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Fe(III)-haemoglobin is shown to catalyse the hydrolysis of 2,3-bis(phospho)-D-glycerate to Pi and 3-phosphoglycerate, although the rate is slow, even when the protein is present at concentrations in the millimolar range. The rate of hydrolysis is proportional to the subtrate concentration up to at least 10 mM, so if the process is enzymic, the Km must be high.
The effect of inositol hexakisphosphate on the redox equilibria and on the c.d. spectra of ferric derivatives of haemoglobin from Camelus dromedarius has shown that: two distinct functionally relevant binding sites for polyanions are present on the protein; conformational changes promoted by inositol hexakisphosphate are largely dependent on spin state of the iron; tertiary and quaternary changes are not necessarily linked; structures induced by polyanions can be mixed forms that are neither T-state nor R-state.
The cyanide ion is a ligand of ferrous as well as ferric haemoproteins and this study presents a kinetic characterization of the dissociation of its complexes with the two main haemoglobin components from trout blood. Both these haemoglobins bind oxygen co-operatively at neutral or alkaline pH values but one of them is insensitive to pH and allosteric effectors (haemoglobin I, HbI) while the other (haemoglobin IV, HbIV) is strongly sensitive and shows the so-called Root effect (i.e. the incomplete oxygen saturation in air-equilibrated solutions at pH values of < 6.5). Comparison of the kinetics of dissociation of cyanide from ferrous forms of HbI and HbIV reveals that: (i) cyanide dissociates in both cases by a complex reaction, and, at least in the case of HbIV, this may be attributed to functional differences between the alpha and beta subunits; (ii) the reaction is only scarcely co-operative in HbI and not at all so in HbIV; and (iii) the Bohr and Root effects are not manifested in this reaction. The functional heterogeneity of ferrous alpha and beta chains of trout HbI has not been observed for any other ligand; moreover, the observation that co-operativity for cyanide dissociation is expressed by human haemoglobin but not by trout HbIV is surprising.
1. Marrow-iron stores were absent or reduced in twenty-three of thirty-nine patients studied within 52 months of starting maintenance haemodialysis. 2. Oral iron was given to twelve patients (group I) with absent or reduced, and to eleven patients (group II) with normal or increased marrow-iron stores. 3. A significant increase in mean haemoglobin concentration and marrow iron was observed in group I. No significant change in mean haemoglobin concentration or marrow iron occurred in group II. Mean haemoglogin concentration after treatment was significantly higher in group I than in group II. 4. The four patients who had normal or increased marrow iron and who received no oral iron all suffered a fall in haemoglobin concentration, and three of them showed a reduction in marrow iron. 5. These findings indicate that continuous oral iron therapy should be given to all patients on maintenance dialysis to correct or prevent iron deficiency.
Iron transport in reticulocytes is known to occur via the well-described transferrin-receptor-endosome pathway. An alternative pathway for iron transport independent of transferrin has been postulated in reticulocytes and other cells. Transport of iron into reticulocytes from ferric citrate solutions was shown to be saturable and independent of transferrin. During transport of iron from ferric citrate, both cell surface integrins, and a soluble protein, mobilferrin, were labelled. This demonstrated that the reticulocyte transferrin independent pathway for iron transport involved integrins and mobilferrin similar to intestinal absorptive cells. This pathway would be expected to transport iron into cells under conditions of iron overload and was capable of providing iron for haemoglobin synthesis. Mobilferrin was also radiolabelled when radioiron labelled transferrin was incubated with reticulocytes and this occurred with a different time course than was observed following reticulocyte exposure to radiolabelled ferric citrate. This suggested that mobilferrin may serve as an intermediary in both pathways.
