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PubMed1982

H2O2 production, modification of the glutathione status and methemoglobin formation in red blood cells exposed to diethyldithiocarbamate in vitro.

Human red blood cells treated with the CuZn superoxide dismutase inhibitor diethyldithiocarbamate (DDC) undergo metabolic modifications in addition to the superoxide dismutase inhibition: oxidation of the reduced glutathione (GSH) to oxidized glutathione (GSSG), methemoglobin formation, and increased hexose monophosphate shunt activity were observed. The magnitudes of these changes are dependent on the DDC concentration. Under nitrogen, only superoxide dismutase inhibition occurs. After removal of the GSH with N-ethylmaleimide, production of H2O2 can be detected by measuring the red cell catalase inhibition in the presence of 3-amino-1,2,4-triazole. H2O2 production is not altered by conversion of oxyhemoglobin to methemoglobin by sodium nitrite prior to incubation. GSH oxidation and methemoglobin formation are stopped when DDC is eliminated from the incubation medium after completion of the superoxide dismutase inhibition. These data indicate that methemoglobin formation and modification of the GSH status in red cells treated by DDC are not a direct consequence of the CuZn superoxide dismutase inhibition but are due rather to a DDC-dependent production of H2O2.

Ditiocarb↗

PubMed1982

Inhibition of methemoglobin and metmyoglobin reduction by cobalt.

Because cobalt compounds tend to form stable complexes, there has been continued interest in the use of the salts and chelates of cobalt in cyanide poisoning, and continued uncertainty about the precise nature of their protective effects. We have found that cobalt ions inhibit the enzymatic reduction of both methemoglobin and metmyoglobin. Virtually total inhibition of methemoglobin and metmyoglobin reductase activity occurred with the addition of 2.5 mM cobalt acetate to the assay system. Both enzymes were inhibited by lower levels of cobalt in a dose-dependent manner. The similarity in susceptibility of cobalt inhibition is further evidence that the enzymes which reduce methemoglobin and metmyoglobin are functionally comparable. The inhibition of methemoglobin reductase activity may be, in part, responsible for the therapeutic effectiveness of cobalt salts and chelates in cyanide poisoning.

Animals↗

PubMed1991

Mechanistic aspects of the oxidation of phenothiazine derivatives by methemoglobin in the presence of hydrogen peroxide.

Mechanistic aspects of the reaction of hydrogen peroxide with methemoglobin with respect to phenothiazine oxidation have been studied. Three phenothiazines, methoxy- (MoPZ), chlor- (CPZ) and methoxycarbonylpromazine (MaPZ), have been used. These phenothiazines differ only in substitution at the 2-position, which contributes substantially to the electron-donating properties of these compounds. Reaction with hydrogen peroxide oxidizes methemoglobin to ferrylhemoglobin, which contains iron(IV)-oxo porphyrin moiety and a protein radical. The phenothiazines are oxidized by ferrylhemoglobin in the presence of H2O2 mainly to their sulfoxides, with a radical cation as intermediate. The conversion rates (MoPZ greater than CPZ greater than MaPZ) decrease with the electron-withdrawing ability of the 2-substituent, as indicated by Hammett sigma para values. Hydrogen peroxide consumption during the reaction is similar for the three phenothiazines. Denaturation reactions that occur upon exposure of methemoglobin to hydrogen peroxide have been investigated. For this heme-protein cross-linking was studied by means of heme retention by the protein after methyl ethyl ketone extraction. Furthermore, oxygen consumption during the reaction was assayed, which indicates formation of protein-peroxy radicals. The extent of both heme-protein cross-linking and oxygen consumption is decreased by phenothiazines in the same order as the phenothiazine conversion rate. CPZ sulfoxide is not converted by methemoglobin in the presence of hydrogen peroxide, and CPZ sulfoxide shows no effect on heme-protein cross-linking and oxygen consumption. The results are explained by electron transfer from phenothiazine to the protein radical. Stronger electron donors (MoPZ greater than CPZ greater than MaPZ) are converted faster and by reducing the protein radical they better protect hemoglobin against denaturation. A catalytic cycle, that takes into account our observation and the existing knowledge of hemoglobin oxidation states, is presented.

