Carboxyhemoglobin

is a stable complex of carbon monoxide and hemoglobin 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 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 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 ; each heme is capable of reversibly binding with one gaseous molecule, 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. 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. 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. Similarly, the elevated levels in smokers has been suggested to be a basis for the smoker's paradox. 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;

Upon discovering carbon monoxide through a series of experiments originating from coke 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.

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. 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. 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. exhaling the cellular waste product carbon dioxide is arguably the more critical aspect of respiration. Whereas the body can tolerate brief periods of hypoxia, failure to expel carbon dioxide may cause respiratory acidosis. In absence of oxygen, cells switch to anaerobic respiration which if prolonged may significantly increase lactic acid leading to metabolic acidosis.

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 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 ; 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 based on the less-acidic pH. 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. 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" for the deprotonation/unionization of hemoglobin to re-enable oxygen binding as part of the transition to arterial blood. 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. 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.

Toxicokinetics

In common air under normal atmospheric conditions, a typical patient's carboxyhemoglobin has a half-life around 300 minutes.

 

Carboxyhemoglobin pharmaceuticals

As carbon monoxide is now understood to have a therapeutic potential, pharmaceutical efforts have focused on development of carbon monoxide-releasing molecules and selective heme oxygenase inducers.

An alternative method for drug delivery consists of carbon monoxide immobilized on 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
Hemoglobinometer
Hemoprotein
Methemoglobin
Oxyhemoglobin
References
External links

 

 

Bibliography:

Wikipedia

@baygross