View source for Chemistry:Carboxyhemoglobin

{{Hatnote|Not to be confused with [[Biology:Carbaminohemoglobin|carbaminohemoglobin]], the compound formed when {{chem|C|O|2}} binds with hemoglobin.}}{{Short description|A complex of carbon monoxide and hemoglobin}}
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| ImageFileL1    = File:Carboxyhemoglobin from 1AJ9.png
| ImageNameL1    = A heme unit of human carboxyhaemoglobin, showing the carbonyl ligand at the apical position, ''trans'' to the histidine residue.<ref>{{cite journal | vauthors = Vásquez GB, Ji X, Fronticelli C, Gilliland GL | title = Human carboxyhemoglobin at 2.2 A resolution: structure and solvent comparisons of R-state, R2-state and T-state hemoglobins | journal = Acta Crystallographica. Section D, Biological Crystallography | volume = 54 | issue = Pt 3 | pages = 355–366 | date = May 1998 | pmid = 9761903 | doi = 10.1107/S0907444997012250 | name-list-style = vanc }}</ref>
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| PIN            = Carbonylhemoglobin
| OtherNames     = Carboxyhemoglobin<br />Carboxyhaemoglobin<br />Kohlenoxyhaemoglobin<br />Kohlenoxyhämoglobin<br />Kohlenoxydhämoglobin<br />Kohlenmonoxyhämoglobin<br />Carbonmonoxyhemoglobin<br />Carbon-monoxide-hemoglobin<br />Carbon-monoxide-Methemoglobin<br/>Carbonic oxide hæmoglobin
}}

'''Carboxyhemoglobin''' ('''carboxyhaemoglobin''' BrE) (symbol '''COHb''' or '''HbCO''') is a stable [[Chemistry:Complex|complex]] of [[Chemistry:Carbon monoxide|carbon monoxide]] and [[Biology:Hemoglobin|hemoglobin]] (Hb) that forms in [[Biology:Red blood cell|red blood cell]]s upon contact with carbon monoxide. Carboxyhemoglobin is often mistaken for the compound formed by the combination of carbon dioxide ([[Chemistry:Carboxylic acid|carboxyl]]) and hemoglobin, which is actually [[Biology:Carbaminohemoglobin|carbaminohemoglobin]]. Carboxyhemoglobin terminology emerged when carbon monoxide was known by its historic name, "carbonic oxide", and evolved through Germanic and British English etymological influences; the preferred IUPAC nomenclature is '''carbonylhemoglobin'''.<ref>{{Cite web|title=IUPAC Glossary of Terms Used in Toxicology - Terms Starting with C|url=https://www.nlm.nih.gov/enviro/toxicology-glossary-c.html#carbonylhemoglobin|access-date=2021-05-09|website=www.nlm.nih.gov}}</ref><ref>{{Cite web|last=PubChem|title=Carbon monoxide|url=https://pubchem.ncbi.nlm.nih.gov/compound/281|access-date=2021-05-09|website=pubchem.ncbi.nlm.nih.gov|language=en}}</ref><ref name="Hopper_2021">{{cite journal | vauthors = Hopper CP, Zambrana PN, Goebel U, Wollborn J | title = A brief history of carbon monoxide and its therapeutic origins | journal = Nitric Oxide | volume = 111 | pages = 45–63 | date = June 2021 | pmid = 33838343 | doi = 10.1016/j.niox.2021.04.001 | s2cid = 233205099 }}</ref>

The average non-smoker maintains a systemic carboxyhemoglobin level under 3% COHb whereas smokers approach 10% COHb.<ref name="Hopper_2021" /> The biological threshold for carboxyhemoglobin tolerance is 15% COHb, meaning toxicity is consistently observed at levels in excess of this concentration.<ref name="Motterlini_2017">{{cite journal | vauthors = Motterlini R, Foresti R | title = Biological signaling by carbon monoxide and carbon monoxide-releasing molecules | journal = American Journal of Physiology. Cell Physiology | volume = 312 | issue = 3 | pages = C302–C313 | date = March 2017 | pmid = 28077358 | doi = 10.1152/ajpcell.00360.2016 | doi-access = free }}</ref> The FDA has previously set a threshold of 14% COHb in certain [[Engineering:Clinical trial|clinical trial]]s evaluating the therapeutic potential of carbon monoxide.<ref>{{cite journal | vauthors = Yang X, de Caestecker M, Otterbein LE, Wang B | title = Carbon monoxide: An emerging therapy for acute kidney injury | journal = Medicinal Research Reviews | volume = 40 | issue = 4 | pages = 1147–1177 | date = July 2020 | pmid = 31820474 | pmc = 7280078 | doi = 10.1002/med.21650 }}</ref>

