Brian Mann and Roberto Motterlini of the University of Sheffield and Northwick Park Institute for Medical Research in Harrow, UK, react to carbon monoxide's bad press

Carbon monoxide has a deservedly bad reputation as a silent killer; it causes the death of many people each year. Yet, small quantities of the gas are essential for life.

CO is generated naturally in the body, mainly by enzymes that catalyse the oxidation of heme - the iron-containing pigment in blood. This enzymatic reaction is all apparent to us when we develop a bruise: firstly, purple-red oxygenated hemoglobin is oxidised and heme gradually liberated and oxidised. As the oxygen is used up in heme oxidation, the heme is converted to the deoxygenated blue form, characteristic of venous blood. Later, the bruise turns green and yellow with red spots. The green is due to iron-free biliverdin formed from the heme and the yellow to the pigment bilirubin, also present in urine. The red spots are probably due to CO attached to the iron of the remaining heme.

As a result of heme oxidation, around 0.6 per cent of the hemoglobin circulating in blood has CO attached. This increases markedly for smokers, whose lungs trap CO from the smoke. A person breathes out around 6cm³ of CO generated from heme degradation every day, and this is increased by inflammatory conditions such as asthma and diabetes.

Carbon monoxide is generated naturally in the body where it acts as a signalling molecule

CO functions as a signalling molecule in the body and it is especially important in the cardiovascular system. It possesses a wide range of bioactivities and beneficial effects, including protection against reperfusion injury, which occurs as the blood supply returns to a tissue following interruption (ischaemia). CO also suppresses organ rejection after transplantation and can reverse hypertension.

The beneficial biological activity of CO gas and its therapeutic potential have been demonstrated in animal experiments. However, delivering CO in this way requires very careful monitoring to prevent a dangerous dose being inhaled and unwanted exposure of the medical staff handling the gas. CO inhalation relies on the heme in blood transporting the CO from the lungs and exposes the whole body to increased CO levels, raising concerns about damage elsewhere.

A safer procedure would be to administer CO as a solution or in a solid form that subsequently releases the CO needed. This technique is well established for NO, which also acts as a signalling molecule and performs some of the roles attributed to CO. NO differs from CO in having a very short life-time due its high reactivity. Because of this, NO is pro-inflammatory; CO inhibits its production and is thus anti-inflammatory. NO is administered through NO-releasing compounds: Nitroprusside, [Fe(CN)5(NO)]^2-, nitroglycerine and amyl nitrite have been used for well over 100 years and recently more NO-releasing molecules have been developed. They are now prescribed regularly to control blood pressure and to relieve angina.

Following the same principles, CO-releasing molecules (CORMs) are being developed so that the quantity of CO and its delivery location can be controlled. A range of metal compounds containing CO have been synthesised and some have been shown to release CO relatively quickly. [Ru(CO)₃Cl(glycinate)] (CORM-3) reduces blood pressure, protects hearts from ischaemic damage and myocardial infarction - heart attack - and prolongs cardiac muscle life considerably following heart transplantation. More recently, further biologically active CORMs based on iron, manganese and molybdenum have been developed. But CORMs are not restricted to transition metal complexes; boranocarbonates such as [H3BCO2]^2- also liberate CO at physiological pH and reduce blood pressure.

The field of developing CORMs as pharmaceuticals is in its infancy. However, we should recapitulate that NO-releasing agents are very well established in medicine. Considering that the bioactive and pharmacological properties of CORMs were first described only five years ago and that there are already many reports of their beneficial application in animals, it can only be a matter of time before CORMs can be considered as a therapeutic stratagem in humans.

Read Mann and Motterlini's feature article 'CO and NO in medicine' in issue 41 of Chemical Communications.