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Cold Spring Harbor Perspectives in... Mar 2013Diseases affecting hemoglobin synthesis and function are extremely common worldwide. More than 1000 naturally occurring human hemoglobin variants with single amino acid... (Review)
Review
Diseases affecting hemoglobin synthesis and function are extremely common worldwide. More than 1000 naturally occurring human hemoglobin variants with single amino acid substitutions throughout the molecule have been discovered, mainly through their clinical and/or laboratory manifestations. These variants alter hemoglobin structure and biochemical properties with physiological effects ranging from insignificant to severe. Studies of these mutations in patients and in the laboratory have produced a wealth of information on hemoglobin biochemistry and biology with significant implications for hematology practice. More generally, landmark studies of hemoglobin performed over the past 60 years have established important paradigms for the disciplines of structural biology, genetics, biochemistry, and medicine. Here we review the major classes of hemoglobin variants, emphasizing general concepts and illustrative examples.
Topics: Hemoglobinopathies; Hemoglobins; Hemoglobins, Abnormal; Humans; Methemoglobin; Mutation; Oxygen
PubMed: 23388674
DOI: 10.1101/cshperspect.a011858 -
International Journal of Molecular... Dec 2022Dapsone (DDS) therapy can frequently lead to hematological side effects, such as methemoglobinemia and DNA damage. In this study, we aim to evaluate the protective...
Dapsone (DDS) therapy can frequently lead to hematological side effects, such as methemoglobinemia and DNA damage. In this study, we aim to evaluate the protective effect of racemic alpha lipoic acid (ALA) and its enantiomers on methemoglobin induction. The pre- and post-treatment of erythrocytes with ALA, ALA isomers, or MB (methylene blue), and treatment with DDS-NOH (apsone hydroxylamine) was performed to assess the protective and inhibiting effect on methemoglobin (MetHb) formation. Methemoglobin percentage and DNA damage caused by dapsone and its metabolites were also determined by the comet assay. We also evaluated oxidative parameters such as SOD, GSH, TEAC (Trolox equivalent antioxidant capacity) and MDA (malondialdehyde). In pretreatment, ALA showed the best protector effect in 2.5 µg/mL of DDS-NOH. ALA (1000 µM) was able to inhibit the induced MetHb formation even at the highest concentrations of DDS-NOH. All ALA tested concentrations (100 and 1000 µM) were able to inhibit ROS and CAT activity, and induced increases in GSH production. ALA also showed an effect on DNA damage induced by DDS-NOH (2.5 µg/mL). Both isomers were able to inhibit MetHb formation and the S-ALA was able to elevate GSH levels by stimulating the production of this antioxidant. In post-treatment with the R-ALA, this enantiomer inhibited MetHb formation and increased GSH levels. The pretreatment with R-ALA or S-ALA prevented the increase in SOD and decrease in TEAC, while R-ALA decreased the levels of MDA; and this pretreatment with R-ALA or S-ALA showed the effect of ALA enantiomers on DNA damage. These data show that ALA can be used in future therapies in patients who use dapsone chronically, including leprosy patients.
Topics: Methemoglobin; Antioxidants; Thioctic Acid; Dapsone; Superoxide Dismutase; DNA Damage
PubMed: 36613503
DOI: 10.3390/ijms24010057 -
American Journal of Hematology Feb 2007Hemoglobin has functions besides carrying oxygen to the tissues, and regulates vascular tone and inflammation via a redox couple with methemoglobin. Hemoglobin has iron... (Review)
Review
Hemoglobin has functions besides carrying oxygen to the tissues, and regulates vascular tone and inflammation via a redox couple with methemoglobin. Hemoglobin has iron in the reduced valance Fe(II) and methemoglobin has iron in the oxidized valance Fe (III), with a free energy capable of producing water from oxygen. In generating methemoglobin the couple functions as a nitrite reductase. The degree of oxidation of hemoglobin senses the oxygen level in the blood and uses its ability to produce nitric oxide from nitrite to control vascular tone, increasing blood flood when the proportion of oxygenated hemoglobin falls. Additional cardiovascular damage is produced by methemoglobin mediated oxidation of light density lipoproteins, accelerating arteriosclerosis. In addition, the release of heme from methemoglobin is an important factor in inflammation. These physiologic functions are paralleled by the well-described role in the oxidation of various drugs resulting in methemoglobinemia.