== Overview ==
The average [[Biology:Red blood cell|red blood cell]] contains 250 million [[Biology:Hemoglobin|hemoglobin]] molecules.<ref name="Hopper_2020">{{cite journal|display-authors=6|vauthors=Hopper CP, De La Cruz LK, Lyles KV, Wareham LK, Gilbert JA, Eichenbaum Z, Magierowski M, Poole RK, Wollborn J, Wang B|date=December 2020|title=Role of Carbon Monoxide in Host-Gut Microbiome Communication|journal=Chemical Reviews|volume=120|issue=24|pages=13273–13311|doi=10.1021/acs.chemrev.0c00586|pmid=33089988|s2cid=224824871}}</ref> Hemoglobin contains a [[Biology:Globin|globin]] protein unit with four [[Biology:Prosthetic group|prosthetic]] [[Biology:Heme|heme]] groups (hence the name [[Biology:Heme|heme]] [[Medicine:List of medical roots, suffixes and prefixes|-o-]] [[Biology:Globin|globin]]); each heme is capable of reversibly binding with one gaseous molecule (oxygen, carbon monoxide, cyanide, etc.),<ref>{{cite book | vauthors = Berg JM, Tymoczko JL, Stryer L | title = Biochemistry | edition = 5th | location = New York | publisher = W H Freeman | date = 2002 | isbn = 978-0-7167-3051-4 | url-access = registration | url = https://archive.org/details/biochemistrychap00jere }}</ref> therefore a typical red blood cell may carry up to one billion gas molecules. As the binding of carbon monoxide with hemoglobin is reversible, certain models have estimated that 20% of the carbon monoxide carried as carboxyhemoglobin may dissociate in remote tissues.<ref name="Hopper_2020" />

== Endogenous carbon monoxide production ==
In biology, carbon monoxide is naturally produced through many enzymatic and non-enzymatic pathways.<ref name="Hopper_2020" /> The most extensively studied pathway is the metabolism of [[Biology:Heme|heme]] by [[Biology:Heme oxygenase|heme oxygenase]] which occurs throughout the body with significant activity in the spleen to facilitate [[Biology:Hemoglobin|hemoglobin]] breakdown during erythrocyte recycling. Therefore heme can both carry carbon monoxide in the case of carboxyhemoglobin, or, undergo enzymatic catabolism to generate carbon monoxide.

Carbon monoxide was characterized as a neurotransmitter in 1993 and has since been subcategorized as a [[Biology:Gasotransmitter|gasotransmitter]].<ref name="Hopper_2021" />

Most endogenously produced carbon monoxide is stored as carboxyhemoglobin. The gas primarily undergoes pulmonary excretion, however trace amounts may be oxidized to [[Chemistry:Carbon dioxide|carbon dioxide]] by certain [[Biology:Cytochrome|cytochrome]]s, metabolized by resident [[Biology:Human microbiome|microbiota]], or excreted by transdermal diffusion.<ref name="Hopper_2021" /><ref name="Hopper_2020" />

==Affinity of hemoglobin for carbon monoxide== 
Compared to oxygen, carbon monoxide binds with approximately 240 times greater affinity,<ref>{{cite book|title=Biochemistry|vauthors=Berg JM, Tymoczko JL, Stryer L|date=2011|publisher=W H Freeman|isbn=978-1-4292-7635-1|edition=7th|location=New York}}</ref><ref name="Hopper_2021" /> however the affinity of carbon monoxide for hemoglobin varies both across species and within a species. In the 1950s, Esther Killick was among the first to recognize a difference in carbon monoxide affinity between adult and foetal blood, and a difference between humans and sheep.<ref name="Hopper_2021" /><ref>{{Cite journal|last1=Stevenson|first1=DK|last2=Wong|first2=RJ|last3=Ostrander|first3=CR|last4=Maric|first4=I|last5=Vreman|first5=HJ|last6=Cohen|first6=RS|date=April 2020|title=Increased Carbon Monoxide Washout Rates in Newborn Infants|url=https://pubmed.ncbi.nlm.nih.gov/31634890/|journal=Neonatology|volume=117|issue=1|pages=118–122|doi=10.1159/000503635|issn=1661-7819|pmid=31634890|s2cid=204834990}}</ref><ref name=":0">{{Cite journal|last=Boor|first=AK|date=January 1930|title=A Crystallographic Study Of Pure Carbonmon-Oxide Hemoglobin|journal=The Journal of General Physiology|volume=13|issue=3|pages=307–316|doi=10.1085/jgp.13.3.307|issn=0022-1295|pmc=2141039|pmid=19872525}}</ref> In humans, the Hb-Kirklareli mutation has a relative 80,000 times greater affinity for carbon monoxide than oxygen resulting in systemic carboxyhemoglobin reaching a sustained level of 16% COHb.<ref name="Motterlini_2017" /> Other human mutations have been described (see also: [[Biology:Hemoglobin variants|hemoglobin variants]]).<ref>{{Cite web|date=March 2008|title=Blood Discovery: New Hemoglobin Type Found|url=https://www.sciencedaily.com/releases/2008/03/080317102452.htm|url-status=live|access-date=2021-10-27|website=ScienceDaily|language=en|archive-url=https://web.archive.org/web/20080318100517/http://www.sciencedaily.com:80/releases/2008/03/080317102452.htm |archive-date=2008-03-18 }}</ref><ref name=":1">{{Cite web|title=The Hemoglobin Page|url=https://faculty.etsu.edu/currie/hemoglobin.htm|url-status=live|access-date=2021-10-31|website=East Tennessee State University|archive-url=https://web.archive.org/web/20040919171244/http://faculty.etsu.edu:80/currie/hemoglobin.htm |archive-date=2004-09-19 }}</ref> Structural variations and mutations across other [[Biology:Hemoprotein|hemoprotein]]s likewise affect carbon monoxide's interaction with the heme prosthetic group as exemplified by [[Biology:Cytochrome P450|Cytochrome P450]] where certain forms of the [[Biology:CYP3A|CYP3A]] family is relatively less affected by the inhibitory effects of carbon monoxide.<ref name="Hopper_2021" />

