One problem with human exposure to carbon monoxide (CO) is that directly demonstrating CO toxicity is difficult as symptoms of CO poisoning are non-specific. CO can also be rapidly eliminated from the body.

Once the level of suspicion in the medical practitioner is raised, methods to confirm CO exposure require specialist equipment: blood gas or breath analysers, which tend to be utilised some time after the patient has been removed from the source of exposure. This makes detection difficult and poisoning harder to confirm due to the half-life of CO in the body.

It is considered likely that CO poisoning is under diagnosed and if diagnosed, not necessarily detected or confirmed, making accurate morbidity and mortality statistics caused by exposure to CO, difficult to obtain.

There is a need therefore, to identify markers of exposure to CO which indicate both the presence and levels of toxicity, for use by medical practitioners and coroners. Such markers need to be robust and long lasting.

The terminal enzyme of the mitochondrial respiratory chain, cytochrome c oxidase (COX) is a major cellular target for CO inhibition. Evidence suggests that CO may cause long lasting inhibition of COX, even when CO exposure has stopped, indicating that COX activity may be an indicator of CO exposure.

The purpose of this study was to:

  1. Determine if mitochondrial COX activity levels are stable post mortem, to permit COX to be used as a screening tool in Coroner’s investigations of suspected CO poisoning.
  2. Determine levels of mitochondrial COX in post mortem human brain tissues exposed to CO in vivo, and to determine if COX levels differ from those found in normal tissues.

This study permitted the evaluation of the potential of COX as a biomarker of CO exposure in the investigation of CO poisoning, where fatalities occur. The intention would be to eventually use COX activity in other tissues as a marker of CO exposure at post mortem and also in accident and emergency departments.


The investigations demonstrated that COX activity is relatively stable to a wide range of agonal and post mortem factors, which may impact Coronial investigations. Therefore, COX could be used as a marker if a need can be identified.

Using the unique access to tissues from individuals acutely exposed to high levels of CO, it was demonstrated that COX activity is unaffected by CO exposure. This indicated that tissue hypoxia is the likely cause of death under these circumstances. Extending these investigations showed that the major protein subunits of COX, COX1 and COX2, are also unaffected by high level acute CO exposure.

Whilst these studies indicated that acute CO mediates its effect through hypoxia, chronic lower level exposures which are known to cause neurological and cognitive effects 60, 61 may act via different mechanisms over and above those of hypoxia.

Although investigation of such low level chronic exposures should be a priority, it is unlikely that novel biochemical investigations, such as those undertaken as part of this study, could be repeated due to the absence of available tissue.

Extending the work using the available CO exposed tissues, to investigate the physiological CO signalling system, it was shown that acute high level CO exposure causes a reduction in the CO target enzyme soluble guanylate cyclase (sGCSβ) and an increase of the downstream effector p38 mitogen activated protein kinase (p38MAPK).

These novel findings suggested that the system which normally responds to low levels of endogenously produced CO, may at high exogenous CO levels be altered in an attempt to reduce the toxic effects of CO.

These findings indicate that by investigating changes in the physiological CO system, it may be possible to monitor CO exposure. Understanding the chronic effects of CO exposure would be of use, since many symptoms of CO exposure such as fatigue, headache, loss of concentration, may stem from prolonged CO exposures and from longer term changes to cells and tissues.


The finding of an altered physiological CO response system lends itself to further investigations into the effects of CO. Using in vitro approaches with human cells (peripheral blood cells, lymphocyte cell lines), it should be possible to determine the acute and subacute effects of CO exposure by profiling gene expression, to identify the relevant proteins and systems which are altered in response to CO exposure.

These could then be carried forward to in vivo animal studies, where confirmation of changes could be obtained in a controlled environment. Such markers of CO exposure would enable clinical studies to be put in place to determine the expression of these proteins in blood. This would demonstrate CO exposure in the absence of raised carboxyhaemoglobin (COHb), particularly where the non-specific symptoms of exposure are present (e.g. headache, nausea, dizziness fatigue), and where there is a suspicion of CO exposure.

Such a test may also be useful as an adjunct for monitoring individuals who are known to have been exposed to CO to determine how rapidly tissues return to normal following removal from exposure. This would also provide some insight into why delayed effects from CO exposure are experienced by patients after apparent recovery.

Final Report

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