Chlorpromazine↗

PubMed1978

Effects of hemolysate concentration, ionic strength and cytochrome b5 concentration on the rate of methemoglobin reduction in hemolysates of human erythrocytes.

An assay for determining the rate of methemoglobin reduction in hemolysates of human erythrocytes has been developed. The rates obtained by this assay, when corrected for dilution, are comparable to those obtained with intact cells. Increased ionic strength inhibits the reaction, whereas EDTA increases the rate of reduction. The rate with NADPH as electron donor is 65-70% of the rate with NADH. Added cytochrome b5 stimulates the reaction. The assay has been used to examine erythrocytes from two methemoglobinemic sisters and their asymptomatic mother. Hemolysates of the two patients have both decreased dichlorophenolindophenol reductase activity and decreased ability to reduce methemoglobin. Hemolysates from the heterozygous mother have intermediate dichlorophenolindophenol reductase activity and intermediate methemoglobin reduction ability. The data presented in this paper indicate that the concentrations of cytochrome b5 and cytochrome b5 reductase determine the rate of methemoglobin reduction in hemolysates.

Cytochrome-B(5) Reductase↗

PubMed2006

The effects of conductivity and electrochemical doping on the reduction of methemoglobin immobilized in nanoparticulate TiO2 films.

Methemoglobin (bovine) is immobilized from aqueous phosphate buffer (pH 5.5) solution into thin porous TiO(2) (anatase) films at ITO electrode surfaces. Films of TiO(2) are produced in a deposition process employing 40 nm diameter TiO(2) nanoparticles suspended in dry methanol followed by calcination. The pore size in these films is sufficient for methemoglobin (ca. 6 nm diameter) to diffuse into the porous structure (over several hours) and to remain immobilized in electrochemically active form. The electrochemical reduction of methemoglobin immobilized in TiO(2) and immersed in aqueous phosphate buffer at pH 5.5 is observed in two steps with (i) a small quasi-reversible voltammetric response at -0.16 V vs. SCE (Process 1) and (ii) an irreversible reduction peak at ca. -0.5 V vs. SCE (Process 2). The irreversible response is recovered only after slow chemical re-oxidation of hemoglobin to methemoglobin. At sufficiently negative applied potential "electrochemical doping" of the TiO(2) host is observed to lead to a considerably enhanced reduction Process 1. TiO(2) can be temporarily switched from a non-conducting (irreversible electron transfer) into a conducting (reversible electron transfer) state.

Adsorption↗

PubMed1995

Electron-electron spin-spin interaction in spin-labeled low-spin methemoglobin.

Nitroxyl free radical electron spin relaxation times for spin-labeled low-spin methemoglobins were measured between 6 and 120 K by two-pulse electron spin echo spectroscopy and by saturation recovery electron paramagnetic resonance (EPR). Spin-lattice relaxation times for cyano-methemoglobin and imidazole-methemoglobin were measured between 8 and 25 K by saturation recovery and between 4.2 and 20 K by electron spin echo. At low temperature the iron electron spin relaxation rates are slow relative to the iron-nitroxyl electron-electron spin-spin splitting. As temperature is increased, the relaxation rates for the Fe(III) become comparable to and then greater than the spin-spin splitting, which collapses the splitting in the continuous wave EPR spectra and causes an increase and then a decrease in the nitroxyl electron spin echo decay rate. Throughout the temperature range examined, interaction with the Fe(III) increases the spin lattice relaxation rate (1/T1) for the nitroxyl. The measured relaxation times for the Fe(III) were used to analyze the temperature-dependent changes in the spin echo decays and in the saturation recovery (T1) data for the interacting nitroxyl and to determine the interspin distance, r. The values of r for three spin-labeled methemoglobins were between 15 and 15.5 A, with good agreement between values obtained by electron spin echo and saturation recovery. Analysis of the nitroxyl spin echo and saturation recovery data also provides values of the iron relaxation rates at temperatures where the iron relaxation rates are too fast to measure directly by saturation recovery or electron spin echo spectroscopy. These results demonstrate the power of using time-domain EPR measurements to probe the distance between a slowly relaxing spin and a relatively rapidly relaxing metal in a protein.

