly one quarter died. Of the ten nutritional markers studied, only serum transferrin had predictive value in determining post-operative outcome. The mean level of serum transferrin for patients with major complications was 162.0 mg/dl as compared with 221.2 mg/dl for those with none or minor complications. Patients with a serum transferrin level below the reference range of 200 mg/dl had most of the major life threatening complications and deaths. The other nutritional markers studied did not correlate well with post-operative outcome. We feel that serum transferrin is a useful nutritional marker to predict post-operative outcome and also to monitor the effect of nutritional support. However, based on a preliminary study, nutritional support may be required for periods longer than two weeks to show significant improvement in protein-calorie malnutrition. We will consider giving adequate support for a longer period on a further study using serum transferrin as a marker to determine its value in monitoring any reversal of malnutrition.

Female↗
PubMed1988

Characterization of proteins that associate with an unglycosylated form of the transferrin receptor in A431 cells.

A protein doublet (Mr = 135,000/130,000) was found to coprecipitate with an unglycosylated form of the transferrin receptor in tunicamycin-treated A431 cells. This doublet is not detected with either a monoclonal or polyclonal antibody to the transferrin receptor on Western blots indicating that these proteins do not interact directly with transferrin receptor antibody. Proteolytic digestion patterns of the individual proteins of the Mr = 135,000/130,000 doublet suggest that they are related to one another and are distinct from the transferrin receptor. Further characterization of these proteins indicates that they form a high molecular weight complex with the unglycosylated but not the glycosylated form of the transferrin receptor. Pulse-chase experiments demonstrate that the proteins post-translationally associate with the receptor.

Blotting, Western↗
PubMed1988

[The coefficient of saturation of iron in transferrin].

Theoretical iron fixation capacity of transferrin (FCT) can be calculated on its immunochemical titration: (FCT (mumol/l = transferrin (g/l) x 25). Today, its reckoning is more advisable to serum total iron binding capacity measurement. The authors studied the effects of this new proceeding upon usual values interval of transferrin saturation (i.e. serum iron/FCT ratio). The mean value and the distribution of transferrin saturation appear displaced with regard to those achieved by chemical measurement of serum total iron binding capacity. We discuss interpretation of transferrin saturation related to its methods of determination and its semiological interest.

Adolescent↗
PubMed1988

A high yield purification of the human transferrin receptor and properties of its major extracellular fragment.

Human transferrin receptor is a disulfide-linked homodimer of 90-kDa glycoprotein subunits, capable of binding two transferrins. We report a new high yield affinity purification protocol for transferrin receptor from placenta which produces 3-4 mg of highly purified protein. Trypsin cleaves the protein at arginine-121, producing a stable fragment that contains 95% of the extracytoplasmic sequence; similar fragments are produced by several other proteases. The tryptic fragment is a nondisulfide-linked dimer in solution and binds two transferrin molecules. The dimensions of both the dimer fragment and its complex with transferrin are estimated by gel filtration.

Algorithms↗
PubMed1987

Plasma lipoproteins and transferrin regulate the proliferation of a continuous T lymphocyte cell line.

Lipoproteins of hydrated densities less than 1.063 g/ml, very low density (VLDL) and low density (LDL) lipoproteins, could both enhance and suppress the proliferation of T lymphocyte cell lines. Enhancement and suppression were dependent on lipoprotein and transferrin concentrations. Enhancement occurred at low lipoprotein and high transferrin; suppression, at high lipoprotein and low transferrin. Lipoprotein suppression required a constituent of cell-conditioned medium as evidenced by the fact that lipoproteins did not suppress the replicative response of the IL-2-dependent murine cell line CTLL-2 to purified IL-2 but could suppress the response to cell-conditioned medium IL-2. For lipoprotein suppression and its relief by transferrin, both growth-regulating factors were required early in the cell cycle, suggesting that events important to progression through G1 are influenced. The data establish that the interplay between plasma lipoproteins, transferrin, and an unknown constituent of cell-conditioned medium can regulate the proliferation of T lymphocytes.