Topics: Animals; Atherosclerosis; Humans; Inflammation; Iron; Lipoproteins, LDL; Methemoglobin; Methemoglobinemia; Nitric Oxide; Oxidation-Reduction; Oxygen
PubMed: 16986127
DOI: 10.1002/ajh.20738 -
Occupational and Environmental Medicine Sep 2001
Review
Topics: Enzyme Inhibitors; Humans; Hypoxia; Methemoglobin; Methylene Blue; Occupational Diseases; Occupational Exposure; Oxidation-Reduction
PubMed: 11511749
DOI: 10.1136/oem.58.9.611 -
Journal of Biomedical Optics Feb 2021Untreated methemoglobinemia may cause severe hypoxemia and even death when methemoglobin levels in the blood stream exceed 70%. Although CO-oximetry can be used to...
SIGNIFICANCE
Untreated methemoglobinemia may cause severe hypoxemia and even death when methemoglobin levels in the blood stream exceed 70%. Although CO-oximetry can be used to monitor the response to treatment for methemoglobinemia, it is costly and requires an invasive procedure for collecting blood samples from patients. A pulse CO-oximeter with a contact probe can be used to continuously and non-invasively measure the percentage of methemoglobin, as well as the percutaneous oxygen saturation. In terms of the prevention of infectious diseases, however, it is desirable to monitor methemoglobin and oxygen saturation levels in a non-contact manner. Diffuse reflectance spectral imaging is promising as a non-contact, non-invasive, and cost-effective clinical diagnostic tool for methemoglobinemia.
AIM
To demonstrate the feasibility of visible spectral diffuse reflectance for in vivo monitoring of hemoglobin derivatives and evaluating methemoglobin production and reduction as well as hypoxemia during methemoglobinemia in rats.
APPROACH
A new imaging approach based on the multiple regression analysis aided by Monte Carlo simulations for light transport was developed to quantify methemoglobin, oxygenated hemoglobin, and deoxygenated hemoglobin using a hyperspectral imaging system. An in vivo experiment with rats exposed to sodium nitrite (NaNO2) at different doses was performed to confirm the feasibility of the method for evaluating the dynamics of methemoglobin, oxygenated hemoglobin, and deoxygenated hemoglobin during methemoglobinemia. Systemic physiological parameters, including the percutaneous arterial oxygen saturation, heart rate (HR), and pulse distention, were measured by a commercially available pulse oximeter, and the results were compared to those obtained by the proposed method.
RESULTS
Both the methemoglobin concentration and methemoglobin saturation rapidly increased with a half-maximum time of <20 min. They reached their maximal values nearly 60 min after the administration of NaNO2. Tissue oxygen saturation dramatically dropped to a minimum of 33.7 % ± 0.4 % , 23.1 % ± 5.6 % , 8.8 % ± 1.7 % , and 9.7 % ± 5.1 % on average for NaNO2 doses of 25, 37.5, 50, and 75 mg/kg, respectively. Changes in methemoglobin concentration and tissue oxygen saturation are indicative of the temporary production of methemoglobin and severe hypoxemia during methemoglobinemia. Profound increases in the HR and pulse distention implied an elevated cardiac output caused by tachycardia and the resultant increase in peripheral blood volume to compensate for the hypoxia and hypoxemia during methemoglobinemia. This was in agreement with the time course of the peripheral hemoglobin volume concentration obtained by the proposed method.
CONCLUSIONS
The proposed method is capable of the in vivo non-contact simultaneous evaluation of methemoglobin levels and hypoxemia during methemoglobinemia, and that it has potential as a tool for the diagnosis and management of methemoglobinemia.
Topics: Animals; Hemoglobins; Humans; Methemoglobin; Methemoglobinemia; Oximetry; Oxyhemoglobins; Rats
PubMed: 33583153
DOI: 10.1117/1.JBO.26.3.033708 -
PloS One 2016A major concern during pesticide development and use is the impact on non-target species, such as raptors or domestic cats and dogs. Sodium nitrite and...
A major concern during pesticide development and use is the impact on non-target species, such as raptors or domestic cats and dogs. Sodium nitrite and para-aminopropiophenone (PAPP) are two toxicants currently being studied for the control of invasive species, such as starlings and feral swine. When given to an animal these compounds oxidize hemoglobin, which renders it unable to carry oxygen resulting in methemoglobinemia. This study developed a method to estimate methemoglobin levels in mammals and birds by examining the efficacy of sodium nitrite to induce the conversion of hemoglobin to methemoglobin. Varying concentrations of sodium nitrite were added to aliquots of coyote, vole, feral swine, starling, and duck blood, collected from captive animals. The blood samples were analyzed spectrophotometrically to determine percent methemoglobin and digitally to determine red color values (RCV) associated with different methemoglobin levels. The avian and mammalian blood reached 100% methemoglobin levels at 200 mM and 15 mM sodium nitrite, respectively. All animals had similar RCV for a given percent methemoglobin. In conclusion, this study developed a procedure to quickly determine methemoglobin levels in mammals and birds. Furthermore, percent methemoglobin can be estimated with one standard curve from any animal species and an image of a blood spot. The technique will be useful during field studies, in agricultural areas, or in a veterinarian's office for the rapid diagnosis of methemoglobinemia in non-target animals that have eaten toxicants/baits or baited animals.
