Metabolism

In vivo and in vitro studies have shown that methylene chloride is metabolised by two different pathways. One is a microsomal oxidation process (involving cytochrome P450) and the other is a glutathione dependent cytosolic pathway. Carbon monoxide is formed by the microsomal oxidation pathway (Gargas et al., 1986).

Methylene chloride is largely metabolised in the liver (a small proportion may undergo transformation in the lungs and kidneys). In the liver, methylene chloride is metabolised by two pathways. The first pathway utilises the mixed function oxidase cytochrome P450 enzymes (including P450 CYP2E1) and converts methylene chloride into carbon monoxide and carbon dioxide. This pathway is the most important in humans and becomes saturated at a few hundred ppm. The second pathway utilises glutathione transferase and results in the formation of carbon dioxide (via formaldehyde and formate). This pathway appears not to be saturable, at least at concentrations up to 10,000 ppm. The metabolic contribution of each pathway appears to vary in humans, particularly with the exposure concentration. These metabolic pathways seem to have a different significance in laboratory animals so that interspecies comparisons are difficult and there may be a possibility of enzyme polymorphism (Their et al., 1991). The metabolic formation of carbon monoxide and its subsequent binding to haemoglobin, producing carboxyhaemoglobin, may continue for several hours after cessation of methylene chloride exposure, as fat and other tissues continue to release accumulations of the lipophilic solvent. This endogenous release of methylene chloride prolongs the duration of cardiovascular stress to about twice that caused by a comparable carboxyhaemoglobin concentration resulting from exposure to carbon monoxide (ATSDR, 1993a,b; IPCS, 1996).

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