[[Biology:Murinae|Murinae]] species have a COHb half-life of 20 minutes compared to 300 minutes for a typical human ([https://en.wikipedia.org/w/index.php?title=Carboxyhemoglobin&section=7#Toxicokinetics see toxicokinetics below]).<ref name="Hopper_2021" /> As a result, the metabolic kinetics, blood saturation point, and tolerance for carbon monoxide exposure vary across species, potentially leading to data inconsistencies pertaining to the [[Chemistry:Toxicology|toxicology]] of [[Medicine:Carbon monoxide poisoning|carbon monoxide poisoning]] and [[Biology:Pharmacology|pharmacology]] of low-dose therapeutic protocols.<ref name="Hopper_2021" />

Some deep-diving marine mammal species are known to contain concentrations of carbon monoxide in their blood that resembles levels seen in chronic cigarette smokers, which may provide benefits against hypoxia.<ref>{{Cite journal|last1=Tift|first1=Michael S.|last2=Alves de Souza|first2=Rodrigo W.|last3=Weber|first3=Janick|last4=Heinrich|first4=Erica C.|last5=Villafuerte|first5=Francisco C.|last6=Malhotra|first6=Atul|last7=Otterbein|first7=Leo E.|last8=Simonson|first8=Tatum S.|date=2020|title=Adaptive Potential of the Heme Oxygenase/Carbon Monoxide Pathway During Hypoxia|journal=Frontiers in Physiology|volume=11|pages=886|doi=10.3389/fphys.2020.00886|issn=1664-042X|pmc=7387684|pmid=32792988|doi-access=free}}</ref> Similarly, the elevated levels in smokers has been suggested to be a basis for the smoker's paradox.<ref name="Hopper_2021" /> Prolonged exposure to carbon monoxide and elevated carboxyhemoglobin, such as in smoking, results in erythremia.<ref name="Hopper_2021" /> Furthermore, humans can [[Biology:Acclimatization|acclimate]] to toxic levels of carbon monoxide based on findings reported by Esther Killick.<ref name="Hopper_2021" />

== History ==
A bright red skin complexion is commonly associated with elevated carboxyhemoglobin levels. Trace evidence for an endogenous presence of carbon monoxide dates back to Marcellus Donato circa 1570 who noted an unusually red complexion upon conducting an autopsy of victims who died from charcoal fumes in Mantua.<ref name="Hopper_2021" /> Similar findings pertaining to red complexion later emerged as documented by Johann Jakob Wepfer in the 1600s, and M. Antoine Portal in the late 1700s.<ref name="Hopper_2021" />

[[Physics:Phlogiston theory|Phlogiston theory]] is a trace origin for the first chemical explanations of endogenous carboxyhemoglobin exemplified by the work of [[Biography:Joseph Priestley|Joseph Priestley]] in the eighteenth century who suspected phlogiston to be a cellular waste product carried by the blood of animals which was subsequently exhaled.<ref name="Hopper_2021" />

Thomas Beddoes, James Watt, [[Biography:Humphry Davy|Humphry Davy]], James Lind, and many others investigated the therapeutic potential of inhaling [[Physics:Factitious airs|factitious airs]] in the late eighteenth century (see also: Pneumatic Institution). Among the gases experimented with, [[Chemistry:Hydrocarbonate (gas)|hydrocarbonate]] had received significant attention. Hydrocarbonate is [[Chemistry:Water gas|water gas]] generated by passing steam over [[Chemistry:Coke (fuel)|coke]], the process of which generates carbon monoxide and hydrogen, and some considered it contain [[Physics:Phlogiston theory|phlogiston]]. Beddoes and Watt recognized hydrocarbonate brightened venous blood in 1793. Watt suggested coal fumes could act as an [[Chemistry:Antidote|antidote]] to the oxygen in blood, and Beddoes and Watt likewise speculated hydrocarbonate has a greater affinity for animal fiber than oxygen in 1796.<ref name="Hopper_2021" />

