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Carboxyhemoglobin (carboxyhaemoglobin
BrE British English (BrE, en-GB, or BE) is, according to Lexico, Oxford Dictionaries, "English language, English as used in Great Britain, as distinct from that used elsewhere". More narrowly, it can refer specifically to the English language in ...
) (symbol COHb or HbCO) is a stable complex of carbon monoxide and hemoglobin (Hb) that forms in red blood cells upon contact with carbon monoxide. Carboxyhemoglobin is often mistaken for the compound formed by the combination of carbon dioxide ( carboxyl) and hemoglobin, which is actually 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. The average non-smoker maintains a systemic carboxyhemoglobin level under 3% COHb whereas smokers approach 10% COHb. The biological threshold for carboxyhemoglobin tolerance is 15% COHb, meaning toxicity is consistently observed at levels in excess of this concentration. The
FDA The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food s ...
has previously set a threshold of 14% COHb in certain clinical trials evaluating the therapeutic potential of carbon monoxide.


Overview

The average red blood cell contains 250 million hemoglobin molecules. Hemoglobin contains a globin protein unit with four prosthetic heme groups (hence the name heme -o- globin); each heme is capable of reversibly binding with one gaseous molecule (oxygen, carbon monoxide, cyanide, etc.), 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.


Endogenous carbon monoxide production

In biology, carbon monoxide is naturally produced through many enzymatic and non-enzymatic pathways. The most extensively studied pathway is the metabolism of heme by heme oxygenase which occurs throughout the body with significant activity in the spleen to facilitate 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 gasotransmitter. Most endogenously produced carbon monoxide is stored as carboxyhemoglobin. The gas primarily undergoes pulmonary excretion, however trace amounts may be oxidized to carbon dioxide by certain cytochromes, metabolized by resident
microbiota Microbiota are the range of microorganisms that may be commensal, symbiotic, or pathogenic found in and on all multicellular organisms, including plants. Microbiota include bacteria, archaea, protists, fungi, and viruses, and have been found t ...
, or excreted by transdermal diffusion.


Affinity of hemoglobin for carbon monoxide

Compared to oxygen, carbon monoxide binds with approximately 240 times greater affinity, however the affinity of carbon monoxide for hemoglobin varies both across species and within a species. In the 1950s,
Esther Killick Esther Margaret Killick (3 May 1902 – 31 May 1960) was an English physiologist who was a professor of physiology at the London School of Medicine for Women (Royal Free Hospital School of Medicine) from 1941 until her death in 1960. Her main r ...
was among the first to recognize a difference in carbon monoxide affinity between adult and foetal blood, and a difference between humans and sheep. 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. Other human mutations have been described (see also: hemoglobin variants). Structural variations and mutations across other hemoproteins likewise affect carbon monoxide's interaction with the heme prosthetic group as exemplified by
Cytochrome P450 Cytochromes P450 (CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are ...
where certain forms of the CYP3A family is relatively less affected by the inhibitory effects of carbon monoxide. Murinae species have a COHb half-life of 20 minutes compared to 300 minutes for a typical human
see toxicokinetics below
. 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 toxicology of carbon monoxide poisoning and
pharmacology Pharmacology is a branch of medicine, biology and pharmaceutical sciences concerned with drug or medication action, where a drug may be defined as any artificial, natural, or endogenous (from within the body) molecule which exerts a biochemica ...
of low-dose therapeutic protocols. 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. Similarly, the elevated levels in smokers has been suggested to be a basis for the
smoker's paradox Tobacco use has predominantly negative effects on human health and concern about health effects of tobacco has a long history. Research has focused primarily on cigarette smoking. Tobacco smoke contains more than 70 chemicals that cause ca ...
. Prolonged exposure to carbon monoxide and elevated carboxyhemoglobin, such as in smoking, results in erythremia. Furthermore, humans can acclimate to toxic levels of carbon monoxide based on findings reported by
Esther Killick Esther Margaret Killick (3 May 1902 – 31 May 1960) was an English physiologist who was a professor of physiology at the London School of Medicine for Women (Royal Free Hospital School of Medicine) from 1941 until her death in 1960. Her main r ...
.