Cyclic N-Oxides↗

PubMed1993

Cyanide and methemoglobin kinetics in smoke inhalation victims treated with the cyanide antidote kit.

STUDY OBJECTIVE: To evaluate serial cyanide, methemoglobin, and carbon monoxide levels in smoke inhalation patients. SETTING: Regional poison center and regional toxicology treatment center. PARTICIPANTS: Seven critically ill smoke inhalation patients referred to the regional poison center. INTERVENTIONS: Peak level and half-life were determined by obtaining serial carboxyhemoglobin, cyanide, and methemoglobin levels. RESULTS: The mean observed half-life of cyanide was 3.0 +/- 0.6 hours. Methemoglobinemia was evaluated in four patients after sodium nitrite administration. The peak measured methemoglobin levels (mean, 10.5% +/- 2%; range, 7.9% to 13.4%) did not occur until a mean of 50 minutes (range, 35 to 70 minutes) following administration of sodium nitrite. The total oxygen-carrying capacity reduced by the combination of carboxyhemoglobin and methemoglobin was never more than 21% (range, 10% to 21%) in this series. CONCLUSION: The administration of sodium nitrite to smoke inhalation patients in the presence of concomitant carbon monoxide poisoning may be relatively safe.

Adult↗

PubMed1988

Anomalously slow cyanide binding to Glycera dibranchiata monomer methemoglobin component II: implication for the equilibrium constant.

In comparison to sperm whale metmyoglobin, metleghemoglobin a, methemoglobins, and heme peroxidases, the purified Glycera dibranchiata monomer methemoglobin component II exhibits anomalously slow cyanide ligation kinetics. For the component II monomer methemoglobin this reaction has been studied under pseudo-first-order conditions at pH 6.0, 7.0, 8.0, and 9.0, employing 100-250-fold mole excesses of potassium cyanide at each pH. At 20 degrees C, with micromolar protein concentrations, kobsd varies between 9.11 x 10(-5) s-1 at pH 6.0, 100-fold KCN mole excess, and 1.12 x 10(-2) s-1 at pH 9.0, 250-fold KCN mole excess. Our analysis shows that the concentration-independent bimolecular rate constant (k1app) is small in comparison to those of the other heme proteins. For example, at pH 7.0 it is 0.491 M-1 s-1, compared to 1.1 x 10(5) M-1 s-1 for cytochrome c peroxidase; 111 M-1 s-1 for guinea pig methemoglobin; approximately 400 M-1 s-1 for sperm whale metmyoglobin; and 692 M-1 s-1 for soybean metleghemoglobin a, at the same pH and similar temperatures. Furthermore, our results show that the dissociation rate is extremely slow, with k-1app no larger than 10(-6) s-1. Separation of the bimolecular rate constant into contributions from kCN- (the rate constant for CN- binding) and from kHCN (the rate constant for HCN binding) shows that the former is approximately 90 times greater. These results indicate that cyanide ligation reactions are not instantaneous for this protein, which is important for those attempting to study the ligand-binding equilibria.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1989

Spin equilibrium in human methemoglobin: effects of inositol hexaphosphate and bezafibrate as measured by resonance Raman spectroscopy.

