Mode of action

It is the metabolites of chloroform, not the solvent itself, which cause toxicity. Inhibition of microsomal enzymes has been shown to protect against chloroform induced hepatotoxicity in animals (Scholler, 1970).

Phosgene is the major metabolite responsible for chloroform toxicity, it is highly electrophilic and binds to tissue macromolecules. The trichloromethyl radical is also suggested as the agent responsible for chloroform induced hepatotoxicity, since this is the species thought to be involved in carbon tetrachloride hepatotoxicity. However, there are a number of observations which do not support this theory:

• Chloroform depletes glutathione, but carbon tetrachloride does not, so the trichloromethyl radical cannot be responsible for this effect.

• A larger proportion of a dose of 14C-labelled carbon tetrachloride binds to lipids than with 14C-labelled chloroform. This suggests that the chemical intermediates differ in their properties.

• In a study of deuterium-labelled chloroform no exchange of deuteriums occurred. This would be expected if the trichloromethyl radical was formed, i.e., a mixture of chloroform and deuterium-labelled chloroform would result (Pohl, 1979).

Chloroform depletes liver glutathione stores in animals. This process appears to involve a metabolite of chloroform, since pretreatment of rats with an enzyme inducer, such as phenobarbital, increases the amount of depletion (Masuda et al., 1980). No depletion of glutathione in the kidney or blood occurs in the rat (Docks and Krishna, 1976).

Nephrotoxicity is probably due to prolonged hypoxia rather than a direct toxic effect. Well oxygenated patients do not develop nephrotoxicity.

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