Animals↗
PubMed1987

Diferric transferrin reductase in the plasma membrane is inhibited by adriamycin.

Diferric transferrin which is often necessary for growth of cells is reduced by the transplasma membrane electron transport system of HeLa cells with release of ferrous iron outside the cell. Reduction of external diferric transferrin is reflected in oxidation of internal NADH. Adriamycin, an antitumor drug, inhibits diferric transferrin reduction by the HeLa cells and inhibits concomittant oxidation of cytosolic NADH at concentrations, 10(-8)-10(-6)M, which inhibit cell growth. Isolated liver plasma membranes have an NADH diferric transferrin reductase activity which is inhibited by similar adriamycin concentrations. We propose that inhibition of cell growth by adriamycin can be based on inhibition of transplasmalemma diferric transferrin reductase.

Cell Membrane↗
PubMed1986

The influence of uncoordinated histidines on iron release from transferrin. A chemical modification study.

Histidine residues that influence the chelate-mediated removal of iron from transferrin have been investigated. Diferric human serum transferrin was chemically modified to various extents using ethoxyformic anhydride, a reagent for histidines. A kinetic analysis of the modification reaction revealed the presence of a fast reacting pool of 9 +/- .8 histidine residues and a slow reacting pool of 5.8 +/- .6 residues. There are 18 histidine residues in transferrin. The rates of modification of the two pools differed by a factor of 5. The pyrophosphate-mediated removal of iron from the two binding sites of native and partially modified transferrins was studied at pH 6.9 using desferrioximine B as a terminal iron acceptor. Under these conditions, the rate of iron removal from the NH2-terminal site was about six times faster than from the COOH-terminal site. Both rates were significantly reduced, i.e. by a factor of approximately 6-8, upon complete ethoxyformylation of all reactive histidines on the protein. The kinetic data of partially modified transferrins were analyzed by the Tsou Chen-Lu statistical method; the results are consistent with the hypothesis that modification of a single uncoordinated histidine in each of the two iron binding domains stabilizes the protein kinetically against loss of iron. The dependence of the iron removal reaction on pH is consistent with such an interpretation. The putative histidines, although not ligands, may be close to the metal in both binding sites, thus influencing the rate of iron removal by pyrophosphate. These histidines belong to the pool of rapidly modified residues and thus are readily accessible to solvent and chelators.

Diethyl Pyrocarbonate↗
PubMed1986

Iron release from transferrin: synergistic interaction between adenosine triphosphate and an ammonium sulfate fraction of hemolysate.

In previous work we have shown that red cell hemolysates, at neutral pH, will release iron from transferrin; with molecular sieve chromatography, that activity separated into low molecular weight and high molecular weight components, both susceptible to destruction by phosphatases. Thus the possibility that nucleotides might be involved was suggested. We have studied the interaction of adenosine triphosphate (ATP) and an ammonium sulfate fraction of hemolysate with transferrin. ATP, as well as adenosine diphosphate and 2,3-diphosphoglyceric acid, interacts synergistically with the ammonium sulfate hemolysate fraction to promote iron release from transferrin. This activity is not limited to phosphorylated compounds, because citrate shows a similar effect. This activity is not a nonspecific chelating effect, because deferoxamine is without activity. All the synergistic anions labilize transferrin's HCO3. We therefore suggest that they form a non-HCO3 ternary complex with transferrin and iron, and that release of iron from this complex is promoted by a high molecular weight constituent of the hemolysate.

2,3-Diphosphoglycerate↗
PubMed1985

Calmodulin antagonists inhibit and phorbol esters enhance transferrin endocytosis and iron uptake by immature erythroid cells.

