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Iron deficiency anaemia in pregnancy is not a common problem among Black patients in the Durban area, and prophylactic iron supplements do not lead to an increase in haemoglobin values. Prophylactic iron therapy should give way to investigation and appropriate treatment of patients with low haemoglobin values.
Measurement of specific adducts to haemoglobin can be used to establish the dosimetry of electrophilic compounds and metabolites in experimental animals and in man. Adducts of 1,2-epoxybutene with the N-terminal valine in haemoglobin were determined in male B6C3F1 mice and Sprague-Dawley rats following exposure by inhalation to low concentrations of 1,3-butadiene (0, 2, 10 or 100 ppm, 6 h/day, 5 days/week, 4 weeks; animals killed within 1 h after the last exposure). The adduct level increased linearly with butadiene concentration in the mice, whereas a deviation from linearity was observed in the rats. After exposure to 100 ppm butadiene, the adduct levels were four times higher in mice than in rats; at lower concentrations of butadiene, the species difference was less pronounced. Adduct levels of about 1-3 pmol/g globin were recorded in human subjects (nonsmokers) who worked in a production area where butadiene levels of about 1 ppm had been recorded in a survey conducted three to nine months prior to this study. Increased adduct levels were also observed in cigarette smokers (two subjects) who were not exposed occupationally to butadiene. Although preliminary, the data suggest that the adduct levels, and consequently the doses of epoxybutene per parts per million-hour of butadiene are lower in humans than in mice and rats. The adduct levels are much lower than those seen after occupational exposures to corresponding air levels of ethylene oxide and are lower than those seen after exposure to ethylene.
Major blood loss following trauma is common, but severe anemia is generally not life-threatening when managed with the administration of blood and blood products. Severe anemia becomes particularly challenging and potentially lethal when the patient is a Jehovah's Witness, for whom receiving a transfusion is contrary to religious principles. This case report describes the management and hospital course of a Jehovah's Witness who was seriously injured in an airplane crash.
This case report illustrates a potentially common cause for the inhibition of iron absorption that can be overlooked at the initial consultation and may lead to extensive investigation of a patient with iron deficiency. The case shows that early questioning of the patient regarding their beverage intake can lead to a positive outcome and avoid unnecessary investigation or treatment.
The short-chain fatty acid butyrate has been shown to elevate fetal hemoglobin (HbF) by inducing expression of the gamma-globin gene. Regulation of gene expression by butyrate is thought to proceed via inhibition of the enzyme histone deacetylase, leading to elevated levels of core histone acetylation which affect chromatin structure and transcription rates. To determine whether changes in histone acetylation are critical for the regulation of the gamma-globin gene, we tested three potent and specific inhibitors of histone deacetylase, the cyclic tetrapeptides trapoxin and Helminthsporium carbonum toxin (HC toxin), and the antifungal antibiotic trichostatin A for their ability to induce fetal hemoglobin expression in erythroid cells. These compounds induced fetal hemoglobin in both primary erythroid cell cultures and human erythroleukemia (K562) cells. A butyrate-responsive element spanning the duplicated CCAAT box region of the gamma-globin promoter has been identified in transient transfection assays using a reporter construct in K562 cells, and we show that the same promoter region is required for response to trapoxin and trichostatin. Mutational analysis of the gamma-globin promoter indicates that the distal CCAAT box and 3' flanking sequence (CCAATAGCC) is critical for activation by butyrate, trapoxin, and trichostatin, whereas the proximal element (CCAATAGTC) plays a less important role. These results show that inhibition of histone deacetylase can lead to transcriptional activation of gamma-globin promoter reporter gene constructs through proximal promoter elements, and suggest that butyrate induces gamma-globin expression via such changes in histone acetylation.
