Effect on CO Binding to cytochrome aa3

Cytochrome a-a3 is the terminal enzyme of intra-mitochondrial respiratory chain; it catalyzes the reduction of molecular diatomic oxygen into water in a four-step electron transfer. The enzyme complex accounts for around 90 % of the total O2 uptake of the body. Inhibition of cytochrome a-a3 by CO blocks the flow of electrons from substrate to O2 which normally provides cell energy (ATP) via oxidative phosphorylation18,19.

Under usual conditions of cellular pO2, CO binding to cytochrome a-a3 is opposed by the greater affinity of O2 to the binding site. However, when COHb increases, jugular venous pO2 has been shown to drop to a level where - given heterogeneous circulation, capillary density and metabolic demands - pO2 may decrease sufficiently to allow CO to bind to cytochrome a-a320. Moreover, failure to adapt microcirculatory O2 delivery to local O2 demand has also been reported to be a potential direct toxic effect of CO on vascular smooth muscle21. This could contribute to the regional differences in CO uptake as dysregulation of blood flow renders certain areas hypoxic.

Evidence of CO binding to cytochrome a-a3 has in fact been shown by Brown and Piantadosi22 who demonstrated this using in vivo reflectance near-infrared spectrophotometry. As COHb levels rise, cytochrome a-a3 inhibition occurs. This is followed by a decrease in intracellular ATP and pH23 leading to neuronal depolarization, cathecholamine and excitatory amino-acid (in particular glutamate) intrasynaptic release and a concomitant decrease in re-uptake. These processes are independent of the hypoxia. They may explain the observation of seizures in CO poisoned patients. They may also initiate a process of apoptosis contributing to neuronal degeneration, especially in vulnerable areas such as the hippocampus24,25.

In summary, in addition to hypoxemic hypoxia, CO poisoning induces a histotoxic hypoxia, and this process is self-perpetuating. This is also consistent with the clinical experience.

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