Spatone Iron-Plus is a naturally occurring mineral water from Trefriw Wells Spa in Conwy County, North Wales, UK. It contains approximately 0.20 mg of iron per millilitre as ferrous sulphate and has been shown to provide iron in a highly bio-available form. A 24 ml sachet contains approximately 5 mg of iron. Iron deficiency is common in the obstetric population. However, compliance with traditional iron supplements is poor because of gastrointestinal side-effects. We designed a randomized, double-blind, placebo-controlled trial. A total of 102 low-risk antenatal patients, who were noncompliant with routinely prescribed ferrous sulphate tablets, were randomized to receive 48 ml of Spatone water or placebo. The study was conducted between 22 and 28 weeks gestation. Primary outcome measures were compliance, gastrointestinal side-effects and changes in ferritin levels during the trial period. Compliance in the intervention group was 57% compared with 67% in the control group, P = 0.22. Dyspepsia scores, as determined by a recognized and well-validated questionnaire, did not differ between the two groups. During the trial period, mean ferritin levels fell by 24% in the Spatone Iron-Plus group compared with a mean fall of 51% in ferritin levels among the control group, P = 0.016.
BACKGROUND: Iron supplements may increase disease activity in inflammatory bowel disease through the production of the hydroxyl radical because of its catalytic activity in the Fenton reaction. The purpose of this study was to assess the effect of dietary and locally administered iron in the IL-10 knock-out (-/-) mouse, a model of chronic inflammatory bowel disease. MATERIALS AND METHODS: IL10-/- and wild-type mice received a standard or a high-iron diet (35 mg kg(-1) ferrosulphate vs. 500 mg kg(-1) ferrosulphate) after weaning. After 4 weeks the mice were sacrificed. Furthermore, a group of adult IL-10 knock-out mice was given three iron-containing enema's (0.2 mL of 1 mM ferrous-ammonium sulphate) or phosphate buffered saline. These mice were sacrificed after 1 week. Production of pro-inflammatory cytokines by colon tissue cultures, haematological parameters and histology was determined to assess inflammatory activity. RESULTS: Oral as well as rectal administration of iron resulted in increased pro-inflammatory cytokine production in IL-10-/- mice. Neutrophil counts in IL10-/- on a high iron diet increased as well. No enhanced colonic inflammation was noted on histology after iron supplementation. CONCLUSION: We conclude that dietary or topical administered iron increases pro-inflammatory cytokine production in the colon of IL10-/- mice. No significant increase of histological intestinal inflammation was observed.
Patients undergoing total hip or knee replacement frequently receive blood transfusion. Homologous blood transfusion carries appreciable risks and should therefore be reduced to a minimum. We have investigated the use of preoperative oral iron supplements to optimize haemoglobin concentration and iron stores prior to surgery. All patients attending a preadmission clinic 4 weeks prior to primary hip or knee replacement had a haemoglobin measurement. If the haemoglobin concentration (Hb) was less than 12 g dL-1 they were given a four week course of ferrous sulphate. If it was greater than or equal to 12 g dL-1 they were randomized to a control group or given a supplementation course of ferrous sulphate. One hundred patients were seen. Of these 18 (18%) had haemoglobin less than 12 g dL-1 and 16 were treated with iron. The mean Hb was 10.8 g dL-1 and mean cell volume (MCV) 86. These patients increased their Hb by a mean 1.1 g dL-1 prior to admission (P = 0.008). MCV was the best predictor of response (r = -0.63, P < 0.02). This group dropped their haemoglobin by a mean 1.4 g dL-1 in the first post-operative week. In the study groups there was no significant preoperative rise in Hb. However, the control group dropped their Hb by a mean 1.3 g dL-1 in the week following surgery compared with 0.4 g dL-1 in the group which had received iron supplements (P < 0.001). We conclude that at least 18% of patients attending for hip or knee replacement in this region are frankly anaemic and benefit significantly from preoperative iron supplements over 4 weeks. Iron supplementation in patients without obvious anaemia protects against a fall in Hb during the immediate post-operative period, suggesting a widespread underlying depletion of iron stores in this group despite a normal Hb. Preoperative iron supplements may reduce transfusion requirements as part of a co-ordinated strategy in this group of patients.