Iron and iron compounds--including mammalian hemoglobins--catalyze hydroxyl radical production and lipid peroxidation. To determine whether hemoglobin-mediated lipid peroxidation might be important in hemorrhagic injuries to the central nervous system (CNS), we studied the effects of purified hemoglobin on CNS homogenates and injected hemoglobin into the spinal cords of anesthetized cats. Hemoglobin markedly inhibits Na/K ATPase activity in CNS homogenates and spinal cords of living cats. Hemoglobin also catalyzes substantial peroxidation of CNS lipids. Importantly, the potent iron chelator, desferrioxamine, blocks these adverse effects of hemoglobin, both in vitro and in vivo. Because desferrioxamine is not known to interact with heme iron, these results indicate that free iron, derived from hemoglobin, is the proximate toxic species. Overall, our data suggest that hemoglobin, released from red cells after trauma, can promote tissue injury through iron-dependent mechanisms. Suppression of this damage by desferrioxamine suggests a rational therapeutic approach to management of trauma-induced CNS injury.
The effects of modification of heme carboxylic groups by omega-aminoenantic acid and L-phenylalamine on the peroxidase activity of hemoglobin were studied. For this purpose the peroxidase activities of the original compounds--hemin, hemin-aminoenantic acid, hemin-phenylalanine and hemoglobins prepared from the hemin and globin compounds--hemoglobin, aminoenantyl-hemoglobin and phenylalanine hemoglobin--were determined. The dependence of the peroxidase activity of these compounds on their concentrations and pH was analyzed. It was shown that 40--50% modification of the heme carboxylic groups by amino acids decreases the peroxidase activity of the modified hemins and that of modified hemoglobins reconstructed from these hemins and globin. A decrease of the catalytic activity of the hemoglobin derivatives is due to a lower peroxidase activity (as compared to hemin) of the modified hemins. It is thus concluded that the amino acid modification of the carboxylic groups of heme does not affect the heme-protein interactions in the hemoglobin molecule.
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The formation of ferryl heme (Fe(IV) = O) species, i.e., compound I and compound II, has been identified as the main intermediates in heme protein peroxidative reactions. We report stopped-flow kinetic measurements which illustrate that the reaction of hemoglobin I (HbI) from Lucina pectinata with hydrogen peroxide produce ferryl intermediates compound I and compound II. Compound I appears relatively stable displaying an absorption at 648 nm. The rate constant value (k'(2)) for the conversion of compound I to compound II is 3.0 x 10(-2) s(-1), more than 100 times smaller than that reported for myoglobin. The rate constant value for the oxidation of the ferric heme (k'(12) + k'(13)) is 2.0 x 10(2) M(-1) s(-1). These values suggest an alternate route for the formation of compound II (by k'(13)) avoiding the step from compound I to compound II (k'(2)). In HbI from L. pectinata the stabilization of compound I is attribute to the unusual collection of amino acids residues (Q64, F29, F43, F68) in the heme pocket active site of the protein.
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We found that half-oxidized hemoglobins such as (alpha 2+ beta 3+)2 and (alpha 3+ beta 2+)2, and methemoglobin were significantly increased in the erythrocytes of workers handling chemical compounds in a chemical plant of Japan. In addition, we found two unusual anodic hemoglobins (hemoglobin X and hemoglobin Y) to be present to a large extent in the erythrocytes of the workers investigated (21 persons), using isoelectric focusing electrophoresis on polyacrylamide gel plates. For example, the hemoglobin analysis of a worker showed: hemoglobin X, 6.2%; hemoglobin Y, 26.8%; hemoglobin A + hemoglobin F, 54.5%, half-oxidized hemoglobins, 9.8%; methemoglobin, 1.5%; hemoglobin A2, 2%. Since contents of hemoglobin A decreased by more than 40% of normal levels, and those of oxidized and modified hemoglobins increased up to 40% of total hemoglobins in the erythrocytes of several workers in the plant, we may consider these cases as ones having toxic methemoglobinemia with oxidized and modified hemoglobins. The changes of intracellular hemoglobins in these cases may be due to oxidation and modification of the proteins by chemical compounds absorbed from skin and lungs. Therefore, these hemoglobins may be a good indicator to monitor the health of workers in chemical plants. We also studied the formation mechanism of modified hemoglobins such as hemoglobin X and hemoglobin Y, investigating the reactions of hemoglobin with various aromatic compounds in vitro. On the other hand, we had the opportunity to analyze the changes in oxidized hemoglobins and modified hemoglobins in the blood of a man who drank cresol solution to commit suicide and was sent to a hospital.(ABSTRACT TRUNCATED AT 250 WORDS)