The spin equilibria of several derivatives of human methemoglobin were probed by resonance Raman scattering. The intensity of lines in the Raman spectrum gives a measure of the high-spin (S = 5/2) to low-spin (S = 1/2) ratio which agrees well with the spin equilibria determined from direct magnetic susceptibility measurements. The addition of bezafibrate (BZF) to methemoglobin in the absence of organic phosphate, IHP, has very little effect on the spin equilibrium, whereas in the presence of IHP it augments the change in spin significantly. When both IHP and BZF are added to the mixed-spin derivatives (H2O, SCN-, OCN-, and NO2-) of human methemoglobin, the spin equilibrium is shifted toward higher spin by about 700 cal/mol, similar to the spin change detected in derivatives of carp methemoglobin upon addition of IHP alone. These data support a general mechanism for the allosteric transition in which a constant fraction of the cooperative energy (approximately 20%) is detected at the heme of the ferric ligand-bound forms.

Animals↗

PubMed2000

Lipid oxidation in a chicken muscle model system: oxidative response of lipid classes to iron ascorbate or methemoglobin catalysis.

Catalysis by iron ascorbate and activated methemoglobin generated different oxidative responses in chicken muscle model systems. In iron ascorbate systems, large increases in hydroperoxides and thiobarbituric acid-reactive substances (TBARS) occurred during the initial stage of incubation. Thereafter, iron ascorbate catalysis led to a slow increase in the oxidation of triacylglcyerol (TG) and sarcoplasmic reticulum (SR) membrane lipids. By the end of incubation, 24, 36, and 32% of the initial content of n-3 fatty acids in free fatty acids, TG, and SR single-lipid model systems catalyzed by iron ascorbate had been lost. Reduced losses of n-3 fatty acids were observed in the SR and TG fractions (0 and 24%, respectively) when iron ascorbate model systems contained all three lipid fractions (mix). Hydroperoxides and TBARS in model systems catalyzed by activated methemoglobin were characterized by a lag phase during most of the incubation. Consistent with their role as antioxidants, losses of alpha-tocopherol (42-49%), gamma-tocopherol (36-42%), and protein sulfhydryls (41-52%) were observed in model systems catalyzed by activated methemoglobin. SR and mix model systems were 30-50% slower to oxidize than TG model systems when activated methemoglobin served as the catalytic agent.

Animals↗

PubMed2002

Postcollection rise in methemoglobin level in frozen blood specimens.

A patient with nonspecific complaints had four previous venous blood samples showing elevated methemoglobin fractions of 15.6-20.1%. Cooximetry on a fresh specimen revealed a methemoglobin fraction of 0.8%, while that reported by the original laboratory on the simultaneously collected specimen was 14.9%. The laboratory assayed the specimen after holding it in frozen storage. Venous blood from a healthy volunteer was assayed by cooximetry after storage under conditions of room temperature (22-24 degrees C), refrigeration (1-4 degrees C), and freezing (-14 to -12 degrees C). Methemoglobin level in frozen-thawed specimens rose over time from 1.8% (0.29 g/dL) at 6 hour to 10.9% (1.71 g/dL) after 6 days. With the exception of a single specimen stored in an EDTA-containing tube at room temperature for 6 days, methemoglobin in nonfrozen specimens never exceeded 0.8% (0.12 g/dL).

Aged↗

PubMed1989

Methemoglobin formation and reduction in canine erythrocytes with inherited high Na,K-ATPase activity.

Methemoglobin formation and reduction in canine erythrocytes with inherited high Na,K-ATPase activity (HK cells) were compared with those in normal canine cells (LK cells). Nitrite-induced methemoglobin formation in hemoglobin solutions indicated that the hemoglobin from HK cells was oxidized at essentially the same rate as that of LK cells. However, methemoglobin formation in HK cells was slower due to the inhibition by high glutathione (GSH) concentration. Methemoglobin reduction was allowed to take place on nitrite-treated and washed erythrocytes in a glucose medium and was reduced more rapidly in HK cells than in LK cells. During the reduction, the amounts of lactate and pyruvate increased more rapidly in HK cells, indicating enhanced glycolysis in HK cells. It is thus evident that the hemoglobin of HK cells is more securely protected from nitrite-induced oxidation by the GSH presence in great excess and by the increase in glycolysis.