1. An experiment was conducted with female broilers from 1 to 39 d of age in which the effects of increasing amounts of extra dietary ferrous sulphate on growth performance, some haematological measurements and Fe, Zn and Cu status were studied. A conventional maize-soyabean diet (107 mg Fe/kg) was supplemented with 0, 20, 60, 180, 540 and 1620 mg Fe to provide 6 treatments. 2. Weight gain responses rose to a plateau between 20 and 60 mg added Fe/kg diet, but further additions of Fe increasingly depressed growth. 3. In this study the apparent Fe requirement was 100 mg/kg diet (80 mg from dietary components and 20 mg Fe from supplement). 4. The efficiency of food utilisation decreased linearly, while the proportion of chicks affected by leg weakness increased. 5. In blood, the haemoglobin concentration increased slightly with extra dietary Fe. 6. The iron content of the liver increased with higher dietary Fe supplementation. Furthermore, increased liver Fe content was associated with a higher Zn content in the liver. 7. This study indicated that a maize-soyabean diet containing about 30% more Fe than has generally been accepted to be adequate for healthy broilers was still marginal in Fe concentration.
OBJECTIVE: To present a new method for measuring the relative bioavailability (RBV) of commercial elemental iron powders by investigating induced changes of serum iron concentration (S-Fe) in relation to ferrous sulphate (FeSO4). Earlier studies have shown that in a group of subjects there is good agreement between the increase in S-Fe and the amount of iron absorbed from a simple iron salt as FeSO4. METHODS: The study included two groups of male blood donors (n=2 x 16 subjects) who were served three meals with an interval of approximately nine weeks between each one. In one group the meal was fortified with reduced iron, ferrous sulphate or no iron at all. In the other group the meal was fortified with electrolytic iron, ferrous sulphate or no iron. The S-Fe increase was followed for 6 h. Studying the non-iron meals was necessary so that the basal diurnal variation in the S-Fe during the six hours could be measured and subtracted. RESULTS: The mean S-Fe increase calculated as the area under the curve (AUC) from the reduced iron (RBV=0.43) and the electrolytic iron (RBV=0.73) differed significantly from the AUC following FeSO4 (p=0.002 and p=0.021, respectively). The difference between the reduced and the electrolytic iron was also statistically significant (p=0.036). CONCLUSION: Measuring increases in S-Fe could be a reliable and simple method to determine the RBV in comparative studies of elemental iron powders in relation to FeSO4.
Argentina has been largely considered as having an adequate diet in terms of iron availability. However, children aged 9-24 mo do not meet requirements from their regular diet. The aim of this study was to assess the incidence of iron deficiency in a representative sample of children living in Greater Buenos Aires. Hematologic indicators were measured in venous blood from 384 children. Weighted incidence of anemia was 46.7%. Mean corpuscular volume was less than 73 fL in 28.2% of subjects, free erythrocyte protoporphyrin was greater than 1.77 mumol/L erythrocytes in 57.1%, and serum ferritin was less than 12 micrograms/L in 60.2%.incidence of two or three abnormal values for iron status indicators was 46.1%. This extremely high incidence of anemia is associated with low iron intakes (5.6 +/- 3.5 mg/d means +/- SD), early introduction of cow milk, and low consumption of iron-fortified foods and iron supplements.
Iron EDTA is an effective fortificant in meals of low iron bioavailability. Na2EDTA, added to food to prevent oxidation, enhances iron bioavailability by chelating added iron. This study examines the optimal ratio of EDTA to iron causing enhanced iron absorption. Iron absorption from a rice-based meal of low iron bioavailability containing increasing molar ratios of EDTA to iron, was compared in 127 women volunteers by using standard double isotope techniques. Iron deficiency was present in 38% of the women. Mean standardized absorptions, at EDTA-iron ratios of 0.25, 0.5, and 1, were 11.3%, 13.5%, and 8.8%, respectively, compared with 3.8% when no Na2EDTA was present. In meals of high iron bioavailability, Na2EDTA (EDTA:Fe, 1.0) produced little enhancement (potato-based meal) nor inhibited iron absorption (apple-based meal). Na2EDTA added to meals with molar ratios of EDTA to iron between 1.0 and 0.25 significantly increases iron absorption provided the meal is of low iron bioavailability.
