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PubMed1981

Methemoglobin pathophysiology.

The biochemical processes involved in the formation of methemoglobin, in the protection of hemoglobin against oxidation to methemoglobin, and in the reduction of methemoglobin to hemoglobin are reviewed. Special emphasis is directed to the major and minor metabolic pathways in human erythrocytes that are involved in the reduction of methemoglobin, and evidence is presented that the NADH-methemoglobin reductase system, involving a soluble cytochrome b5 and NADH-cytochrome b5 reductase, it is the most important reductive mechanism. Toxic methemoglobinemia, methemoglobinemia due to hemoglobin M's, and hereditary methemoglobinemia due to deficiency in NADH-methemoglobin reductase activity are considered. Their clinical manifestations, diagnosis, and treatment are discussed briefly.

Cytochrome-B(5) Reductase↗
PubMed1981

Proximal strain and visible absorption changes in the model complexes of imidazole methemoglobin.

The visible absorption changes upon addition of 1-methylimidazole to ferric protohemin(2-methylimidazole)2 were examined in dimethylsulfoxide at 21 degrees C. The formation of the mixed ligand complex, protohemin(1-methylimidazole)(2-methylimidazole), was confirmed with the equilibrium constant of 5.50 +/- 0.41. The absorption changes accompanied with a rise of the high spin bands and a fall of the low spin bands were interpreted to reflect the structural change of the iron-imidazole bond in going from the strained to unstrained states. The calculated difference spectrum between the mixed ligand complex and protohemin(2-methylimidazole)2 exhibited peaks at 420, 500, 540, 560, and 620 nm. These peak positions were in good agreement with those reported for imidazole methemoglobin upon addition of inositol of hexaphosphate (IHP). The proton NMR observation for 1-methylimidazole-ligated methemoglobin showed that IHP induces a structural change in the globin of the ligand bound methemoglobin. This proton NMR observation and the visible difference spectral similarity between imidazole methemoglobin and its model complex suggest that IHP imposes a proximal strain of 300 +/- 50 cal/mol in imidazole methemoglobin. Consideration on the strain energy and the sixth ligand affinity in the model system suggests that the changes in the noncovalent interactions between the globin and the porphyrin or ligand are important to regulate the imidazole affinity of imidazole methemoglobin bound with IHP.

Adult↗
PubMed1993

Inhibitory effect of alpha-tocopherol on methemoglobin formation by nitric oxide in normal and acatalasemic mouse hemolysates.

The inhibitory effect of alpha-tocopherol on methemoglobin formation in normal and acatalasemic mice was studied by exposing their hemolysates to nitric oxide. Methemoglobin formation in normal and acatalasemic mouse hemolysates exposed to nitric oxide were significantly inhibited by the addition of alpha-tocopherol at final concentrations ranging from 1.2 to 5.8 mM. Negative correlations were observed between the logarithm of alpha-tocopherol concentration and the methemoglobin formation. The formation of methemoglobin in acatalasemic mouse hemolysates was greater than that in normal mouse hemolysates with or without added alpha-tocopherol. The methemoglobin formation in acatalasemic mice was also significantly inhibited by addition of more than 500 units/ml of catalase, and the methemoglobin formation in normal and acatalasemic mice was also inhibited with sodium diethyldithiocarbamate at a final concentration of 1 M.

Acatalasia↗
PubMed2001

Effect of beta-arteether treatment on erythrocytic methemoglobin reductase system in Plasmodium yoelii nigeriensis infected mice.