Topics: Animals; Animals, Wild; Arvicolinae; Bird Diseases; Colorimetry; Coyotes; Ducks; Methemoglobin; Methemoglobinemia; Sodium Nitrite; Spectrophotometry; Starlings; Swine; Swine Diseases
PubMed: 27930713
DOI: 10.1371/journal.pone.0167942 -
Respiratory Care Dec 2016Newer pulse oximetry technology is available that uses multiple wavelengths of light and is thereby able to measure more than 2 forms of hemoglobin, including...
Newer pulse oximetry technology is available that uses multiple wavelengths of light and is thereby able to measure more than 2 forms of hemoglobin, including carboxyhemoglobin (SpCO), methemoglobin (SpMet), and total hemoglobin (SpHb). Several studies have shown relatively low bias, but poor precision, for SpCO compared with HbCO. Evaluations of SpMet have been conducted primarily in normal subjects. Clinical evaluations of SpHb suggest that it might not yet be accurate enough to make transfusion decisions. Respiratory waveform variability of the pulse oximeter plethysmogram might be useful to assess pulsus paradoxus in patients with airway obstruction; it might also be used to measure the breathing frequency. The change in pulse pressure over the respiratory cycle has been used to assess fluid responsiveness in mechanically ventilated patients, and similarly, the pulse oximetry plethysmogram waveform amplitude variability might be used to assess fluid responsiveness. However, there are limitations to this approach, and it remains to be determined how well it can be applied clinically using existing pulse oximetry technology. The pulse oximeter signal is probably useful for applications beyond S However, the current technology is not mature, and improvements are necessary. With technology improvements, the use of pulse oximetry to detect SpCO, SpMet, SpHb, pulsus paradoxus, breathing frequency, and fluid responsiveness is likely to improve in the future.
Topics: Blood Pressure; Carboxyhemoglobin; Hemoglobins; Humans; Methemoglobin; Oximetry; Plethysmography; Respiration
PubMed: 27899542
DOI: 10.4187/respcare.05208 -
Journal of Biomedical Optics Dec 2021For optical methods to accurately assess hemoglobin oxygen saturation in vivo, an independently verifiable tissue-like standard is required for validation. For this...
SIGNIFICANCE
For optical methods to accurately assess hemoglobin oxygen saturation in vivo, an independently verifiable tissue-like standard is required for validation. For this purpose, we propose three hemoglobin preparations and evaluate methods to characterize them.
AIM
To spectrally characterize three different hemoglobin preparations using multiple spectroscopic methods and to compare their absorption spectra to commonly used reference spectra.
APPROACH
Absorption spectra of three hemoglobin preparations in solution were characterized using spectroscopic collimated transmission: whole blood, lysed blood, and ferrous-stabilized hemoglobin. Tissue-mimicking phantoms composed of Intralipid, and the hemoglobin solutions were characterized using spatial frequency-domain spectroscopy (SFDS) and enhanced perfusion and oxygen saturation (EPOS) techniques while using yeast to deplete oxygen.
RESULTS
All hemoglobin preparations exhibited similar absorption spectra when accounting for methemoglobin and scattering in their oxyhemoglobin and deoxyhemoglobin forms, respectively. However, systematic differences were observed in the fitting depending on the reference spectra used. For the tissue-mimicking phantoms, SFDS measurements at the surface of the phantom were affected by oxygen diffusion at the interface with air, associated with higher values than for the EPOS system.
CONCLUSIONS
We show the validity of different blood phantoms and what considerations need to be addressed in each case to utilize them equivalently.
Topics: Hemoglobins; Methemoglobin; Oxygen; Oxygen Saturation; Oxyhemoglobins
PubMed: 34850613
DOI: 10.1117/1.JBO.27.7.074708 -
Chemical Research in Toxicology Mar 2016Arylamines (AAs) and heterocyclic aromatic amines (HAAs) are structurally related carcinogens formed during the combustion of tobacco or cooking of meat. They undergo...