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 Marcellus may refer to: * Marcellus (name) * Marcus Claudius Marcellus, Roman commander Places * Marcellus, Lot-et-Garonne, France * Marcellus Township, Michigan ** Marcellus, Michigan, a village in Marcellus Township ** Marcellus Community Schoo ...
circa 1570 who noted an unusually red complexion upon conducting an autopsy of victims who died from charcoal fumes in Mantua. Similar findings pertaining to red complexion later emerged as documented by
Johann Jakob Wepfer Johann Jakob Wepfer (December 23, 1620 – January 26, 1695) was a Swiss pathologist and pharmacologist who was a native of Schaffhausen. He studied medicine in Strasbourg, Basel and Padua, and in 1647 returned to Schaffhausen to practice med ...
in the 1600s, and M.
Antoine Portal Baron Antoine Portal (January 5, 1742 РJuly 23, 1832) was a French anatomist, doctor, medical historian and founding president of the Acad̩mie Nationale de M̩decine. Biography Born on January 5, 1742, in Gaillac, he was the eldest of 12 s ...
in the late 1700s. Phlogiston theory is a trace origin for the first chemical explanations of endogenous carboxyhemoglobin exemplified by the work of 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. Thomas Beddoes,
James Watt James Watt (; 30 January 1736 (19 January 1736 OS) – 25 August 1819) was a Scottish inventor, mechanical engineer, and chemist who improved on Thomas Newcomen's 1712 Newcomen steam engine with his Watt steam engine in 1776, which was fun ...
, Humphry Davy, James Lind, and many others investigated the therapeutic potential of inhaling factitious airs in the late eighteenth century (see also:
Pneumatic Institution The Pneumatic Institution (also referred to as Pneumatic Institute) was a medical research facility in Bristol, England, in 1799–1802. It was established by physician and science writer Thomas Beddoes to study the medical effects of gases, know ...
). Among the gases experimented with,
hydrocarbonate In inorganic chemistry, bicarbonate (IUPAC-recommended nomenclature: hydrogencarbonate) is an intermediate form in the deprotonation of carbonic acid. It is a polyatomic anion with the chemical formula . Bicarbonate serves a crucial biochemic ...
had received significant attention. Hydrocarbonate is water gas generated by passing steam over coke, the process of which generates carbon monoxide and hydrogen, and some considered it contain
phlogiston The phlogiston theory is a superseded scientific theory that postulated the existence of a fire-like element called phlogiston () contained within combustible bodies and released during combustion. The name comes from the Ancient Greek (''burni ...
. Beddoes and Watt recognized hydrocarbonate brightened venous blood in 1793. Watt suggested coal fumes could act as an antidote to the oxygen in blood, and Beddoes and Watt likewise speculated hydrocarbonate has a greater affinity for animal fiber than oxygen in 1796. After the discovery of carbon monoxide by William Cruickshank in 1800, Johann Dömling (1803) and
John Bostock John Joseph Bostock (born 15 January 1992) is an English professional footballer who plays as a midfielder for club Notts County. Bostock made his professional debut for Crystal Palace at the age of 15. In 2008, he signed for Tottenham Hotsp ...
(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. Later in 1854,
Adrien Chenot Adrien C. B. Chenot (born on August 30, 1803; died November 27, 1855) was a French engineer best known for his inventions in metallurgy as well as his research on manufactured gases. He is notably the inventor of one of the first modern methods of ...
similarly suggested carbon monoxide could remove oxygen from blood and be oxidized within the body to carbon dioxide. 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". 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 Josef von Fodor.


Etymology

Carbon is derived from the Latin term ''carbo'', meaning coal, first appeared in 1786 French publication as charbone. The 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 carbonic acid () as the most oxidized form; Lavoisier's system was superseded by other obsolete oxide nomenclature systems. Upon discovering carbon monoxide through a series of experiments originating from coke (short for coal-cake),
Cruickshank Cruickshank is a Scottish surname. Notable people with the surname include: * Adrian Cruickshank (born 1936), Australian politician * Alexander M. Cruickshank (1919–2017), American chemist * Andrew Cruickshank (1907–1988), Scottish actor * ...
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. As carbonic acid () 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, and globin is Latin derived from ''globus'' typically accepted to mean glob/spherical/round object; the terms are conjoined with an -o- . Regarding haem, the use of "ae / æ" remains prevalent in British English in modern day whereas the American English spelling evolved to heme from hema. Felix Hoppe-Seyler coined the name "hämoglobin" in 1864. 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 which may have similarly been directly translated back into English as "carbonic oxide hæmoglobin". 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. The term "carbon monoxide" was formally introduced in 1879, but the name would not become mainstream for several decades. Variations of COHb terminology, such as carbonmonoxyhemoglobin, followed and eventually evolved and simplified back into "carboxyhemoglobin". As carboxy is now firmly associated with the CO2 carboxyl group, and carbon monoxide is generally regarded as a carbonyl, IUPAC has recommended "carbonylhemoglobin" as the preferred COHb nomenclature. Despite the IUPAC guidance, carboxyhemoglobin remains the most widely used term (akin to the survival of bicarbonate nomenclature).