Seven antagonists of the calcium-binding protein calmodulin were found to inhibit iron and transferrin uptake by reticulocytes. This inhibition could be completely accounted for by inhibition of the endocytosis and exocytosis of transferrin. When four of the antagonists were tested with the nucleated erythroid cells from the liver of the fetal rat, inhibition of iron uptake was also observed but at higher concentrations than required for the same degree of inhibition with reticulocytes. The tumor promoters phorbol 12-myristate 13-acetate (PMA) and phorbol 12,13-dibutyrate (PDB) were shown to increase the rates of iron and transferrin uptake by reticulocytes and fetal liver erythroid cells by accelerating the rates of transferrin endocytosis and exocytosis. Since these substances are known to stimulate the calcium-activated enzyme protein kinase C while calmodulin antagonists are inhibitory, it is concluded that this enzyme plays an important role in the endocytosis and intracellular cycling of transferrin, and iron uptake by immature erythroid cells. However, the possibilities that calmodulin is also involved or that the inhibitory effects of the calmodulin antagonists are due to nonspecific actions on the cell membrane cannot be excluded.

Adenosine Triphosphate↗
PubMed1985

Use of chromatofocusing to detect a transferrin variant in serum of alcoholic subjects.

We describe a technique for detecting an abnormal (pl 5.7) transferrin component in serum, which appears after prolonged heavy consumption of alcohol. Serum transferrin was purified by chromatography on DEAE-Affi-Gel Blue and analyzed by chromatofocusing on an ion-exchange column (Mono P). The abnormal transferrin component was detected in 17 of 20 patients (85%) with a history or prolonged consumption of alcohol (100 g per day), and in control subjects who ingested up to 80 g of alcohol per day for seven days, but not in 14 normal control subjects or 14 patients with liver disease unrelated to alcohol. The variant consistently disappeared from the serum within three weeks of cessation of alcohol consumption. It is apparently produced by desialylation of ordinary human transferrin. We find that chromatofocusing on an ion-exchange column is a sensitive and reliable technique for its identification and conclude that detection of this desialylated transferrin indicates recent prolonged alcohol ingestion.

Adult↗
PubMed1985

Quantitation of apo-, mono-, and diferric transferrin by polyacrylamide gradient gel electrophoresis in patients with disorders of iron metabolism.

We have developed a polyacrylamide gradient gel electrophoretic method to quantitate apo-, mono-, and diferric transferrin based upon differences in their molecular size. Purified transferrin saturated to different extents (3% to 98%) with iron showed proportions of the three forms as predicted from an approximately random distribution of iron between the two metal-binding sites. The iron distributions in sera of 14 normal individuals similarly correlated with the predicted values. In contrast, 22 of 43 patients with diseases associated with abnormalities in iron or transferrin metabolism had a disproportionate increase in monoferric transferrin. This abnormality occurred in seven of nine patients who had received bone marrow transplants, seven of 14 with chronic liver disease, and eight of nine menstruating women with probable iron deficiency anemia. Interestingly, 11 patients with malabsorption or chronic renal disease had normal iron distributions. The finding of abnormal distributions of iron on transferrin suggests that gradient gel analysis may be a useful tool for studying the physiologic mechanisms controlling iron utilization.

Anemia, Hypochromic↗
PubMed1985

Effect of desferrioxamine, rhodotorulic acid and cholylhydroxamic acid on transferrin and iron exchange with hepatocytes in culture.

The mechanism of action of the hydroxamate iron chelators desferrioxamine (DFO), rhodotorulic acid (RHA) and cholylhydroxamic acid (CHA) was studied using rat hepatocytes in culture. Each chelator affected both the uptake and, to a much smaller extent, the release of transferrin-125I-59Fe from the cells. All chelators reduced the 59Fe uptake and incorporation into ferritin in a concentration-dependent manner. Uptake of 59Fe into the membrane (stromal-mitochondrial) fraction was also decreased by DFO and RHA but increased by CHA. Transferrin-125I binding was reduced slightly by DFO and RHA and increased by CHA. All chelators released 59Fe transferrin-125I from hepatocytes prelabelled by incubation with rat transferrin-125I-59Fe and washed before reincubation in the presence of the chelators. DFO decreased membrane 59Fe but had little effect on ferritin-59Fe. RHA decreased 59Fe in both membrane and ferritin fractions. CHA decreased hepatocyte-59Fe but increased 59Fe in the hepatocyte membrane fraction. Higher concentrations of the chelators had little further effect on 59Fe release but promoted transferrin-125I release from hepatocytes. All chelators appeared to act on kinetically important iron pools of limited size and hence are likely to be most effective when given by continuous infusion rather than bolus injection.

