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Methaemoglobin is haemoglobin in which haem iron is oxidised to iron (III) and therefore cannot function as an effective oxygen transporting protein. Small amounts of methaemoglobin are produced continually, but the proportion of total haemoglobin that is present as methaemoglobin is maintained at around 1% by the action of an NADH dependent methaemoglobin reductase. A methaemoglobin concentration greater than 1% (methaemoglobinaemia) ensues if the rate of methaemoglobin formation exceeds its rate of reduction. Not only is methaemoglobin incapable of binding oxygen but, in addition, the oxidation of one or more of the haem iron atoms in the haem tetramer distorts the tetramer structure, so that the remaining non-oxidised haem subunits bind oxygen avidly but release it less efficiently, which shifts the oxygen dissociation curve to the left. Methaemoglobinaemia manifests therefore as tissue hypoxia.
MECHANISMS OF METHAEMOGLOBIN FORMATION
The aetiology of methaemoglobinaemia may be congenital (for example, due to methaemoglobin reductase deficiency) or acquired (caused by exposure to oxidising chemicals or drugs). The mechanism of methaemoglobin formation has not been elucidated fully for all agents, but can be divided broadly into those that directly oxidise haemoglobin, those that indirectly oxidise haemoglobin, and those that require biochemical transformation to be capable of forming methaemoglobin.1-3
Direct oxidation
Examples of compounds that are theoretically capable of oxidising haemoglobin directly include chlorates, hexavalent chromates, and copper (II) salts. Direct haemoglobin oxidation is dependent not only on the redox potential of the chemical agent relative to haemoglobin (agents with a higher redox potential than haemoglobin being capable of its oxidation), but also on the ability of the agent to penetrate red cells. Ferricyanide, for example, is capable of directly oxidising haemoglobin in vitro but cannot cause methaemoglobinaemia since it is unable to penetrate the erythrocyte membrane.3 In addition, the redox potential of haemoglobin varies depending on its chemical conformation and …