BACKGROUND: Recent studies in humans suggest that ferritin iron in soybeans has high bioavailability. However, direct evidence for this is lacking because the soybeans were intrinsically labeled; thus, iron bound to other ligands, such as phytate, was also labeled. OBJECTIVE: The objectives of the study were to evaluate the absorption of iron from extrinsically labeled, purified ferritin (horse spleen) reconstituted with either high-phosphate iron mineral (plant-type) or low-phosphate iron mineral (animal-type) and to compare it with iron absorption from ferrous sulfate. DESIGN: Nonanemic, healthy young women were fed a standard breakfast meal supplemented with (59)Fe-labeled ferritin or ferrous sulfate, in randomized order. Fifteen subjects received ferritin with the low-phosphate iron mineral, and 15 subjects received ferritin with the high-phosphate iron mineral. Iron absorption was measured in a whole-body counter after 14 and 28 d and by red blood cell incorporation after 28 d. RESULTS: There was no significant difference in iron absorption between ferritin and ferrous sulfate: low-phosphate iron mineral ferritin (x +/- SD: 21.4 +/- 14.7%) compared with ferrous sulfate (21.9 +/- 14.6%), or high-phosphate iron mineral ferritin (22.2 +/- 19.2%) compared with ferrous sulfate (16.7 +/- 7.1%). Results obtained by using whole-body retention of iron and red blood cell incorporation differed with the type of iron, which suggests that pathways for iron uptake and utilization differed for the 2 forms. CONCLUSIONS: Iron is equally well absorbed from ferritin and ferrous sulfate independent of the phosphate content of the ferritin iron mineral. Thus, dietary ferritin iron is likely to be a good source of iron.
BACKGROUND: Dietary ferritin, a protein cage around an iron mineral, is an underestimated source of bioavailable iron. Plant ferritin, the most common dietary ferritin, has not been studied. Iron from animal ferritin is absorbed as well as is iron from FeSO4 in women. OBJECTIVE: The objective was to examine iron absorption from purified soybean ferritin. DESIGN: Healthy, nonanemic women (n = 16) were fed a standardized meal (bagel, cream cheese, and apple juice) containing 1 microCi 59Fe/meal as FeSO4 or (extrinsically labeled) as iron-free soybean ferritin reconstituted with the high phosphate characteristic of plant ferritin (iron:phosphorus = 4:1). Iron-free, apo-soybean ferritin was prepared (with the use of thioglycolic acid and extensive dialysis) from purified ferritin. In a randomized crossover design, the other labeled meal, which contained FeSO4 or ferritin, was given after 4 wk. The subjects received 140 microg Fe as ferritin (2.5 mg) or as FeSO4. After 28 d, whole-body 59Fe and 59Fe in red blood cells were measured before and after dosing. RESULTS: There was no significant difference in whole-body iron absorption from soybean ferritin (29.9 +/- 19.8%) and that from FeSO4 (34.3 +/- 23.6%) or in iron absorption calculated from red blood cell incorporation (33.0 +/- 20.1% for soybean ferritin and 35.3 +/- 23.4% for FeSO4), which confirmed previous results with animal ferritin that was mineralized and labeled similarly. An inverse relation was observed between serum ferritin and iron absorption from both ferritin and FeSO4, which suggested that sensors regulating iron absorption respond similarly to iron provided as ferrous salts or as ferritin mineral. CONCLUSION: Iron from soybean ferritin is well absorbed and may provide a model for novel, utilizable, plant-based forms of iron for populations with a low iron status.