Analytical detection methods

Historically, carboxyhemoglobin detection has been achieved by colorimetric analysis, chemical reactivity, spectrophotometry, gasometric and
thermoelectric The thermoelectric effect is the direct conversion of temperature differences to electric voltage and vice versa via a thermocouple. A thermoelectric device creates a voltage when there is a different temperature on each side. Conversely, when ...
detection methods.
Gas chromatography Gas chromatography (GC) is a common type of chromatography used in analytical chemistry for separating and analyzing compounds that can be vaporized without decomposition. Typical uses of GC include testing the purity of a particular substance, ...
analysis emerged in 1961 and remains a commonly used method. Modern methods include pulse oximetry with a CO-oximeter, and a variety of other analytical techniques. Most methods require laboratory equipment, skilled technicians, or expensive electronics therefore rapid and economical detection technologies remain in development. Breath carbon monoxide is another detection method that may correlate with carboxyhemoglobin levels.


Carbon monoxide poisoning

Carbon monoxide poisoning, also known as carboxyhemoglobinemia, 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. In general, 30% COHb is considered severe carbon monoxide poisoning. The highest reported non-fatal carboxyhemoglobin level was 73% COHb.


Mode of toxic action

Gas exchange is an essential process for many organisms to maintain homeostasis. Oxygen accounts for about 20% of Earth's atmospheric air. While inhaling air is critical to supply cells with oxygen for
aerobic respiration Cellular respiration is the process by which biological fuels are oxidised in the presence of an inorganic electron acceptor such as oxygen to produce large amounts of energy, to drive the bulk production of ATP. Cellular respiration may be des ...
via the
Bohr effect The Bohr effect is a phenomenon first described in 1904 by the Danish physiologist Christian Bohr. Hemoglobin's oxygen binding affinity (see oxygen–haemoglobin dissociation curve) is inversely related both to acidity and to the concentration o ...
and
Haldane effect The Haldane effect is a property of hemoglobin first described by John Scott Haldane, within which oxygenation of blood in the lungs displaces carbon dioxide from hemoglobin, increasing the removal of carbon dioxide. Consequently, oxygenated blood ...
(and perhaps local low oxygen partial pressure e.g. active muscles), exhaling the cellular waste product carbon dioxide is arguably the more critical aspect of respiration. Whereas the body can tolerate brief periods of
hypoxia Hypoxia means a lower than normal level of oxygen, and may refer to: Reduced or insufficient oxygen * Hypoxia (environmental), abnormally low oxygen content of the specific environment * Hypoxia (medical), abnormally low level of oxygen in the tis ...
(as commonly occurs in
anaerobic exercise Anaerobic exercise is a type of exercise that breaks down glucose in the body without using oxygen; ''anaerobic'' means "without oxygen". In practical terms, this means that anaerobic exercise is more intense, but shorter in duration than aerobi ...
, 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). In absence of oxygen, cells switch to anaerobic respiration which if prolonged may significantly increase lactic acid leading to
metabolic acidosis Metabolic acidosis is a serious electrolyte disorder characterized by an imbalance in the body's acid-base balance. Metabolic acidosis has three main root causes: increased acid production, loss of bicarbonate, and a reduced ability of the kidneys ...
. 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
conformational change In biochemistry, a conformational change is a change in the shape of a macromolecule, often induced by environmental factors. A macromolecule is usually flexible and dynamic. Its shape can change in response to changes in its environment or oth ...
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 ions annotated as H+; 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+ ions as the scale approaches pH 1); the local acidity is caused by an increase in the biotransformation of carbon dioxide waste into carbonic acid via
carbonic anhydrase The carbonic anhydrases (or carbonate dehydratases) () form a family of enzymes that catalyze the interconversion between carbon dioxide and water and the dissociated ions of carbonic acid (i.e. bicarbonate and hydrogen ions). The active site ...
. In other words, oxygenated arterial blood arrives to cells in the " hemoglobin R-state" which has deprotonated/unionized amino acid
residues Residue may refer to: Chemistry and biology * An amino acid, within a peptide chain * Crop residue, materials left after agricultural processes * Pesticide residue, refers to the pesticides that may remain on or in food after they are appli ...
(regarding hemoglobin's amines transitioning between the deprotonated/unionized Hb-NH2 to the protonated/ionized Hb-NH3+ state) based on the less-acidic pH (arterial blood averages pH 7.407 whereas venous blood is slightly more acidic at pH 7.371). 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 (i.e. oxygen is 'ejected' upon arrival at the cell due to H+ ions bombarding the hemoglobin surface residues to convert Hb from "R-state" to "T-state"). Furthermore, the mechanism for formation of carbaminohemoglobin generates additional H+ 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 Hyperventilation is irregular breathing that occurs when the rate or tidal volume of breathing eliminates more carbon dioxide than the body can produce. This leads to hypocapnia, a reduced concentration of carbon dioxide dissolved in the blood. ...
) 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 chemoreceptors, 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. 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 carbaminohemoglobin which accounts for approximately 30% of carbon dioxide exportation. Therefore a patient suffering from carbon monoxide poisoning may experience severe
hypoxia Hypoxia means a lower than normal level of oxygen, and may refer to: Reduced or insufficient oxygen * Hypoxia (environmental), abnormally low oxygen content of the specific environment * Hypoxia (medical), abnormally low level of oxygen in the tis ...
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 cytochrome c oxidase).