Animals↗
PubMed1977

Interaction of anions with iron-transferrin-chelate complexes.

Preliminary evidence suggested that phosphate or borote destabilize iron-ovotransferrin-nitrilotriacetate complexes in the absence of added bicarbonate. The iron-ovotransferrin-EDTA complex was prepared in the absence of bicarbonate, and a number of anions, including phosphate, sulfate, and citrate, were found to perturb the visible absorbance (lambdamax = 490 nm) of this complex. Other anions, such as chloride, nitrate, and perchlorate, had little or no effect on the spectrum. Also, when bicarbonate was added to a solution of the iron-transferrin-EDTA complex (A515 = 0.45), within 2 min, the visible absorbance had decreased to A515 = 0.13. Slowly a new peak appeared (lambdamax = 470 nm), evidently the iron-transferrin-CO3 complex. When these spectral changes were monitored in detail, the lack of an isosbestic point indicated the existence of one or more intermediates in the conversion of iron-transferrin-EDTA complex to the iron-transferrin-CO3 complex. Experiments using ternary complexes containing either 59Fe or [14C]EDTA show that both iron and EDTA nearly completely dissociate from the protein (most likely concomitantly within 2 min after bicarbonate is added. These observations are best explained by a paradigm which includes anion binding to the apoprotein. It is clear that there is an intimate relationship between anions and the binding of iron chelates by transferrin.

Bicarbonates↗
PubMed1980

The chicken transferrin gene. Restriction endonuclease analysis of gene sequences in liver and oviduct DNA.

The organization of the chicken transferrin gene and its surrounding sequences was determined by a comparison of the restriction map of the cloned structural gene (double-stranded cDNA) with the map of the transferrin gene in genomic DNA. This analysis reveals a complex arrangement of the transferrin gene in which structural sequences are interrupted by a minimum of 6 intervening sequences, and span at least 10 kilobases in genomic DNA. Furthermore, comparison of the DNA from individual chickens of the same breed indicates considerable allelic diversity in the restriction sites for Eco RI, HindIII, and Bam HI. Quantitation of the number of transferrin genes by saturation hybridization confirms that both liver and oviduct DNAs contain only 1 transferrin gene/haploid complement, and, in addition, comparison of the restriction patterns obtained with DNA from these two tissues, as well as erythrocyte DNA, does not reveal any difference in the structural organization of the gene. We conclude that the distinct tissue-specific transcriptional regulation of this gene by steroids and iron levels in the oviduct and liver cannot be explained either by a multiplicity of genes or by somatic reorganization of the gene.

Animals↗
PubMed1981

Covalent binding of fatty acid to the transferrin receptor in cultured human cells.

The human transferrin receptor could be fluorographically detected after immunoprecipitation from a leukemic T-cell line labeled with [3H]palmitic acid. The label was found ony in association with the human transferrin receptor and not in association with two other major plasma membrane glycoproteins, demonstrating that the incorporation of radioactivity was not due to metabolism of the palmitate. Treatment of sodium dodecyl sulfate-polyacrylamide gels containing the [3H]palmitate-labeled transferrin receptor with hydroxylamine, prior to fluorography, resulted in release of a substantial fraction of the label from the molecule. In addition, at least part of the label released from immunoprecipitates of the transferrin receptor by treatment with hydroxylamine was identified as palmitohydroxamate, providing further evidence that the labeled fatty acid is covalently bound to the receptor. A proteolytic fragment (Mr = 70,000) derived from the portion of the transferrin receptor exposed on the cell surface can be obtained by trypsin digestion of intact or Nonidet P-40-solubilized cells. When cells were labeled with [3H]palmitic acid, none of the radioactivity could be detected in the tryptic fragment. Thus, the bound palmitate appears to be associated with the region of the molecule that is in close proximity to the plasma membrane.

Cell Line↗