BACKGROUND: The methemoglobin reductase system plays a vital role in maintaining the equilibrium between hemoglobin (Hb) and methemoglobin (MetHb) in blood. Exposure of red blood cells to an oxidative stress (pathological/physiological) may cause impairment in this equilibrium. OBJECTIVE: The status of MetHb and the related reductase system was studied during Plasmodium yoelii nigeriensis (P. y. nigeriensis) infection and beta-arteether treatment in mice. METHODS: Mice were divided into four groups. Normal group, normal mice treated with beta-arteether, P. y. nigeriensis infected mice and P. y. nigeriensis infected mice treated with beta-arteether. RESULTS: The present investigation revealed a marked decrease in the activity of MetHb reductase, with concomitant rise in MetHb levels during P. y. nigeriensis infection in mice erythrocytes (P < 0.001) as compared to normal mice. However, the activities of the associated enzymes viz., lactate dehydrogenase, glucose 6-phosphate dehydrogenase and glutathione reductase were found to be increased with progressive rise in parasitemia. beta-Arteether treatment (12.5 mg/kg body weight) of infected mice (parasitemia 20-25%) from day 5 of post infection resulted in complete clearance of parasitemia on day 7 of post infection, which was accompanied by restoration of all the altered above mentioned indices to near normal levels as compared to infected mice (P < 0.001). CONCLUSION: These results suggest that there is a marked impairment of methemoglobin and methemoglobin reductase system during P. y. nigeriensis infection in mice. beta-Arteether treatment of infected mice resulted in complete clearance of parasitemia which also caused the restoration of methemoglobin and methemoglobin reductase system to near normal levels.

Animals↗
PubMed1998

Elevated methemoglobin in patients with sepsis.

BACKGROUND: It has been reported that large amounts of nitric oxide (NO) are released in patients with sepsis. NO is converted to methemoglobin and nitrate. This study was designed to determine whether blood methemoglobin levels were increased in patients with sepsis or septic shock. METHODS: Forty-five critically ill patients including 8 with sepsis but without shock, 6 with septic shock and 31 non-septic patients were enrolled in the study. For septic and septic shock patients, blood methemoglobin concentrations were measured during sepsis or septic shock and at the time of recovery or just before the onset of sepsis. For the remaining non-septic patients, methemoglobin concentrations were measured at ICU admission and discharge. RESULTS: Blood methemoglobin levels in the presence of sepsis or septic shock were significantly (P < 0.05) higher than those in non-septic patients and those at recovery or just before the onset of sepsis in both septic and septic shock patients. CONCLUSIONS: Blood methemoglobin concentration may be useful as a marker of the onset of sepsis or septic shock.

APACHE↗
PubMed1984

NADH-methemoglobin reductase and methemoglobinemia among leprosy patients.

The NADH-methemoglobin reductase activity as well as hemoglobin and methemoglobin levels were investigated in blood samples of 182 adult leprosy patients and 137 Brazilian army enlisted men. The level of sulfones in the blood samples of the leprosy patients, all of them ingesting a daily dose of 100 mg dapsone, was also investigated. The mean value of NADH-methemoglobin reductase activity exhibited by the leprosy patients did not differ from that observed among the healthy individuals. However, the variance of the former group was significantly higher than that observed among the healthy subjects. As a consequence, the proportion of individuals showing a partial deficiency of NADH-methemoglobin reductase was significantly higher among the leprosy patients (22.5%) than among the healthy individuals (2.9%). The activity of this enzyme among the leprosy patients was negatively correlated to the hemoglobin level and slightly positively correlated to age. The concentration of methemoglobin among the leprosy patients was slightly but significantly higher as compared to the healthy individuals. The increase of the methemoglobin level among the leprosy patients was influenced by the amount of sulfones in the blood. However, no case in which dapsone was ingested in a daily dose of 100 mg presented the signs or symptoms of toxic methemoglobinemia.

Adult↗
PubMed2007

Methemoglobin--it's not just blue: a concise 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.

Animals↗
PubMedDate not supplied

Potency ranking of methemoglobin-forming agents.

This study represents the first systematic attempt to rank methemoglobin-forming agents. It is a quantitative potency ranking study utilizing linear regression analysis of dose-response data for comparative purposes. Six agents that are direct-acting and eight that require bioactivation were tested for their ability to induce methemoglobin formation in Dorset sheep erythrocytes under defined in vitro conditions. The agents were then ranked according to three complementary methods based on the slope of the linear regression, the calculated dose expected to induce a given amount of methemoglobin formation and the calculated percentage methemoglobin response induced by 1 mmol l-1 of the agent. The direct-acting agents, ranked from most to least potent inducers of methemoglobin formation, are: p-dinitrobenzene > o-dinitrobenzene > copper = nitrite > chlorite > chlorate. The ranking from most to least potent inducers of the bioactivated agents are: alpha-naphthol > p-nitroaniline > m-nitroaniline, o-nitroaniline > p-nitrotoluene = aniline > m-nitrotoluene = o-nitrotoluene. The ranking procedures are discussed and issues of interindividual variation and agent-specific sensitivities are addressed.