Toxicokinetics

In common air under normal atmospheric conditions, a typical patient's carboxyhemoglobin has a half-life around 300 minutes. 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 Esther Margaret Killick (3 May 1902 – 31 May 1960) was an English physiologist who was a professor of physiology at the London School of Medicine for Women (Royal Free Hospital School of Medicine) from 1941 until her death in 1960. Her main r ...
. Additionally, treatment in a hyperbaric chamber is a more effective manner of reducing the half-life of carboxyhemoglobin to 30 minutes and allows oxygen to dissolve in biological fluids for delivery to tissues. Supplemental oxygen takes advantage of
Le Chatelier's principle Le Chatelier's principle (pronounced or ), also called Chatelier's principle (or the Equilibrium Law), is a principle of chemistry used to predict the effect of a change in conditions on chemical equilibria. The principle is named after French c ...
to quicken the decomposition of carboxyhemoglobin back to hemoglobin: :HbCO + O2 ⇌ Hb + CO + O2 ⇌ HbO2 + CO


Carboxyhemoglobin pharmaceuticals

As carbon monoxide is now understood to have a therapeutic potential, pharmaceutical efforts have focused on development of
carbon monoxide-releasing molecules Carbon monoxide-releasing molecules (CORMs) are chemical compounds designed to release controlled amounts of carbon monoxide (CO). CORMs are being developed as potential therapeutic agents to locally deliver CO to cells and tissues, thus overcomin ...
and selective heme oxygenase inducers. An alternative method for drug delivery consists of carbon monoxide immobilized on polyethylene glycol (PEG)-lyated bovine carboxyhemoglobin which is currently in late clinical development. Similarly, maleimide PEG conjugated human carboxyhemoglobin had previously been the subject of pharmaceutical development.


See also

* Carbaminohemoglobin (Hb associated with ) *
Hemoglobinometer A hemoglobinometer or haemoglobinometer (British English) is a medical device used to measure hemoglobin concentration in blood. It can operate by spectrophotometric measurement of hemoglobin concentration. Portable hemoglobinometers provide ...
* Hemoprotein * Methemoglobin (ferric Hb, or ferrihemoglobin) * Oxyhemoglobin (with diatomic oxygen, colored blood-red)


References


External links

* {{Hemeproteins Carbon monoxide Hemoglobins Natural gas safety Respiratory physiology