BACKGROUND: Lactoferrin is a major protein component of human milk, and it binds iron with high affinity. Because the human small intestine has receptors for lactoferrin, a role for it in iron absorption has been suggested. OBJECTIVE: The objective was to study the absorption of iron from extrinsically labeled purified recombinant human lactoferrin produced in rice and to compare it with the absorption of iron from ferrous sulfate. DESIGN: On 2 occasions 4 wk apart, healthy young women (n = 20) were fed a standardized meal supplemented in randomized order with 59Fe as lactoferrin or as ferrous sulfate. Ten subjects received lactoferrin that had been heat-treated, and 10 subjects received untreated lactoferrin. Iron absorption was measured in a whole-body counter after 14 and 28 d and also was measured by red blood cell incorporation after 28 d. RESULTS: The difference in whole-body iron absorption between heat-treated (24.6 +/- 20.8%; n = 10) and untreated (16.2 +/- 4.4%; n = 10) lactoferrin was not significant. The difference in whole-body iron absorption between the groups given lactoferrin (20.4 +/- 15.3%; n = 20) or ferrous sulfate (18.8 +/- 13.2%; n = 20) also was not significant. Serum ferritin and iron absorption were inversely correlated in subjects when they received either lactoferrin or ferrous sulfate, which suggested that iron is absorbed from the 2 sources by a similar mechanism. CONCLUSIONS: Iron is equally well absorbed from lactoferrin (whether heat-treated or untreated) and ferrous sulfate. Thus, iron provided by dietary lactoferrin is likely to be well utilized in human adults.
The level of N-(2-hydroxypropyl)valine adducts in haemoglobin has been shown to correlate well with workplace exposure to propylene oxide (PO). However, the analytical method, using the modified Edman degradation procedure, is prohibitively time-consuming and expensive for use as a routine workplace exposure measurement tool. As an alternative, AB Biomonitoring Ltd of Cardiff, Wales, developed a competitive immunoassay for the determination of N-(2-hydroxypropyl)valine adducts in human haemoglobin. Studies showed that whole blood samples analysed using an enzyme linked immunosorbent assay (ELISA) and the modified Edman degradation procedure over the concentration range 3.7-992 nmol N-(2-hydroxypropyl)valine g(-1) haemoglobin are in good agreement (correlation coefficient 0.998, n = 10). The intervariance and intravariance data indicate the repeatability of the ELISA method over the assay conditions employed and show that it is robust over its working range [2-200 pmol N-(2-hydroxypropyl)valine g(-1) haemoglobin]. The assay employs a whole blood matrix and has a working range of 2-6000 pmol g(-1) Hb (equivalent to up to 5 ppm PO exposure, 8 h per day, 5 days per week, over 4 months). The practicality of the assay was tested by assessing exposures to PO at three world-scale manufacturing sites in France and The Netherlands. Over 800 samples were taken over a 2 year period from operators, maintenance fitters and office staff. The data, typically <50 pmol g(-1) globin, indicate that exposures were significantly <0.1 ppm at all times (The Dutch occupational exposure limit is 2.5 ppm over 8 h). Samples were taken after a major turnaround and also before and after the start-up of a newly commissioned plant. All data indicated that high levels of control were effective in minimizing exposure. This study has shown that the immunoassay is a powerful tool for the exposure component of future epidemiology studies, as well as a definitive demonstration of the effectiveness of exposure controls.
Styrene-specific N-7- and O6-guanine DNA adducts and N-terminal valine adducts were determined in mice tissues after the intraperitoneal administration of styrene. Blood, liver, lungs and spleen were collected 3 h after administration of various doses (from 0 to 4.35 mmol/kg b.w.) of styrene. DNA adducts were analysed by the modified 32P-postlabelling assay and N-terminal valine adducts were detected by GC-MS according to the modified Edman degradation technique. In the dose-range studied, for all adducts a clear dose-response relationship was observed. 7-Alkylguanines and O6-styrene guanine adducts were most abundant in lungs, approximately 30% more than in liver and spleen. In all analysed tissues 7-alkylguanines were more abundant than O6-styrene guanine adducts. We found a considerably lower rate of N-terminal valine adduct formation as compared with both DNA adducts. The ratio between 7-alkylguanines and O6-guanine adducts was 1.9, 1.6 and 7.8 in liver, lung and spleen, respectively. In vitro determination of both DNA adducts by 32P-postlabelling resulted also in a lower ratio than that reported earlier using an HPLC analysis. All correlation's between dose, haemoglobin and DNA adducts were very high and significant. However, at the highest injected doses the adduct formation showed a levelling off. To explain this phenomenon a model simulation was performed revealing that 3 h after the injection of the higher doses styrene was not completely converted into styrene-7,8-oxide.
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