Analysis of Variance↗
PubMed1994

Redox conversions of methemoglobin during redox cycling of quinones and aromatic nitrocompounds.

The study focused on the effects on various redox states of hemoglobin during NADPH: cytochrome P-450 reductase-catalyzed redox cycling of quinones and nitrocompounds. The following reactions involving quinone/semiquinone and methemoglobin/oxyhemoglobin redox couples were observed: (i) the direct oxidation of oxyhemoglobin by quinones, (ii) the reduction of methemoglobin by quinones, (ii) the reduction of methemoglobin during redox cycling of quinones and nitrocompounds was partially inhibited by superoxide dismutase, and (iii) the reoxidation of oxyhemoglobin by hydrogen peroxide, formed during redox cycling was accompanied by the formation of choleglobin. Hydrogen peroxide was produced during redox cycling, and upon depletion of hydrogen peroxide by catalase, the reduction of methemoglobin significantly prevailed over oxidation of oxyhemoglobin. Furthermore, the reduction of ferrylhemoglobin to oxyhemoglobin during redox cycling was about twice as slow as the reduction of methemoglobin. For a series of compounds possessing a single-electron reduction potential (E1(7)) between 0.01 and -0.355 V, the rate constants for methemoglobin reduction by their corresponding radicals was estimated to range from 4.1 x 10(5) to 7.6 x 10(7) M-1 S-1. Radicals of the nitrocompounds were approximately 10 times less reactive as compared to quinones possessing similar E1(7) values.

Acetophenones↗
PubMed1977

[On the mechanism of ascorbic acid induced methemoglobin reduction of human erythrocytes (author's transl)].

Ascorbic acid and dehydroascorbic acid penetrate the human erythrocyte membrane. In vitro methemoglobin is reduced nonenzymatically by both substances in concentrations of 10(-2) M to 10(-3) M. Dehydroascorbic acid is reduced nonenzymatically to ascorbic acid by GSH, even with low GSH-content of erythrocytes. Under physiological conditions ascorbic acid induced methemoglobin reduction is far less important than reduction by the NADH dependent methemoglobin reductase system. In methemoglobinemic conditions caused by toxic effects or by congenital methemoglobin reductase deficiency treatment with ascorbic acid is possible. However, critically increased methemoglobin content of the blood higher than 30% makes therapy with methylene blue necessary.

Ascorbic Acid↗
PubMed1979

Inhibition of NADH-methemoglobin reductase by organic phosphates.

The organic phosphate allosteric effectors of hemoglobin, inositol hexaphosphate, 2,3-diphosphoglycerate, and ATP, interact with NADH-methemoglobin reductase (NADH-diaphorase). Significant inhibitory effects on the enzyme were found when dichlorophenolindophenol, or ferricyanide were used as electron acceptors in place of methemoglobin. In contrast, apparent stimulation of enzyme activity was observed when adult human methemoglobin was used as the electroganic phosphate on the rate of reaction due to its interaction with the substrate methemoglobin to produce the favored T type of quaternary conformation. The inhibitory effect of inositol hexaphosphate on the enzyme is associated with a perturbation in the reactivity of essential sulfhydryl group(s) on the enzyme. It is suggested that the interaction of the organic phosphate with the enzyme as well as with the substrate is significant in determining the overall rate of methemoglobin reduction.

2,6-Dichloroindophenol↗
PubMed1976

One electron reduction of metmyoglobin and methemoglobin and the reaction of the reduced molecule with oxygen.