After the discovery of carbon monoxide by [[Biography:William Cruickshank (chemist)|William Cruickshank]] in 1800, Johann Dömling (1803) and John Bostock (1804) developed hypotheses suggesting blood returned to the heart loaded with carbon monoxide to subsequently be oxidized to carbon dioxide in the lung prior to exhalation.<ref name="Hopper_2021" /> Later in 1854, Adrien Chenot similarly suggested carbon monoxide could remove oxygen from blood and be oxidized within the body to carbon dioxide.<ref name="Hopper_2021" /> The mechanism for carbon monoxide poisoning in the context of carboxyhemoglobin formation is widely credited to Claude Bernard whose memoirs beginning in 1846 and published in 1857 notably phrased, "prevents arterials blood from becoming venous".<ref name="Hopper_2021" /> Felix Hoppe-Seyler independently published similar conclusions in the following year.

The first analytical method to detect carboxyhemoglobin emerged in 1858 with a colorimetric method developed by Felix Hoppe-Seyler, and the first quantitative analysis method emerged in 1880 with [[Biography:Josef von Fodor|Josef von Fodor]].<ref name="Hopper_2021" />

=== Etymology ===
[[Chemistry:Carbon|Carbon]] is derived from the Latin term ''carbo'', meaning coal, via the French {{lang|fr|charbone}}, which first appeared in print in 1786.<ref name=":2">{{Cite web|title=History of Carbon|url=https://www.tf.uni-kiel.de/matwis/amat/iss/kap_4/advanced/t4_2_1.html|url-status=live|access-date=2021-10-31|website=University of Kiel|archive-url=https://web.archive.org/web/20151224140152/http://www.tf.uni-kiel.de:80/matwis/amat/iss/kap_4/advanced/t4_2_1.html |archive-date=2015-12-24 }}</ref>  The [[Chemistry:Oxygen#Etymology|etymology of oxygen]] is generally accepted mean 'acid' based on Lavoisier's system, which also recognized carbon as a nonmetallic element capable of oxidation, although the original degrees of oxides were based on diamond, graphite, coal and [[Physics:Factitious airs#carbon dioxide|carbonic acid ({{CO2}})]] as the most oxidized form;<ref name=":2" /> Lavoisier's system was superseded by other obsolete oxide nomenclature systems.<ref>{{Cite book|last=Cooley|first=AJ|url=https://books.google.com/books?id=jG4DAAAAYAAJ&q=oxide|title=A Cyclopaedia of Practical Receipts: And Collateral Information in the Arts, Manufacutres, and Trades, Including Medicine, Pharmacy, and Domestic Economy|date=1845|publisher=John Churchill|pages=647–648; 224|language=en}}</ref>  

Upon discovering carbon monoxide through a series of experiments originating from [[Chemistry:Coke (fuel)|coke]] (short for coal-cake<ref name=":2" />), [[Biography:William Cruickshank (chemist)|Cruickshank]] named the new molecule "gaseous oxide of carbon" which evolved to "carbonic oxide" and was translated into German as "kohlenoxyd". Kohlen is the German word for coal.<ref name="Hopper_2021" /><ref>{{Cite journal| vauthors = Coutts A |date=June 1959|title=William Cruickshank of Woolwich  |journal=Annals of Science|language=en|volume=15|issue=2|pages=121–133|doi=10.1080/00033795900200118|issn=0003-3790}}</ref> As carbonic acid ({{CO2}}) was considered to be the most highly oxidized form in Lavoisier's system, the name carbonic oxide implied an intermediate oxidized species between coal and carbonic acid (i.e. use of the word acid indicated maximum oxidation). 

Haem is derived from Greek meaning blood,<ref>{{Cite journal| vauthors = Meletis J |date=January 2002|title=The derivatives of the Hellenic word "Haema" (hema, blood) in the English Language|url=https://www.researchgate.net/publication/215529701|journal=Haema|volume=5|issue=2|pages=140–163|via=ResearchGate}}</ref><ref name=":3">{{cite journal | vauthors = Meletis J, Konstantopoulos K | title = The beliefs, myths, and reality surrounding the word hema (blood) from homer to the present | journal = Anemia | volume = 2010 | pages = 857657 | date = 2010 | pmid = 21490910 | pmc = 3065807 | doi = 10.1155/2010/857657 | doi-access = free }}</ref> and globin is Latin derived from ''globus'' typically accepted to mean glob/spherical/round object; the terms are conjoined with an [[Medicine:List of medical roots, suffixes and prefixes|-o-]] . Regarding haem, [[Social:American and British English spelling differences#ae and oe|the use of "ae / æ" remains prevalent in British English]] in modern day<ref>{{cite journal | vauthors = Campbell NK, Fitzgerald HK, Dunne A | title = Regulation of inflammation by the antioxidant haem oxygenase 1 | journal = Nature Reviews. Immunology | volume = 21 | issue = 7 | pages = 411–425 | date = July 2021 | pmid = 33514947 | doi = 10.1038/s41577-020-00491-x | s2cid = 231762031 }}</ref> whereas the American English spelling evolved to heme from hema.<ref name=":3" />   

