Methemoglobin - It's Not Just Blue
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Transcript of Methemoglobin - It's Not Just Blue
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MethemoglobinIts Not Just Blue: A Concise Review
Jay Umbreit*PPD Inc., Wilmington, North Carolina
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 damageis produced by methemoglobinmediated oxidation of light densitylipo-
proteins, accelerating arteriosclerosis. In addition, the release of heme from methemoglobinis an important factor in inflammation. These physiologic functions are paralleled by the
well-described role in the oxidation of various drugs resulting in methemoglobinemia. Am. J.
Hematol. 82:134144, 2007. VVC 2006 Wiley-Liss, Inc.
Key words: inflammation; atherosclerosis; methylene blue
INTRODUCTION
Hemoglobins function in oxygen carriage is sooverwhelmingly important that it has obscured someof the other functions hemoglobin plays in physiol-ogy. The heme iron is carried in an (approximately)ferrous state (Fe(II)), the reduced form that can beoxidized to the ferric Fe(III) form (methemoglobin),analogous to the cytochrome system. It is coupled toredox cycles in the cell, and is recycled itself. Thisallows for the generation of two types of cyclic path-ways. In the first, driven by the NAD-cytochrome b5reductase, hemoglobin and methemoglobin are cycled(Fig. 1). In the second, a cell redox cycle system isdriven by the oxidation of hemoglobin, with metha-moglobin as the product (Fig. 2). These complicatedsystems have important roles in inflammation and
vascular regulation.
REACTION OF HEMOGLOBIN WITH OXYGEN
The transport of oxygen requires oxygen reversiblybound to ferrous hemoglobin, HgbFe(II). The oxy-genated hemoglobin Hgb(Fe(II))O2 is a very stablemolecule but does slowly auto-oxidize at a rateof about 3%/day. This rate is accelerated at loweroxygen tensions if the hemoglobin is partially oxy-genated. The chemistry is actually quite complex.
The auto-oxygenation generates Hgb(Fe(III)), calledmethemoglobin, and superoxide. At least in vitrothe superoxide undergoes dismutation to hydrogenperoxide and oxygen. The hydrogen peroxide is rap-
idly decomposed by catalase. The 6th coordinate ofthe methemoglobin is occupied with water. If not im-mediately destroyed the hydrogen peroxide wouldreact with Hgb(Fe(II))O2 to produce ferrylhemo-globin, Hgb(Fe(IV))O with a rhombic heme thatreacts with further hydrogen peroxide to producefree Fe(III) and porphyrin degradation products [1].
HgbFeIIO2! HgbFeIII O2
2O2 2H !O2H2O2
H2O2HgbFeIIO2! HgbFeIVO
HgbFeIVO ! FeIII porphyrin breakdown:
*Correspondence to: Jay Umbreit, PPD Inc., 3151 S. 17th Street,
Wilmington, NC 28412. E-mail: [email protected]
Received for publication 27 December 2005; Accepted21 June 2006
Published online 19 September 2006 in Wiley InterScience (www.
interscience.wiley.com).
DOI: 10.1002/ajh.20738
American Journal of Hematology 82:134144 (2007)
VVC 2006 Wiley-Liss, Inc.
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It has been difficult to detect ferrylhemoglobin, Hgb(Fe(IV)) in vivo, likely because of a \comproportio-nation" between ferrylhemoglobin and oxyhemoglo-bin, Hgb(Fe(II))O2, to produce Hgb(Fe(III))O2[2].
HgbFeIVOHgbFeIIO2
!
HgbFeIIIO2
The ferrylhemoglobin is very oxidative, and thehydroxgen peroxide breakdown products accumulatein vivo and may initiate further oxidative damage [3].These are not thought to be the major pathway forhemoglobin or heme degradation under most physio-logic conditions.
When the hemoglobin, Hgb(Fe(II))O2, is auto-oxi-dized to methemoglobin, Hgb(Fe(III)), the methemo-
globin, is recycled back to hemoglobin Hgb(Fe(II))so that in the steady state the amount of intracellularmethemoglobin is
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or unstable proteins, and those associated with FADbinding residues [14,15].