Arylamines (AAs) and heterocyclic aromatic amines (HAAs) are structurally related carcinogens formed during the combustion of tobacco or cooking of meat. They undergo cytochrome P450 mediated N-hydroxylation to form metabolites which bind to DNA and lead to mutations. The N-hydroxylated metabolites of many AAs also can undergo a co-oxidation reaction with oxy-hemolgobin (HbO2) to form methemoglobin (met-Hb) and the arylnitroso intermediates, which react with the β-Cys(93) chain of Hb to form Hb-arylsulfinamide adducts. The biochemistry of arylamine metabolism has been exploited to biomonitor certain AAs through their Hb arylsulfinamide adducts in humans. We examined the reactivity of HbO2 with the N-hydroxylated metabolites of 4-aminobiphenyl (ABP, HONH-ABP), aniline (ANL, HONH-ANL), and the HAAs 2-amino-9H-pyrido[2,3-b]indole (AαC, HONH-AαC), 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP, HONH-PhIP), and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx, HONH-MeIQx). HONH-ABP, HO-ANL, and HONH-AαC induced methemoglobinemia and formed Hb sulfinamide adducts. However, HONH-MeIQx and HONH-PhIP did not react with the oxy-heme complex, and met-Hb formation and chemical modification of the β-Cys(93) residue were negligible. Molecular modeling studies showed that the distances between the H-ON-AA or H-ON-HAA substrates and the oxy-heme complex of HbO2 were too far away to induce methemoglobinemia. Different conformational changes in flexible helical and loop regions around the heme pocket induced by the H-ON-AA or H-ON-HAAs may explain the different proclivities of these chemicals to induce methemoglobinemia. Hb-Cys(93β) sulfinamide and sulfonamide adducts of ABP, ANL, and AαC were identified, by Orbitrap MS, following the proteolysis of Hb with trypsin, Glu-C, or Lys-C. Hb sulfinamide and sulfonamide adducts of ABP were identified in the blood of mice exposed to ABP, by Orbitrap MS. This is the first report of the identification of intact Hb sulfinamide adducts of carcinogenic AAs in vivo. The high reactivity of HONH-AαC with HbO2 suggests that the Hb sulfinamide adduct of AαC may be a promising biomarker of exposure to this HAA in humans.
Topics: Amines; Animals; Carcinogens; Hemoglobins; Heterocyclic Compounds; Humans; Hydrocarbons, Aromatic; Male; Methemoglobin; Mice; Mice, Inbred Strains
PubMed: 26824300
DOI: 10.1021/acs.chemrestox.5b00418 -
American Journal of Physiology. Lung... Jan 2014Diffuse alveolar hemorrhage is characterized by the presence of red blood cells and free hemoglobin in the alveoli and complicates a number of serious medical and...
Diffuse alveolar hemorrhage is characterized by the presence of red blood cells and free hemoglobin in the alveoli and complicates a number of serious medical and surgical lung conditions including the pulmonary vasculitides and acute respiratory distress syndrome. In this study we investigated the hypothesis that exposure of human alveolar epithelial cells to hemoglobin and its breakdown products regulates chemokine release via iron- and oxidant-mediated activation of the transcription factor NF-κB. Methemoglobin alone stimulated the release of IL-8 and MCP-1 from A549 cells via activation of the NF-κB pathway; additionally, IL-8 required ERK activation and MCP-1 required JNK activation. Neither antioxidants nor iron chelators and knockdown of ferritin heavy and light chains affected these responses, indicating that iron and reactive oxygen species are not involved in the response of alveolar epithelial cells to methemoglobin. Incubation of primary cultures of human alveolar type 2 cells with methemoglobin resulted in a similar pattern of chemokine release and signaling pathway activation. In summary, we have shown for the first time that methemoglobin induced chemokine release from human lung epithelial cells independent of iron- and redox-mediated signaling involving the activation of the NF-κB and MAPK pathways. Decompartmentalization of hemoglobin may be a significant proinflammatory stimulus in a variety of lung diseases.
Topics: Acetylcysteine; Alveolar Epithelial Cells; Antioxidants; Cell Line, Tumor; Chemokine CCL2; Chemokines; Deferoxamine; Gene Knockdown Techniques; Humans; I-kappa B Kinase; Interleukin-8; Iron Chelating Agents; MAP Kinase Signaling System; Methemoglobin; NF-kappa B; Oxidative Stress; Phenanthrolines; Phosphorylation; Protein Processing, Post-Translational; Pulmonary Alveoli; RNA Interference
PubMed: 24142518
DOI: 10.1152/ajplung.00066.2013