Felix Hoppe-Seyler coined the name "hämoglobin" in 1864.<ref>{{cite journal | vauthors = Westhorpe RN, Ball C | title = The pulse oximeter | journal = Anaesthesia and Intensive Care | volume = 36 | issue = 6 | pages = 767 | date = November 2008 | pmid = 19115641 | doi = 10.1177/0310057X0803600602 | s2cid = 44379880 | doi-access = free }}</ref> In German, an umlaut such as ä is synonymous with spelling as "ae", therefore hämoglobin is commonly spelled as haemoglobin throughout German literature, hence haemoglobin is the term adopted by English literature.  

Hoppe-Seyler likewise coined the name Kohlenoxydhämoglobin<ref>{{Cite book| vauthors = Hoppe-Seyler F |url=https://books.google.com/books?id=zG9LAQAAMAAJ&dq=kohlenoxydh%C3%A4moglobin&pg=PA1|title=Medicinisch-chemische Untersuchungen: Aus dem Laboratorium für angewandte Chemie zu Tübingen|date=1866|publisher=A. Hirschwald|pages=119|language=de}}</ref> which may have similarly been directly translated back into English as "carbonic oxide hæmoglobin".<ref>{{Cite journal| vauthors = Dobell H |date=January 1887|title=On Asthma: Its Nature and Treatment |journal=British Medical Journal|volume=1|issue=1360|pages=161–162|issn=0007-1447|pmc=2534062}}</ref> The term carboxyhæmoglobin appeared as early as 1895 in works by John Haldane while the name for CO was still widely regarded as carbonic oxide.<ref>{{Cite journal|last=Haldane|first=John|date=November 1895|title=The Action of Carbonic Oxide on Man|journal=The Journal of Physiology|language=en|volume=18|issue=5–6|pages=430–462|doi=10.1113/jphysiol.1895.sp000578|pmc=1514663|pmid=16992272}}</ref>

The term "carbon monoxide" was formally introduced in 1879, but the name would not become mainstream for several decades.<ref name="Hopper_2021" /> Variations of COHb terminology, such as carbonmonoxyhemoglobin,<ref>{{cite journal | vauthors = Pauling L, Coryell CD | title = The Magnetic Properties and Structure of Hemoglobin, Oxyhemoglobin and Carbonmonoxyhemoglobin | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 22 | issue = 4 | pages = 210–216 | date = April 1936 | pmid = 16577697 | doi = 10.1073/pnas.22.4.210 | pmc = 1076743 | bibcode = 1936PNAS...22..210P | doi-access = free }}</ref><ref name=":0" /> followed and eventually evolved and simplified back into "carboxyhemoglobin".  

As carboxy is now firmly associated with the CO<sub>2</sub> [[Chemistry:Carboxylic acid|carboxyl]] group, and carbon monoxide is generally regarded as a [[Chemistry:Carbonyl group|carbonyl]], IUPAC has recommended "carbonylhemoglobin" as the preferred COHb nomenclature.<ref name="Hopper_2021" /> Despite the IUPAC guidance, carboxyhemoglobin remains the most widely used term (akin to the [[Physics:Factitious airs#carbon dioxide|survival]] of [[Chemistry:Bicarbonate|bicarbonate]] nomenclature).

== Analytical detection methods ==
Historically, carboxyhemoglobin detection has been achieved by [[Chemistry:Colorimetric analysis|colorimetric analysis]], chemical reactivity, [[Physics:Spectrophotometry|spectrophotometry]], gasometric and [[Physics:Thermoelectric effect|thermoelectric]] detection methods.<ref name="Hopper_2021" /> [[Gas chromatography]] analysis emerged in 1961 and remains a commonly used method.<ref name="Hopper_2021" />