We have used the pulse radiolysis technique to reduce with solvated electrons (see article) a single Fe(III) site in methemoglobin and metmyoglobin. The reduction process was followed spectrophotometrically and the reactions rate constants were measured: (see article) =6.5 +/- 1-10(10) M-1-S-1. (see article)=2.5 +/- 0.3-10(10) M-1-S-1. Approx. 60% of the (see article) have reacted with the hemin group, and the rest of the (see article) have probably reacted with the globin moiety. We followed the reaction of the reduced proteins to yield the oxyderivatives and measured the rate constants of the oxygenation process k reduced methemoglobin + O2 = 2.6 +/- 0.6-10(7) M-1-S-1 and k myoglobin + O2 = 1.8 +/- 0.2-10(7) M-1-S-1, all the rate constants were measured at pH = 6.8, I = 0.004, T = 22 +/- 2 degrees C. The high rate constant for reduced methemoglobin indicates that one-site-reduced methemoglobin is probably in the R state, as predicted for methemoglobin from X-ray analysis. The spectra of the reduced and oxygenated species were measured under similar conditions at gamma = 450-650 nm. We were able to follow slight changes in the micro-second time scale, these changes were attributed to conformational changes. We were not able to detect any reaction between the radical (see article) and the hemin group (which would result in a complex such as heme O-2). This may be due to kinetic reasons.

Animals↗
PubMed1981

Resonance Raman studies of methemoglobin derivatives at room temperature and 77 K.

Raman spectra in preresonance with the Soret absorption band are reported for the following methemoglobin derivatives: cyanide, cyanate, thiocyanate, hydroxy-, azide, and fluoride methemoglobin at 285 K and 77 K. For the mixed-spin derivatives, Raman intensity is observed to shift from the high-spin marker band (approx. 1480 cm-1) to the low-spin marker band (approx. 1505 cm-1) upon cooling to 77 K. In addition, Raman spectra of cyanate methemoglobin were taken as a function of temperature, and the log of the intensity ratio I1480/I1505 was found to be a linear function of 1/T, indicating a thermally activated process. We interpret these results as observations of temperature-induced spin transitions. In the case of cyanate methemoglobin we find the enthalpy and entropy differences between the high-spin and low-spin states to be deltaH = 600 +/- 40 cal x mol-1 and deltaS = 4.7 +/- 0.7 cal x mol-1 x K-1. The high-spin to low-spin ratio for cyanate methemoglobin determined by our experiment disagrees with the value reported for magnetic susceptibility measurements.

Humans↗
PubMed1984

HgCl2 increases the methemoglobin prooxidant activity. Possible mechanism of Hg2+-induced lipid peroxidation in erythrocytes.

In an attempt to elucidate the mechanism of initiation of peroxidation in HgCl2-treated erythrocytes, the effect of HgCl2 on methemoglobin-catalyzed lipid peroxidation was studied. It was found that HgCl2 reinforces the prooxidant action of methemoglobin. This effect seems not to be due to dissociation or degradation of the hemoglobin molecule to heme-containing fragments or iron-containing products of low molecular weight. The results obtained indicate that Hg2+ increases the binding of oxy- and methemoglobin to liposomes. A suggestion is made that the acceleration of methemoglobin-catalyzed peroxidation by HgCl2 is mainly due to increased binding of methemoglobin to liposomes. On the basis of these results and the results obtained previously the possible mechanism of initiation of peroxidation in Hg2+-treated erythrocytes is discussed.

Animals↗
PubMed1993

Induced hemichrome formation of methemoglobins A, S and F by fatty acids, alkyl ureas and urea.

1. Spectral analysis of the Soret region (450-350 nm) has shown that saturated fatty acids, alkyl ureas and urea induce the conversion of methemoglobins A, S, and F to the hemichrome state. 2. In the presence of fatty acids (C8-C16), methemoglobin F is converted to the hemichrome state more readily than either methemoglobins A or S. 3. Using several alkyl ureas (methyl, ethyl, propyl, butyl), the extent of hemichrome formation was as follows: met Hb F > met Hb S > met Hb A. The ability of these compounds to induce hemichrome formation is related to their increasing hydrophobicity. 4. Conversion to the hemichrome state in the presence of urea (5M) led to the formation of molecular aggregates of hemoglobins S, F and A which may be initiated by subunit dissociation and conformational changes, coupled to increased globin-globin interactions. 5. Similar aggregation occurred for methemoglobin S in the presence of octanoic acid; no significant aggregation was evident for methemoglobin A after 10 hr of exposure to octanoic acid.