Animals↗

PubMed1994

Methemoglobin formation after administration of hemoglobin conjugated to carboxylate dextran in guinea pigs. Attempts to prevent the oxidation of hemoglobin.

In 1990, McGown demonstrated in vitro a limitation of extracellular methemoglobin (metHb) formation by releasing and recycling of ascorbic acid by red blood cells. In order to investigate the autoxidation of free or modified hemoglobin in plasma and the possibility of reproducing McGown's phenomenon in vivo, we performed a 50% blood mass exchange in guinea-pigs with a 70 +/- 5 g/l dex-BTC-Hb solution (metHb < 5%). Methemoglobin was determined according to Evelyn-Malloy's method. We observed a clear but limited oxidation of plasmatic hemoglobin (MetHb approximately 30-40% at t = 12 hrs up to t = 24 hrs). A similar blood mass exchange was performed with the same hemoglobin solution which was previously totally oxidized into metHb. 40% of this methemoglobin was found to be reduced after 12 hrs. These results demonstrated a marked reducing activity by residual blood as shown by others. The addition of potentially protective compounds such as ascorbic acid (non enzymatic intraerythrocytar reduction pathway), methylene blue or riboflavin (enzymatic intraerythrocytar pathway), allowed a significant drop in the methemoglobin level. On the contrary, we didn't observe any reducing effect with reduced glutathione.

Animals↗

PubMed1998

Hemoglobin autooxidation/oxidation mechanisms and methemoglobin prevention or reduction processes in the bloodstream. Literature review and outline of autooxidation reaction.

The amount of circulating methemoglobin in healthy humans is the result of a balance between methemoglobin production (from autooxidation and oxidation) and hemoglobin reduction. Hemoglobin autooxidation and oxidation are very complex and are not well understood. This article analyses the literature on hemoglobin autooxidation, oxidation and reduction and sets out a sequence of reactions for the oxidation of hemoglobin and the ways in which the percentage of methemoglobin is regulated or methemoglobin production prevented. Most of the information concerns erythrocyte hemoglobin, but plasma extracellular hemoglobin (from hemolysis or hemoglobin-based blood substitutes) is also considered where possible.

Hemoglobin A↗

PubMed1998

Temporal changes in perivascular concentrations of oxyhemoglobin, deoxyhemoglobin, and methemoglobin after subarachnoid hemorrhage.

UNLABELLED: Hemoglobin released from hemolysed erythrocytes has been postulated to be responsible for delayed cerebral vasospasm after subarachnoid hemorrhage (SAH). However, the evidence is indirect and the mechanisms of action are unclear. Cerebrovascular tone is regulated by a dynamic balance of relaxing and contracting factors. Loss of the endothelium-derived relaxing factor-nitric oxide in the presence of oxyhemoglobin and overproduction of endothelin-1 stimulated by oxyhemoglobin have been postulated as causes of delayed cerebral vasospasm after SAH. OBJECT: The authors aimed to investigate this hypothesis using in vivo microdialysis to examine time-dependent changes in the perivascular concentrations of oxyhemoglobin, deoxyhemoglobin, and methemoglobin in a primate model of SAH. METHODS: Nine cynomolgus monkeys underwent right-sided frontotemporal craniectomy and placement of a semipermeable microdialysis catheter adjacent to the right middle cerebral artery (MCA). Saline (control group, three animals) or an arterial blood clot (SAH group, six animals) was then placed around the MCA and the catheter. Arteriographically confirmed vasospasm had developed in all animals with SAH but in none of the control animals on Day 7. The dialysate was collected daily for 12 days. Levels of oxyhemoglobin, deoxyhemoglobin, and methemoglobin were measured by means of spectrophotometry. Perivascular concentrations of oxyhemoglobin, deoxyhemoglobin, and methemoglobin peaked on Day 2 in the control monkeys and could not be detected on Days 5 to 12. Perivascular concentrations of oxyhemoglobin and deoxyhemoglobin peaked on Day 7 in the SAH group, at which time the concentrations in the dialysate were 100-fold higher than in any sample obtained from the control animals. Methemoglobin levels increased only slightly, peaking between Days 7 and 12, at which time the concentration in the dialysate was 10-fold higher than in samples from the control animals. CONCLUSIONS: This study provides in vivo evidence that the concentrations of oxyhemoglobin and deoxyhemoglobin increase in the cerebral subarachnoid perivascular space during the development of delayed cerebral vasospasm. The results support the hypothesis that oxyhemoglobin is involved in the pathogenesis of delayed cerebral vasospasm after SAH and implicate deoxyhemoglobin as a possible vasospastic agent.