1. Methemoglobin formation was observed when erythrocytes were incubated with xenobiotics such as hydroxylamines or phenols, other metabolites resulting from the interaction of these compounds with erythrocytes being reactive free radicals derived from the respective xenobiotic, and a ferryl-heme oxo-complex. 2. Steady-state levels of these reaction products depended on the permeability of the erythrocyte membrane for the various methemoglobin (MetHb) generators and the presence of antioxidants that downregulate the radicals formed. 3. Electron spin resonance (ESR) spectra of xenobiotic-derived free radicals could be obtained only from the readily water soluble hydroxylamines, whereas the poorly water soluble phenolic compounds did not allow the use of concentrations required for the generation of detectable amounts of ESR-sensitive metabolites in erythrocytes. 4. Previous investigations with oxyhemoglobin solutions and with the MetHb/H2O2 model systems have shown that, apart from ESR-sensitive radical species, excited reaction intermediates such as compound 1 ferryl hemoglobin can be detected as well by using chemiluminescence measurements. 5. A strong correlation was found between the intensity of the emitted light and the MetHb formation rate, indicating that the production of compound 1 ferryl hemoglobin is closely related to the MetHb formation step. 6. The sensitivity of the photon-counting method allowed measurements of excited species in intact erythrocytes not only with the readily soluble hydroxylamines, but also with the less soluble phenolic compounds. 7. In addition, parameters indicative of xenobiotic-induced oxidative alterations were found: a significant decrease in intraerythrocytic thiol levels was a result of all compounds that initiate MetHb formation, as also described for slowly reacting xenobiotics. 8. With the most reactive compound investigated, unsubstituted hydroxylamine, a significant release of iron from the oxidatively modified hemoglobin was detected, facilitated by binding of this transition metal to hydroxylamine and its final oxidation product, nitric oxide. 9. The use of the ESR spin-labeling technique revealed membrane alterations of erythrocytes exposed to the reducing MetHb generators presented in this study. 10. A direct action of BHA and BHT on the integrity of the erythrocyte membrane was observed, leading to hemolysis independent of the formation of prooxidant species. 11. The presence of strong prooxidants (radicals) was indicated both by fluidity changes in the membrane and by an oxidative decrease in cytosolic thiol levels.
The Mössbauer effect in Fe(57) has been used to study the molecules, hemoglobin, O(2)-hemoglobin, CO(2)-hemoglobin, and CO-hemoglobin (within red cells) and the molecules, hemin and hematin (in the crystalline state). Quadrupole splittings and isomeric shifts observed in the Mössbauer spectra of these molecules are tabulated. The temperature dependence of the quadrupole splitting and relative recoil-free fraction for hemoglobin with different ligands has been investigated. An estimate of the Debye-Waller factor in O(2)-hemoglobin at 5 degrees K is 0.83. An asymmetry in the quadrupole splitting observed in hemoglobin is attributed to a directional dependence of the recoil-free fraction which establishes the sign of the electric field gradient in the molecule and indicates that the lowest lying d orbital of the Fe atoms is |xy>. This asymmetry indicates that the iron atoms in hemoglobin are vibrating farther perpendicular to the heme planes than parallel to them, and, in fact, the ratio of the mean square displacements perpendicular and parallel to the heme planes in hemoglobin is approximately 5.5 at 5 degrees K. The temperature dependence of the quadrupole splitting in hemoglobin has been used to estimate a splitting between the lowest lying iron atom d orbitals of approximately 420 cm(-1).
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Type EFPA-30 apparatus for electrophoresis on cellulose acetate films was developed at the Specialized Design Office for Biophysical Equipment of the Moscow Research and Production Association BIOFIZPRIBOR. Three autonomic separation cameras are united in one block, that permits separation of 12, 24, and 36 samples; the apparatus is supplied with time transducer, acoustic and visual indication. Clinical trials of the apparatus were carried out at the Institute of Biological and Medical Chemistry of the USSR Academy of Medical Sciences, its commercial production is to be started. The apparatus is intended for protein separation and may be used for studies of hemoglobins, serum proteins, lipoproteins, enzymes, and other biologic compounds. Methods for hemoglobin and serum protein separation are presented.