Metabolism

There is a large amount of data concerning the metabolism of chloroform some of which is contradictory, but this is probably because metabolism varies between species (Brown et al., 1974; Charlesworth, 1976; Winslow and Gerstner, 1978).

Chloroform is metabolised in the liver by the microsomal cytochrome P450-dependent monoxygenase system to trichloromethanol, which spontaneously dechlorinates to produce phosgene. This process is dependent on reduced nicotinamide adenine nucleotide phosphate (NADPH) and requires oxygen. However, chloroform metabolism may also occur in the absence of oxygen (Testai and Vittozzi, 1984). Phosgene reacts with water to form carbonate (which is eliminated as carbon dioxide) and hydrochloric acid (chloride ion). This explains the formation of carbon dioxide without the formation of methylene chloride. The relative importance of this pathway depends on the dose of chloroform, suggesting that it may become saturated (Pohl, 1979).

The trichloromethyl radical has been suggested as a hepatotoxic metabolite, but this is not supported by evidence (see Mode of action). Dichloromethyl carbene has also been suggested as a metabolite of chloroform. This is a highly reactive species that reacts with water to form formyl chloride, which spontaneously decomposes to carbon monoxide and hydrochloric acid, or hydrolyses to formic acid. Small amounts of carbon monoxide and formic acid are found after the incubation of chloroform with liver microsomes and homogenate, respectively. This indicates that dichloromethyl carbene may be formed, however, it is not likely to be an important metabolite (Pohl, 1979).

When a known dose of 14C-labelled chloroform was given intravenously to mice, about 4% of the dose was found in the liver and duodenum as non-volatile radioactivity. This suggests that metabolites other than chloride ions and carbon dioxide are formed, accumulate in the liver and are excreted into the duodenum in the bile (Cohen and Hood, 1969). Similar results were found in squirrel monkeys where a high concentration of radioactivity was found in the gall bladder (Brown et al., 1974).

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