Recently another factor controlling methemoglobinwas reported, an antioxidant protein AOP2 that pro-tects against methemoglobin formation. It is associated
with the hemoglobin complex and may be involved inthe normal protection of the heme pocket [16].
REACTION WITH NITRIC OXIDE,
NITRITE, AND NITRATE
Nitric oxide is a gas that is continuously producedby nitric oxide synthetase in the endothelial cells usingL-arginine as the substrate. The constitutive enzymerequires calcium and calmodulin. NO is responsiblefor control of the systemic [17] and coronary arteryvascular [18,19] tone, acting as an endothelial relaxing
factor [20,21]. The effects of NO are however limited tothe local area surrounding the cells producing the gas.NO rapidly diffuses from the endothelial cell into
the vessel lumen and enters the red blood cell. Itreacts differently with oxyhemoglobin and deoxyhe-moglobin. With oxy-hemoglobin it produces nitrate(NO3
) and methemoglobin (probably via an initialchemical oxidation to nitrite) (Fig. 3).
The nitrate represents a metabolic end point, andis excreted as an inert salt. The reaction with HgbO2limits the half-life of the NO. The reaction with freehemoglobin is so fast that any NO produced wouldbe consumed immediately. Under most circumstan-
ces the hemoglobin is separated from the plasma bybeing confined to the interior of the red cell. Thisfunctions as a barrier due to (1) the red cell mem-brane itself [22,23], (2) the unstirred layer around theerythrocyte [24], and the (3) erythrocyte-free zonealong the surface of the vascular endothelium [2527], conditioned by the rheological flow patterns ofblood. In the absence of flow, the rate of NO capturewould be increased, and dilation of the vesselsdecreased. These barriers to the uptake and destruc-tion of NO decrease the rate of hemoglobin reactionwith NO by about 600-fold, allowing local concen-
trations of NO to form to permit some vaso-dilation[28,29]. This allows a portion of the NO to escapeboth the diffusion into the vascular smooth muscleand the reaction with hemoglobin in the RBC. ThisNO is able to react with oxygen to form nitrite, or tonitrosylate free thiols, amines, and other unidentifiedcomponents [30].
2NOO2! 2NO2
NO2 HgbFeII O22H !HgbFeIII
NO3 H2O
While the mechanism for this is complex and contro-versial, overall the reaction takes one electron fromthe iron (Fe(II)?Fe(III)) and one electron from theNO2 and both are transferred to oxygen, reducing iteventually to water.
This is a counterintuitive reaction that is a com-mon reaction for hemoglobin, since the nitrite is oxi-dized (loss of electron) and the iron is oxidized (lossof electron), which does not balance, unless the oxy-gen is accounted for, which becomes reduced (gains
electrons) (Fig. 4). One model of the reaction in-volves the production of superoxide and hydrogenperoxide, which may not be correct, but illustratesthe principle [31].
Obviously, reactions with deoxygenated hemoglo-bin must use another mechanism since there is no ox-ygen, and the reactions with the deoxygenated hemo-globin are reductive not oxidative. These also resultin the production of methemoglobin. There are twomajor reactions of the nitrogenous compounds withHgb(Fe(II)), one binding NO to the heme and theother reducing nitrite to NO.
Fig. 3. Oxygenated hemoglobin uses the oxygen to pro-duce nitrate, and in the process methemoglobin. The meth-emoglobin is recycled by the reductase.
Fig. 4. Mechanism for oxidation of nitrite. While the mech-anism is still unclear, one electron is taken from Fe(II) toform Fe(III) and one from the substrate and the two elec-trons added to oxygen to eventually reduce oxygen to
water.
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HgbFeII NO! HgbFeII NO
HgbFeII NO22 H !