Chromatography, Gel↗
PubMed1987

Studies on the influence of nitrite on methemoglobin formation in Amazonian fishes.

Twenty one species of fishes, collected from the Rio Solimões and a tributary lake in the Amazon Basin near Manaus, showed a wide range of methemoglobin formation 1 hr after a dose of 30 mg/kg of sodium nitrite i.p. Methemoglobin formation in two experimental fishes, Brycon cf. melanopterum and Semaprochilodus insignis, maintained in tanks in our INPA laboratory, was studied in detail. Both fishes survived a dose of 10 mg/kg of nitrite i.p. but usually died within 3 hr of a dose of 30 mg/kg with levels of blood methemoglobin in excess of 80%. Methemoglobin produced in vitro by addition of nitrite to fresh blood was slowly reduced back to hemoglobin over a period of several hours at room temperature. Hemoglobin in hemolysates was auto-oxidized to methemoglobin at pH 6.1 and below but not at 6.9 and above.

Animals↗
PubMed2000

Failure of intravenous N-acetylcysteine to reduce methemoglobin produced by sodium nitrite in human volunteers: A randomized controlled trial.

STUDY OBJECTIVE: To determine whether intravenous N -acetylcysteine (NAC) produces a clinically significant decline in sodium nitrite-induced methemoglobinemia in human volunteers. METHODS: We conducted a randomized, control crossover trial with each subject serving as his own control. Methemoglobinemia was induced with intravenous sodium nitrite (4 mg/kg) administered over 10 minutes starting at time 0. At time 30 minutes, subjects were randomly assigned to treatment with intravenous NAC for 100 minutes (150 mg/kg over 1 hour followed by 14 mg/kg per hour for 40 minutes) or administration of an equal volume of 5% dextrose in water. Each subject received the alternative treatment after an interval of at least 1 week. Blood methemoglobin concentrations were measured by multiwavelength co-oximetry at time 0, 15, 30, 50, 70, 90, 110, and 130 minutes. Area under the methemoglobin concentration-time curve (AUC) between 30 and 130 minutes was compared between groups using a 2-tailed, paired t test. RESULTS: There were no statistically significant differences in the control and treatment groups with respect to baseline hemoglobin or methemoglobin concentrations, as well as nitrite-induced methemoglobin concentrations at the initiation of treatment (0.85+/-0.06 g/dL, 0.88+/-0.04 g/dL; mean+/-SEM; P =.31). Mean AUC for the control group (77.1+/-5.7 g x min/dL) was significantly lower than the mean AUC for the treatment group (84.5+/-4.7 g x min/dL); P =.01). CONCLUSION: Intravenous NAC failed to enhance methemoglobin reduction in this model.

Acetylcysteine↗
PubMed1980

Proton magnetic resonance study of p-mercuribenzoate binding and structural changes in methemoglobin.

Interaction of human adult methemoglobin with p-mercuribenzoate (pMB) was examined at 21 degrees C by monitoring the hyperfine-shifted proton nuclear magnetic resonance (NMR) spectra of several high- and low-spin derivatives. The NMR spectra show that the heme methyl proton resonances from the beta subunits in methemoglobin were selectively affected by the binding of pMB regardless of whether the heme iron was saturated with high-spin or low-spin ligand. This observation suggests that the binding of pMB to methemoglobin induces a localized tertiary structural change around the beta heme, leaving the alpha heme unaffected. The structural change of the beta subunit was correlated with an increase in the high-spin character of the beta heme iron. A model study of the azide-methemoglobin complex suggested that the increase of the high-spin character of the beta heme iron is due to a conformational change of the proximal histidine which weakens the interaction between the heme iron and the proximal base. A similar and more pronounced spectral change due to binding of pMB was observed for the isolated beta subunit. The NMR spectral change in the isolated beta subunit also suggests that the binding of pMB to methemoglobin induces a localized conformational change within the beta subunit.

Adult↗