Carboxyhemoglobin

Etymology

Carbon is derived from the Latin term carbo, meaning coal, via the French charbone, which first appeared in print in 1786.^[15] 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were based on diamond, graphite, coal and carbonic acid (CO₂) as the most oxidized form;^[15] Lavoisier's system was superseded by other obsolete oxide nomenclature systems.^[16]

Upon discovering carbon monoxide through a series of experiments originating from coke (short for coal-cake^[15]), 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.^[4][17] 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). Oxides were defined in 1804 to be "the compounds of oxygene not possessing acid properties."^[18]

Haem is derived from Greek meaning blood.^[19][20] 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^[21] whereas the American English adopted the simplified Latinate spelling heme from hema.^[20] 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.^[22] 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.^{[citation needed]} As a result of the haem/heme divergence, COHb has more than one acceptable spelling.

Felix Hoppe-Seyler coined the name "hämoglobin" in 1864.^[23] 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 was the term adopted by English literature. Globin is Latin derived from globus typically accepted to mean glob/spherical/round object, and the suffix -in indicates protein species. Haem/heme and globin are conjoined with an -o- since both heme and globin are root words; -o- is acceptable for two roots despite being in the presence of other vowels at the junction,^[24] however, in this specific case the stylistic vowel -e- is dropped from heme in American English whereas the alternative British English retained the classical Greek etymological double vowel, -ae- thereby retaining the consonant -m. Some sources suggest etymology of haemoglobin is simply a shortened version of hematoglobulin (mentioned as hämatoglobulin by Hoppe-Seyler in the 1864 publication).^[25][26] The term "hæmato-globulin" was coined by Jöns Jacob Berzelius^[27] and published in articles by scientists such as Henry Letheby as early as 1845^[28] long before Hoppe-Seyler's molecular characterization at a time when cruor^[29] was regarded as a synonym due to scientists only having an empirical understanding of the molecule while pursuing early studies of thrombus.

Hoppe-Seyler likewise coined the name oxyhaemoglobin (the prefix oxy- implying addition of oxygen), as well as kohlenoxydhämoglobin^[30] which may have similarly been directly translated back into English as "carbonic oxide hæmoglobin".^[31] The term carboxyhæmoglobin appeared in the 1890s (the prefix carb- added to the existing word oxyhemoglobin to specify presence of both a carbon and oxygen species). The first appearance may have been in 1891 in Journal of the Chemical Society.^{[citation needed]} An example of an early publication using carboxyhemoglobin appeared in 1895 in works by John Haldane while the name for CO was still widely regarded as carbonic oxide.^[32]

The term "carbon monoxide" was formally introduced in 1879, but the name would not become mainstream for several decades.^[4] Variations of COHb terminology, such as Linus Pauling's usage of carbonmonoxyhemoglobin in the 1930s,^[33][11] followed and eventually evolved and simplified back into "carboxyhemoglobin" to likewise express a ligand containing both carbon and oxygen. In German, kohlenmonoxidhämoglobin (identical to Pauling's carbonmonoxyhemoglobin) currently remains a commonly used term alongside carboxyhämoglobin.^[34][35]

As the modern chemistry language has redefined carboxy to encompass two functional groups (contraction of carbonyl + hydroxy)^[36] which is now firmly associated with the R—CO₂^— carboxyl group, and carbon monoxide is generally regarded as a carbonyl, IUPAC has recommended "carbonylhemoglobin" as the preferred COHb nomenclature.^[4] The name carbonyl consists of two parts: carbon- originating from the historical name carbonic acid (CO₂), and -yl from the Greek word hylē meaning 'the stuff from which a thing is made' (i.e. the carbonyl group appears within carbonic acid)^[37] although the substituent -yl now carries a different meaning present day. Despite the IUPAC guidance, carboxyhemoglobin remains the most widely used term (akin to the survival of bicarbonate nomenclature).

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 via the Bohr effect and Haldane effect (and perhaps local low oxygen partial pressure e.g. active muscles),^[44] exhaling the cellular waste product carbon dioxide is an equally critical aspect of respiration. Whereas the body can tolerate brief periods of hypoxia (as commonly occurs in 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).^[45] In absence of oxygen, cells switch to anaerobic respiration which if prolonged may significantly increase lactic acid leading to metabolic acidosis.^[46]

In general, carbon monoxide is considered to displace and prevent oxygen from binding to heme thereby preventing delivery of oxygen throughout the body which induces hypoxia. To provide a simplified synopsis of the molecular mechanism of systemic gas exchange from an acid-base chemistry perspective, upon inhalation of air it is an accepted mechanism that oxygen binding to any of the heme sites triggers a 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 in-part 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 a low pH based on the acidity of pH 1-7 having a low number due to the inverse logarithmic calculations); the local acidity is caused by an increase in the biotransformation of carbon dioxide waste into carbonic acid via carbonic anhydrase. In other words, oxygenated arterial blood arrives to cells in the "hemoglobin R-state" which has deprotonated/unionized amino acid residues (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^[47]). 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^[48] (i.e. in a theatric example, oxygen is 'ejected' into dissolution upon arrival at the cell due to H⁺ ions bombarding the hemoglobin surface residues to convert Hb from "R-state" to "T-state", and equilibria dynamics drives the spatial diffusion and distribution throughout the tissue region). 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) 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, pO₂ equilibria and many 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.^[13]

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 10% - 30% of carbon dioxide exportation.^[49] Therefore a patient suffering from carbon monoxide poisoning may experience severe 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 cytochrome c oxidase).^[7][50]

Toxicokinetics

In common air under normal atmospheric conditions, a typical patient's carboxyhemoglobin has a half-life around 300 minutes.^[4] 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.^[4] Additionally, treatment in a hyperbaric chamber is a more effective manner of reducing the half-life of carboxyhemoglobin to 30 minutes^[4] and allows oxygen to dissolve in biological fluids for delivery to tissues.^{[citation needed]}

Supplemental oxygen takes advantage of Le Chatelier's principle to quicken the decomposition of carboxyhemoglobin back to hemoglobin:^[51]

HbCO + O₂ ⇌ Hb + CO + O₂ ⇌ HbO₂ + CO