HgbFeIII NOOH
Nitrite could potentially be produced from dietarynitrates, and a salivary gland nitrate reductase (prob-ably due to bacterial) rapidly converts nitrates tonitrites. Nitrite in the stomach is acidified and nitrosy-lates thiols, forming S-nitrosothiols, and react withamines to form N-nitrosoamines. With electron donorssuch as ascorbate or excess nitrite the acidified nitritegenerates NO gas, which may help in mucosal bloodflow regulation and protection. In the plasma themajority of nitrite (NO2) is derived from the auto-oxi-
dation of NO.2NOO2! 2NO2
The nitrite is stable compared to NO, but can chemi-cally react with NO to form NO+, which can itselfform S-nitrosothiols and N-nitrosamines. Moreimportantly, it can be reduced by deoxy-hemoglobinto form methemoglobin and NO.
NO2HgbFeII ! HgbFeIII NO
Since the methemoglobin (Hgb(Fe(III))) can then berecycled, it yields an enzymatic conversion of nitrite
into vasoactive NO. Nitrite levels may be as high as150 nM to 1 mM, but nitrite is oxidized by oxyhemo-globin to nitrate with a half life of about 11 min [32].
Hemoglobin therefore functions as a nitrite reduc-tase (Fig. 5), resulting in the production of methhe-moglobin.
The methemoglobin is regenerated to hemoglobinby the NADH-cytochrome b5 reductase system. Butthe deoxy-form of hemoglobin is not the nitrite re-ductase, because the maximal rate of NO productionoccurs at the oxy-to-deoxy transition [33]. The rateof NO synthesis is maximal at 4060% hemoglobin
saturation. This reductase couple might be the sensorfor the oxygen tension to cause increased vasodila-tion and decrease in arteriole resistance. The hemo-globin directed production of NO would be effectiveat oxygen tension of 4015 mmHg [34], and below
about 10 mmHg direct nitrite reduction to NO bynonenzymatic disproportionation and enzymatic re-duction by xanthine oxidoreductase might contributeto NO formation.
For completeness it can be noted that peroxynitritewill react with Hgb(Fe(II))O2to produce nitrate (NO3)with a ferryl hemoglobin (Fe(IV)) as an intermediateand methemoglobin (Hgb(Fe(III))) as the final prod-uct, a reaction probably of significance in free radicalscavenging [35].
So when fully oxygenated the HgbFe(II)O2 caninactivate NO or nitrite, thereby allowing contrac-tion of the vessels and decrease in blood flow. When
partially deoxygenated electrons from NADPH areused to reduce NO2to produce NO, via the hemoglo-bin/methemoglobin couple, to decrease vascular toneand increase blood flow and therefore oxygen to thetissues. The hemoglobin/methemoglobin couple actsas the oxygen sensor and is therefore essential inmaintenance of the vascular flow and the regulationof blood flow in response to oxygen tensions in theendothelial cells.
ROLE OF METHEMOGLOBIN IN INFLAMMATION
Beside the local control of blood flow, the hemo-globin-methemoglobin redox couple plays a role ininflammation and the development of atheroscleroticdisease. Methemoglobin, or the heme-Fe(III) releasedfrom methemoglobin, promotes inflammation andoxidizes lipoproteins promoting atherosclerosis.
The production of methemoglobin is not always tothe benefit of the organism. NO produced during in-flammation and other oxygen reactive species resultsin conversion of hemoglobin to methemoglobin, andthis consequently results in an increased rigidity of theRBC with increased RBC lysis [3639]. This results inrelease of free methemoglobin (now without the reduc-
tion mechanism) [40]. Any free hemoglobin (HbgFe(II))or heme (Fe(II)) released into the tissues or circulationis promptly converted by spontaneous oxidation tomethemoglobin, Hgb(Fe(III)), or hemin, (heme Fe(III))[41]. Methemoglobin is an activator of endothelialcells by stimulation of IL-6, IL-8, and E-selectin [42].This is independent of the release of heme or iron andappears to be NF-kB mediated. The release of cyto-kines and the expression of adhesion molecules wouldintensify the inflammation response.