Modern methods include [[Engineering:Pulse oximetry|pulse oximetry]] with a [[Chemistry:CO-oximeter|CO-oximeter]], and a variety of other analytical techniques.<ref>{{cite book | vauthors = Vreman HJ, Wong RJ, Stevenson DK | chapter = Sources, sinks, and measurements of carbon monoxide. | title = Carbon monoxide and cardiovascular functions. | date = 2001 | pages = 273–307 | publisher = CRC Press | doi = 10.1201/9781420041019-23 |isbn=978-0-429-12262-0 }}</ref><ref>{{Cite book|last1=Peng|first1=H|title=Gasotransmitters: Physiology and Pathophysiology|last2=Chen|first2=W|last3=Wang|first3=B|publisher=Springer|date=July 2012|editor-last=Hermann|editor-first=A|location=Berlin, Heidelberg|pages=99–137|chapter=Methods for the Detection of Gasotransmitters|editor-last2=Sitdikova|editor-first2=GF|editor-last3=Weiger|editor-first3=TM}}</ref> Most methods require laboratory equipment, skilled technicians, or expensive electronics therefore rapid and economical detection technologies remain in development.

[[Chemistry:Breath carbon monoxide|Breath carbon monoxide]] is another detection method that may correlate with carboxyhemoglobin levels.<ref>{{cite journal | vauthors = Wald NJ, Idle M, Boreham J, Bailey A | title = Carbon monoxide in breath in relation to smoking and carboxyhaemoglobin levels | journal = Thorax | volume = 36 | issue = 5 | pages = 366–369 | date = May 1981 | pmid = 7314006 | pmc = 471511 | doi = 10.1136/thx.36.5.366 }}</ref>

== Carbon monoxide poisoning ==
{{main|Medicine:Carbon monoxide poisoning}}
Carbon monoxide poisoning, also known as carboxyhemoglobinemia,<ref name="pmid16041521">{{cite journal | vauthors = López-Herce J, Borrego R, Bustinza A, Carrillo A | title = Elevated carboxyhemoglobin associated with sodium nitroprusside treatment | journal = Intensive Care Medicine | volume = 31 | issue = 9 | pages = 1235–1238 | date = September 2005 | pmid = 16041521 | doi = 10.1007/s00134-005-2718-x | s2cid = 10197279 | doi-access = free }}</ref><ref name="pmid19615844">{{cite journal | vauthors = Roth D, Hubmann N, Havel C, Herkner H, Schreiber W, Laggner A | title = Victim of carbon monoxide poisoning identified by carbon monoxide oximetry | journal = The Journal of Emergency Medicine | volume = 40 | issue = 6 | pages = 640–642 | date = June 2011 | pmid = 19615844 | doi = 10.1016/j.jemermed.2009.05.017 }}</ref> has plagued humankind since primitive ancestors first harnessed fire. In modern times, carboxyhemoglobin data assist physicians in making a poisoning diagnosis. However, carboxyhemoglobin levels do not necessarily correlate with the symptoms of carbon monoxide poisoning.<ref>{{cite journal | vauthors = Hampson NB, Hauff NM | title = Carboxyhemoglobin levels in carbon monoxide poisoning: do they correlate with the clinical picture? | journal = The American Journal of Emergency Medicine | volume = 26 | issue = 6 | pages = 665–669 | date = July 2008 | pmid = 18606318 | doi = 10.1016/j.ajem.2007.10.005 }}</ref> In general, 30% COHb is considered severe carbon monoxide poisoning.<ref name="Hopper_2021" /> The highest reported non-fatal carboxyhemoglobin level was 73% COHb.<ref name="Hopper_2021" />

=== Mode of toxic action ===
[[Physics:Gas exchange|Gas exchange]] is an essential process for many organisms to maintain homeostasis. Oxygen accounts for about 20% of Earth's atmospheric [[Earth:Atmosphere of Earth|air]]. While inhaling air is critical to supply cells with oxygen for aerobic respiration via the [[Medicine:Bohr effect|Bohr effect]] and [[Biology:Haldane effect|Haldane effect]] (and perhaps local low oxygen partial pressure e.g. active muscles),<ref>{{cite book | vauthors = Schmidt-Nielsen K |title=Animal Physiology: Adaptation and Environment |isbn=978-0-521-57098-5 | date = 1997 |edition=Fifth | publisher =  Cambridge University Press | location = Cambridge, UK }}</ref> exhaling the cellular waste product [[Chemistry:Carbon dioxide|carbon dioxide]] is arguably the more critical aspect of respiration. Whereas the body can tolerate brief periods of [[Medicine:Hypoxia (medical)|hypoxia]] (as commonly occurs in [[Medicine:Anaerobic exercise|anaerobic exercise]], although the brain, heart, liver and kidney are significantly less tolerant than skeletal muscle), failure to expel carbon dioxide may cause respiratory acidosis (meaning bodily fluids and blood become too acidic thereby affecting homeostasis).<ref>{{Cite web|title=Respiratory acidosis: MedlinePlus Medical Encyclopedia|url=https://medlineplus.gov/ency/article/000092.htm|access-date=2021-05-10|website=medlineplus.gov|language=en}}</ref> In absence of oxygen, cells switch to [[Biology:Anaerobic respiration|anaerobic respiration]] which if prolonged may significantly increase [[Chemistry:Lactic acid|lactic acid]] leading to metabolic acidosis.<ref>{{cite journal |title=Carbon Monoxide Poisoning | journal = ToxUpdate | pages = 1–3 | volume = 6 | issue = 3 |date=2004 |url=https://poisoncontrol.utah.edu/newsletters/pdfs/toxicology-today-archive/Vol6_No3.pdf|url-status=dead | archive-url = https://web.archive.org/web/20150913035918/https://poisoncontrol.utah.edu/newsletters/pdfs/toxicology-today-archive/Vol6_No3.pdf | archive-date = 13 September 2015 | publisher = Utah Poison Control Center }}</ref>