Analysis of Variance↗

PubMedDate not supplied

[The experimental treatment of cyanide poisoning with a methemoglobin solution].

The stroma-free methemoglobin solution proved to be an effective antidote against acute cyanide poisoning in experiment. The poisoning was induced by intraperitoneal administration to rats of cyanide solutions in doses of 5, 10 and 15 mg/kg. Methemoglobin solutions were injected intravenously in doses of 2 and 4 g/kg. All the rats given methemoglobin solution after the administration of cyanide survived. Spectrophotometry of rat urine demonstrated rapid excretion of methemoglobin cyanide.

Animals↗

PubMed1992

Diagnostic significance of methemoglobin determination in colorless cerebrospinal fluid.

The presence of various heme derivatives can be demonstrated spectrophotometrically in colorless cerebrospinal fluid (CSF). Because of the high sensitivity of the method, it may detect compounds that reflect a "traumatic tap" rather than a disease process. However, the presence of methemoglobin excludes the possibility of a hemorrhagic CSF being caused by traumatic lumbar puncture. Here we describe a highly sensitive spectrophotometric method involving measurement at the Soret band (400-420 nm) to detect methemoglobin (greater than or equal to 15%) in trace amounts of hemoglobin mixture (less than 0.3 mumol/L). We demonstrated methemoglobin in colorless CSF samples in 9% of 454 patients with cerebrovascular pathology and in 4% of 449 patients with other neurological diseases (n = 449). In a group of 21 patients with verified acute cerebral hematomas, methemoglobin was confirmed in 66% of colorless CSF samples after ultrafiltration. We conclude that routine spectrophotometric analysis of all CSF samples is very useful, allowing detection of xanthochromic compounds in patients with small cerebral and subdural hematomas as well as in those with minimal subarachnoid hemorrhages, hemorrhagic infarctions, or bleedings from aneurysms and neoplasms.

Cerebral Hemorrhage↗

PubMed1978

Quaternary states of methemoglobin and its valence-hybrid. A pulse radiolysis study.

Using the pulse radiolysis technique on solutions of stripped adult human methemoglobin, we found that the heme-iron within a single subunit in the tetramer was reduced to iron(II). The valence-hybrid thus formed was reacted with oxygen and with carbon monoxide. Kinetics of the reactions were studied. The effects of pH, inositol hexaphosphate, and temperature on these reactions were examined. The kinetics of the ligation of O2 and CO were used to characterize the affinity states of the valence-hybrid and its parent methemoglobin. Our results support the description of stripped methemoglobin A as residing in an R state. In the presence of inositol hexaphosphate methemoglobin is stabilized in a T state, but it switches into a high affinity state when the pH is raised a0ove 8.0. This structural transition was not found to coincide with the switch of spin state of the heme-iron that accompanies the ionization of water in aquomethemoglobin A.

Adult↗