Heme moieties that are oxidized (porphyrin-Fe(III)),such as methemoglobin, dissociate more readily from
Fig. 5. Hemoglobin acts as a nitrite reductase, but only inthe deoxygenated from. This is a reduction in contrast to thereaction of NO2with oxygenated hemoglobin (HgbFe(II)(O2)),which is an oxidation.
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the protein than the reduced heme (prophryin-Fe(II))that is tightly bound to the proteins such as in hemo-globin. The heme in methemoglobin is more likely todissociate from the pocket in the protein [43,44]. Thefree heme (as porphryin-Fe(III)) is extremely lipo-
philic and binds to lipids intercalating into the mem-branes of neighboring cells. Heme release or hemeadministration in vivo increases vasopermeability, ad-hesion molecule expression, and the infiltration of tis-sues by leukocytes [45]. Exposure to heme (Fe(III))stimulates expression of adhesion molecules ICAM-1,VCAM-1, and E-selectin [46,47]. In addition to inter-calating into membranes, the oxidized heme slips intothe lipids of lipoproteins.
Methemoglobin becomes the mediator between hy-poxia, red cell lysis, and increased inflammation.
Free hemoglobin released from cells rapidly disso-ciates into ab dimmers. Hemoglobin released from
cells, if not immediately oxidized to methemoglobin,is captured by the peptide complex haptoglobin (Hp).The clearance of the Hp-heme complex is actually amajor macrophage function. The [Hp-Hgb(Fe(II))]
nis
cleared by special cells in the liver via the CD163 re-ceptor. Endocytosis by macrophages results in lysoso-mal degradation of the protein and of the heme byheme oxygenase 1, releasing ferrous iron (Fe(II)), bili-verdin, and CO [48]. Knock-out mice lacking Hp haveno difficulty in clearing Hgb [49], rather the role ofHp would seem to be to protect against oxidativedamage to lipids and LDL [50,51].
Hp also binds methemoglobin (Hgb(Fe(III))) [52],whose oxidative effect can be inhibited by the Hp[53], but there can still be an oxidation of LDL. Sincein methemoglobin has a reduced capacity to bind he-min (Fe(III)), it can be transferred to ApoB in theLDL [54]. There is a linear oxidation of LDL by themethemoglobin and a burst due to hemin breakdownand oxidation by free iron. The Hp2-2 isoform of Hpfails to hold on to globin heme as well as Hp1-1. TheHp2-2 phenotype has more vascular disease thanthose with the Hp1-1 phenotype [55]. Since oxidizedLDL is central to the progress of atherosclerosis, Hpcan be considered to be antiatherosclerotic and me-
themoglobin proatherosclerotic.Methemoglobin by itself, and by the facile releaseof hemin, (Fe(III)-prophyrin, is a major cause of LDLoxidation and atherosclerotic damage (Fig. 6).
Hemin (Fe(III)) released from LDL or from circu-lating methemoglobin is bound to hemopexin, whosepurpose should be to protect the vasculature formoxidation damage. Some is also bound to albuminand both proteins are transported to the endoreticu-lar system in the liver and degraded [56]. Hemebound to hemopexin binds to a specific receptor, thelow-density lipoprotein receptor-related protein (LRP)/
CD91, resulting in cell uptake and lysosomal degrada-tion of the hemopexin and heme [57]. Like sCD163 this
receptor appears to be recycled.Hemin, released from methemoglobin, may bereleased in such quantities that it exceeds the bindingability of hemopexin and there the hemin (Fe(III)) isreleased extracellularly. Infused hemin is profoundlyproinflammatory, and heme-oxygenase is antiinflam-matory, but it is not clear if any free heme actuallycirculates, or if all the heme intercalated into mem-branes is derived directly from methemoglobin(Fig. 7). The hemopexin knockout mouse is viable,and it appears that the hemopexin is not required asprotection against oxidative stress. The only appa-rent difference is a slowed recovery with more renal
damage after hemolysis [58]. Heme-oxygenase is anti-inflammatory due to the removal of heme, and themetabolism of heme results in the production of bili-rubin and CO, both vasodilators. Hemeoxygenaseknockouts have defects in iron metabolism [59], butexaggerated expression results in increased produc-tion of reactive iron species and cytotoxicity [60].
