Carboxyhemoglobin (carboxyhaemoglobin BrE) (symbol COHb or HbCO, also known as carbonylhemoglobin) 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 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.), alternatively, hemoglobin can bind four CO2 molecules at terminal amines to form carbaminohemoglobin, therefore, in either case a typical red blood cell may carry up to one billion gas molecules (for unit comparison, the enzymatic velocity of carbonic anhydrase is estimated to catalyze bioconversion of CO2 to bicarbonate at a rate of ~10 million molecules per second). As the binding of carbon monoxide with a heme moiety of 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, 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 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 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 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 ). 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 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. 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.
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. 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.
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, Humphry Davy, James Lind, and many others investigated the therapeutic potential of inhaling factitious airs in the late eighteenth century (see also: Pneumatic Institution). Among the gases experimented with, hydrocarbonate 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 contained phlogiston. 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 (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 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, via the French , which first appeared in print in 1786. The etymology of oxygen is generally accepted to 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; the suffix -ic in carbonic is derived from Latin -icus and Greek -ikos meaning "pertaining to" or "having the nature of", which, when combined with the word acid as -ic acid, in Lavoisier's system the name carbonic acid is indicative of the maximum oxidation state of carbon (the max number of oxygen atoms attached to the nonmetallic carbon, whereas the a nonmetal with the possibility of fewer oxygen atoms would subsequently be named -ous acid). 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 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 (kohlenstoff is the word for the element carbon which emerged in the Lavoisier era), and oxyd is German for oxide, hence the literal translation is oxide of 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). Oxides were defined in 1804 to be "the compounds of oxygene not possessing acid properties." Therefore, the suffix -ic oxide in carbonic oxide could have the literal translation "carbon having the nature of an oxide". The term carbonous oxide appeared in some ancient texts as an attempt to bridge Lavoisier's nomenclature to the new molecule since the suffix -ic originally indicated two oxygen atoms in CO2 therefore the suffix -ous implies a lesser degree of oxidation with CO having one oxygen atom, but the name was scarcely used.
Haem is derived from Greek meaning blood. Regarding haem, after being translated from Hippocratic texts as haima, haem first appeared in ancient Roman texts and subsequently first appeared in English in the 1400s. The use of "ae / æ" remains prevalent in British English in modern day whereas the American English adopted the simplified Latinate spelling heme from hema. The exact origin of the heme spelling is unclear and may relate to a combination of factors such as: back-formation of heme as a scientific term derived from the established American English term hemoglobin, and in parallel, the novel Americanized root was heavily influenced by previously established terms such as hemorrhage (the first dictionary set of words with hem- prefix/root) which first appeared in Noah Webster's 1828 book An American Dictionary of the English Language during a period of time when American English actively abandoned British ligatures in the English-language spelling reform era. Anecdotal appearances of hæm- to hem-, such as hemoptysis from hæmoptysis, appeared as early as 1787. Due to "hem" visually appearing incomplete, the word may have been modified since English nouns often place a silent -e to the end of adopted terms for aesthetics along with French and scholarly spelling influences. Other benefits may include phonotactic signaling, disambiguation from hem, and lexical separation purposes. Standardization came later with the Simplified Spelling Board. Although it remains unclear, heme may have emerged in literature around 1900. As a result of the haem/heme divergence, COHb has more than one acceptable spelling.