To provide a simplified synopsis of the molecular mechanism of systemic gas exchange, upon inhalation of air it was widely thought oxygen binding to any of the heme sites triggers a [[Biology:Conformational change|conformational change]] in the protein unit of hemoglobin which then enables the binding of additional oxygen to each of the other heme sites. Upon arrival to the cellular region, oxygen is released at the tissue due to a conformational change in hemoglobin as caused by ionization of hemoglobin's surface due to the "acidification" of the tissue's local pH (meaning a relatively higher concentration of 'acidic' protons / hydrogen [[Physics:Ion|ion]]s annotated as H<sup>+</sup>; an acidic pH is commonly referenced to as either low pH based on the acidity of pH 1-7 having a ''low'' number, or, referred to as a high pH due to the ''high'' concentration of H<sup>+</sup> ions as the scale approaches pH 1); the local acidity is caused by an increase in the biotransformation of carbon dioxide waste into [[Chemistry:Carbonic acid|carbonic acid]] via [[Biology:Carbonic anhydrase|carbonic anhydrase]]. In other words, oxygenated arterial blood arrives to cells in the "[[Biology:Hemoglobin#Allosteric|hemoglobin R-state]]" which has deprotonated/unionized amino acid [[Biology:Protein structure|residues]] (regarding hemoglobin's [[Biology:N-terminus|amines]] transitioning between the deprotonated/unionized Hb-NH2 to the protonated/ionized Hb-NH3<sup>+</sup> state) based on the less-acidic pH (arterial blood averages pH 7.407 whereas venous blood is slightly more acidic at pH 7.371<ref>{{cite journal | vauthors = O'Connor TM, Barry PJ, Jahangir A, Finn C, Buckley BM, El-Gammal A | title = Comparison of arterial and venous blood gases and the effects of analysis delay and air contamination on arterial samples in patients with chronic obstructive pulmonary disease and healthy controls | language = english | journal = Respiration; International Review of Thoracic Diseases | volume = 81 | issue = 1 | pages = 18–25 | date = 2011 | pmid = 20134147 | doi = 10.1159/000281879 | doi-access = free }}</ref>). The "T-state" of hemoglobin is deoxygenated in venous blood partially due to protonation/ionization as caused by the acidic environment hence causing a conformation unsuited for oxygen-binding<ref>{{Cite web|title=Transport of Oxygen in the Blood|url=https://www.rsb.org.uk/images/13_Transport_of_oxygen_in_the_blood.pdf|url-status=live|website=Royal Society of Biology|archive-url=https://web.archive.org/web/20201128114044/https://www.rsb.org.uk/images/13_Transport_of_oxygen_in_the_blood.pdf |archive-date=2020-11-28 }}</ref> (i.e. oxygen is 'ejected' upon arrival at the cell due to H<sup>+</sup> ions bombarding the hemoglobin surface residues to convert Hb from "R-state" to "T-state"). Furthermore, the mechanism for formation of [[Biology:Carbaminohemoglobin|carbaminohemoglobin]] generates additional H<sup>+</sup> ions that may further stabilize the protonated/ionized deoxygenated hemoglobin. Upon return of venous blood into the lung and subsequent exhalation of carbon dioxide, the blood is "de-acidified" (see also: hyperventilation) for the deprotonation/unionization of hemoglobin to re-enable oxygen binding as part of the transition to arterial blood (note this process is complex due to involvement of [[Biology:Chemoreceptor|chemoreceptor]]s, pH buffers and other physiochemical functionalities). Carbon monoxide poisoning disturbs this physiological process hence the venous blood of poisoning patients is bright red akin to arterial blood since the carbonyl/carbon monoxide is retained, whereas deoxygenated hemoglobin is dark red and carbaminohemoglobin has a blue hue.<ref name=":1" />