In a famous human case of HO-1, deficiency therewas ongoing erythrocyte fragmentation and hemoly-sis with endothelial damage [61]. In the HO-1 andapoE double knockouts there is exacerbation of athe-rosclerotic lesion formation and defects in vascularremodeling [62] consistent with the critical role of he-
min in oxidative damage and inflammation.Methemoglobin is then a critical mediator of the
inflammatory response, both as a product of NO andnitrate production, as a mediator of oxidative stress,and as the source of heme and iron with additionalproinflammatory and oxidative proclivities.
ACQUIRED METHEMOGLOBINEMIA
The Hgb(Fe(II))O2 methemoglobin Hgb(Fe(III))couple can undertake redox transformations under a
Fig. 6. The hemoglobin/methemoglobin redox couple oxi-dizes LDL, leading to increase arteriosclerotic risk.
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number of important biological situations, and it isno surprise that xenobiotics are substrates, formingmethemoglobin in the process. The acquired forma-tion of methemoglobin can have consequences. WhileHgb(Fe(II)) can be oxidized directly by some xenobi-otics to form methemoglobin, resulting in the reduc-tion of the xenobiotic, the usual reaction is the oxida-tion of the xenobiotic by Hgb(Fe(II))O2, resulting inH2O and methemoglobin.
The production of methemoglobin has clinical con-sequences. The presence of ferric iron in one or bothof the pophyrins causes the oxygen-dissociate curve toshift to the left [63]. The combined effect of less oxy-gen carried and less released can result in respiratory
failure [64]. Healthy individuals without anemia havefew symptoms at 15% methemoglobin, but levels of2030% cause mental status changes, headache, fa-tigue, exercise intolerance, dizziness, and syncope, andlevels of 50% result in dys-rhythmias, seizures, coma,and death [65]. Patients with anemia, lung disease, sep-sis, abnormal hemoglobins, sickle cell, age less than6 months, or the elderly are at greater risk.
There are two basic mechanisms for acquired methe-moglobinemia: direct or indirect oxidation of the hemo-globin. Rarely the Fe(II) in hemoglobin, Hgb(Fe(II)),can be directly oxidized to Fe(III) to form methemo-globin. Direct oxidation can be caused by chlorates,
hexavalent chromates, cobalt [66], and copper II salts.Ferricyanide has an adequate redox potential, butpenetrates membranes poorly. But these high redoxpotential compounds are usually not implicated inmethemoglobinemia, and exposure results in intravasc-ular hemolysis rather than methemoglobinemia. Asimilar mechanism may be involved in the inductionof methemoglobinemia by the ribonucleotide reduc-tase inhibitor triapine (3-aminopyridine-2-carocalde-hyde) [67]. This compound is an iron chelator, but un-like other iron chelators its inhibitory activity towardsthe non-heme iron protein ribonucleotide reductase is
not reduced, but increased by exogenous iron [68,69].As a side effect, triapine can cause methemoglobine-mia, probably by a similar mechanism of direct transferof an electron form the Fe(II) heme to the Fe(III) tria-pine to form methemoglobin (Hgb(Fe(III))), a mecha-nism referred to as \electron steal."
Indirect oxidation is more prevalent. Oxidationoccurs with participation of both the iron and the ox-ygen, with superoxide and hydrogen peroxide pro-duction when the hemoglobin bound oxygen acceptselectrons from ferrous iron [70].
