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An important study in determining the mechanism of CO toxicity was performed by Goldbaum et al. in 1976 https://pubmed.ncbi.nlm.nih.gov/962299/
When students are asked how CO exerts its toxicity most reply that it shifts the oxygen dissociation curve to the left, leading to an increase in hemoglobin's binding affinity for oxygen and resulting decreased oxygen delivery to tissue.
This is true.
Figure - Roughton et al, Effect of Carbon Monoxide on the Oxyhemoglobin Dissociation Curve 1943
Figure - Roughton et al, Effect of Carbon Monoxide on the Oxyhemoglobin Dissociation Curve 1943
However further studies have shown that this is not the primary mechanism of toxicity.
An initial study by DL Drabkin first noted the general lack of toxicity seen when canines were transfused with carboxyhemoglobin of 75% however died when inhalation produced a similar ccn.
An initial study by DL Drabkin first noted the general lack of toxicity seen when canines were transfused with carboxyhemoglobin of 75% however died when inhalation produced a similar ccn.
Drabkin attempted to explain this by the Haldane effect. He suggested inhalation resulted in a fxn anemia of 11% vs only 25% with transfusion, leading the latter more likely to survive.
When Goldbaum replicated the experiment he included a third group where 100% CO was injection intraperitoneally - also resulting in elevated COHb concentrations which cannot be explained by the Haldane effect.
Goldbaum's study also redemonstrated the lack of toxicity when COHb is transfused or when 100% CO is injected intraperitoneally. The explanation of how CO enters cells must be other than dissociation from COHb.
In 1957, Linderholm et al showed the inhalation of CO led to significant carbon monoxide tension in the blood as it leaves the lungs, dissolved CO can then cross into tissue. https://pubmed.ncbi.nlm.nih.gov/13402410/
At the cellular level, CO inhibits mitochondria by binding to cytochrome a3.
So why do some mitochondrial inhibitors like hydrogen cyanide and hydrogen sulfide lead to rapid acidemia whereas carbon monoxide doesn't?
So why do some mitochondrial inhibitors like hydrogen cyanide and hydrogen sulfide lead to rapid acidemia whereas carbon monoxide doesn't?
Despite near equal inhibitory constants, CO only binds to the reduced from of cytochrome oxidase, whereas cyanide and hydrogen sulfide bind to intermediate forms.
Figure from Cooper and Brown's excellent review
https://pubmed.ncbi.nlm.nih.gov/18839291/
Figure from Cooper and Brown's excellent review
https://pubmed.ncbi.nlm.nih.gov/18839291/
Oxygen also binds to the reduced form of cytochrome oxidase, therefore CO is a competitive inhibitor leading to only a dec in Kmax whereas both hydrogen sulfide and CN result in dec Vmax that cannot be overcome with an increase in substrate (ie more oxygen or reduced ER).
The primary mediator of CO's toxicity is endothelial damage and inflammation. Mitochondrial dysfunction leads to an increase in both reactive oxygen species (ROS) and nitrogen species (eg peroxynitrite [ONOO-]).
There are several more specific pathways of how CO initiates inflammatory changes (activation of guanylate cyclase, myelin peroxidase, etc..) but the specifics are still being studied and are too tedious or boring for Twitter.