At toxic concentrations, carbon monoxide as carboxyhemoglobin significantly interferes with respiration and gas exchange by simultaneously inhibiting acquisition and delivery of oxygen to cells, and preventing formation of [[Biology:Carbaminohemoglobin|carbaminohemoglobin]] which accounts for approximately 30% of carbon dioxide exportation.<ref>{{Cite journal| vauthors = Arthurs GJ, Sudhakar M |date=December 2005|title=Carbon dioxide transport |journal=Continuing Education in Anaesthesia, Critical Care & Pain|language=en|volume=5|issue=6|pages=207–210|doi=10.1093/bjaceaccp/mki050|doi-access=free}}</ref> Therefore a patient suffering from carbon monoxide poisoning may experience severe [[Medicine:Hypoxia (medical)|hypoxia]] and acidosis in addition to the toxicities of excess carbon monoxide binding to numerous hemoproteins, metallic and non-metallic targets which affect cellular machinery (such as inhibition of [[Biology:Cytochrome c oxidase|cytochrome c oxidase]]).<ref name="Hopper_2020" /><ref>{{cite journal | vauthors = Yang X, Lu W, Wang M, Tan C, Wang B | title = "CO in a pill": Towards oral delivery of carbon monoxide for therapeutic applications | journal = Journal of Controlled Release | volume = 338 | pages = 593–609 | date = October 2021 | pmid = 34481027 | doi = 10.1016/j.jconrel.2021.08.059 | pmc = 8526413 }}</ref>

=== Toxicokinetics ===
In common air under normal atmospheric conditions, a typical patient's carboxyhemoglobin has a half-life around 300 minutes.<ref name="Hopper_2021" />  This time can be reduced to 90 minutes upon administration of high-flow pure oxygen, and the time is further reduced when oxygen is administered with 5% carbon dioxide as first identified by Esther Killick.<ref name="Hopper_2021" /> Additionally, treatment in a hyperbaric chamber is a more effective manner of reducing the half-life of carboxyhemoglobin to 30 minutes<ref name="Hopper_2021" /> and allows oxygen to dissolve in biological fluids for delivery to tissues.{{citation needed|date=March 2021}}

Supplemental oxygen takes advantage of [[Biology:Le Chatelier's principle|Le Chatelier's principle]] to quicken the decomposition of carboxyhemoglobin back to hemoglobin:<ref>{{Cite web|title=ChemBytes: Week of February 8, 1998|url=http://www.columbia.edu/itc/chemistry/chem-c140498/problems/chembytes/bytes_ch07.html|access-date=2021-05-11|website=www.columbia.edu}}</ref>

:HbCO + O<sub>2</sub> ⇌ Hb + CO + O<sub>2</sub> ⇌ HbO<sub>2</sub> + CO

==Carboxyhemoglobin pharmaceuticals==

As carbon monoxide is now understood to have a therapeutic potential, pharmaceutical efforts have focused on development of [[Chemistry:Carbon monoxide-releasing molecules|carbon monoxide-releasing molecules]] and selective [[Biology:Heme oxygenase|heme oxygenase]] inducers.<ref name="">{{cite journal | vauthors = Motterlini R, Otterbein LE | title = The therapeutic potential of carbon monoxide | journal = Nature Reviews. Drug Discovery | volume = 9 | issue = 9 | pages = 728–743 | date = September 2010 | pmid = 20811383 | doi = 10.1038/nrd3228 | s2cid = 205477130 }}</ref>

An alternative method for drug delivery consists of carbon monoxide immobilized on {{chem name|[[Chemistry:Polyethylene glycol|polyethylene glycol]] (PEG)-lyated}} bovine carboxyhemoglobin which is currently in late clinical development. Similarly, [[Chemistry:Maleimide|maleimide]] PEG conjugated human carboxyhemoglobin had previously been the subject of pharmaceutical development.<ref>{{cite journal | vauthors = Hopper CP, Meinel L, Steiger C, Otterbein LE | title = Where is the Clinical Breakthrough of Heme Oxygenase-1 / Carbon Monoxide Therapeutics? | journal = Current Pharmaceutical Design | volume = 24 | issue = 20 | pages = 2264–2282 | date = 2018-05-31 | pmid = 30039755 | doi = 10.2174/1381612824666180723161811 | s2cid = 51712930 }}</ref>

== See also ==
* [[Biology:Carbaminohemoglobin|Carbaminohemoglobin]] (Hb associated with {{CO2}})
* [[Engineering:Hemoglobinometer|Hemoglobinometer]]
* [[Biology:Hemoprotein|Hemoprotein]]
* [[Biology:Methemoglobin|Methemoglobin]] (ferric Hb, or ferrihemoglobin)
* Oxyhemoglobin (with diatomic [[Chemistry:Oxygen|oxygen]], colored blood-red)

== References ==
{{reflist|2}}

== External links ==
* {{MeshName|Carboxyhemoglobin}}

{{Hemeproteins}}

[[Category:Carbon monoxide]]
[[Category:Hemoglobins]]
[[Category:Respiratory physiology]]

{{Sourceattribution|Carboxyhemoglobin}}