Aniline is a potent inducer of methemoglobinemiaand hemolysis, but is converted first to phenylhy-
droxylamine that is oxidized to nitrosobenzyene byHgb(Fe(II)) and oxygen (Fig. 8).The nitrosobenzene is subsequently reduced by a
NADPH flavin reductase back to aniline, using NADPHderived from glucose-6-phoshate dehydrogenase [71]and the hexose monophosphate shunt. Alternatively,glutathione can be used as a source of reducing power[72,73]. Aniline and nitros-derivatives are transformedinto phenylhydroxylamines by hepatic mixed functionoxidases, and then can become inducers of methemo-globin [74]. Such bioactivation is important for thetoxic effects of dapsone and sulfamethoxazole (thesulfa component in trimethoprim-sulfamethoxazole,
Septra, or Bactrim), probably via the formation ofhydroxylamines. The dapsone hydroxylamine was themore potent in forming methemoglobin and consum-ing glutathione compared to the sulfamethoxazolehydroxyl amine, paralleling the in vivo findings [75].
Along with the production of methemoglobin,reducing power in the cell is depleted. The depletionis explained by the recycling mechanism, and oncethe glutathione is depleted, the continued formationof methemoglobin should stop [76]. The hexose mono-phosphate shunt was also stimulated to produce moreNADPH [77].
Fig. 8. Oxidation of the aniline derivative catalyzed byoxygenated hemoglobin.
Fig. 7. Methemoglobin releases free heme and iron that stim-ulate the inflammatory process. [Color figure can be viewedin the online issue, which is available at www.interscience.wiley.com.]
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omatic amine that could be converted to a phenylhy-droxylamine (Fig. 11). Benzocaine spray has becomean increasing problem, and spray directed to the mu-cosa can gain rapid entry to the blood and result insevere levels of methemoglobin. There are a wide vari-ety of case reports [99], but no systematic study. Inone review from a transesophageal echocardiologylaboratory the incidence was estimated at 0.115%[100].
METHYLENE BLUE
The treatment for symptomatic methemoglobine-mia is infusion of methylene blue.
Methylene blue acts as an electron donor for thenonenyzmatic reduction of methemoglobin. A dis-tinct enzyme, NADPH methemoglobin reductase,converts methylene blue (the oxidized form of thedye) to leukomethylene blue (the reduced form),using NADPH (Fig. 12). The reduced form thenchemically reduces methemoglobin (Hgb(Fe(III))) tohemoglobin Hgb(Fe(II)). The dye is then recycled. Theenzyme responsible, NADPH methemoglobin reduc-
tase, is not the same enzyme involved in the physio-logical reduction of methemoglobin (the NADH-cyto-chrome b5 reductase), and in the absence of methyl-ene blue this enzyme is responsible for less than 6% ofthe restoration of hemoglobin from methemoglobin.
Since symptoms do not occur at levels less than2030%, treatment is not needed below that level,unless other conditions (such as anemia, respiratorydistress, and cardiac disease) contribute to the clini-cal scenario. It should be noted that methylene blueinterferes with oximeter readings of oxygen satura-tion [101].
Individuals with glucose-6-phosphate dehydrogen-ase deficiency lack the ability to produce NADPH.They are more susceptible to oxidative stress becauseNADPH is needed to maintain glutathione (notNADH-cytochorme b5 reductase). Since the methyl-ene blue systems require NADPH as the reductase,methylene blue will be ineffective in these individuals,but by further reducing levels of NADPH and pre-venting reduction of glutathione, the use of methyl-ene blue may actually worsen the methemoglobine-mia [102]. If there is extensive hemolysis, such as
would be seen with the chemically induced methemo-globinemias due to chlorates or with aniline, then theenzymes needed to reduce methylene blue are rel-eased from red cells and the drug is ineffective. Ifmethylene blue cannot be reduced, it can function asan oxidizing agent and convert hemoglobin to methe-moglobin exacerbating the condition it was used totreat. This can occur in individuals with G6PD defi-ciency as well. Patients exposed to anilines may alsoblock the uptake of methylene blue by the productionof phenylhydroxylamine [103,104]. Methylene bluecan worsen the hemolytic anemia due to dapsone viathe formation of hydroxylamine that oxidizes the he-
moglobin, a complication that can be delayed for sev-eral days [105,106].
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