Mode of action

The biological mechanisms of the adverse effects of carbon disulphide are largely unknown, but there are a number of possible mechanisms. Carbon disulphide can react with various biological molecules. The toxic effects may be based on reactions with sulphydryl and amino groups of proteins, amino acids and catecholamines leading to impairment or disturbance of various biochemical parameters. In addition to toxicity from the direct reaction of carbon disulphide with biological molecules, another possible toxic mechanism is that a reactive intermediate may be formed during oxidative metabolism. Disturbance of lipid metabolism may occur and there may be interaction with the microsomal drug-metabolising system. It is thought that liver toxicity from carbon disulphide exposure may be partly explained by the destruction of cytochrome P450 (WHO, 1979; Bus, 1985; BUA, 1991; Feldman, 1999).

Three mechanisms have been proposed to explain the central and peripheral system neurotoxicity produced by carbon disulphide.

1. Dithiocarbamate formed by the reactions of carbon disulphide with amines can chelate the divalent cations of copper and zinc and inhibit critical metabolic enzymes such as dopamines-hydroxylase (McKenna, 1977; Bus, 1985; BUA, 1991). Dopamine-P-hydroxylase contains copper and this metalloenzyme is inhibited by carbon disulphide, resulting in a build up of dopamine, which leads to the Parkinson-like features seen in carbon disulphide toxicity. Although the toxicological consequences of the changes in nerve copper concentrations have not been fully identified, altered metalloenzyme activity within the neurone may be a possibility (Bus, 1985). Other evidence for metalloenzyme inhibition was found in a study of grain workers who self-presented because of neurological symptoms, where two were found to have abnormal zinc excretion (Peters et al., 1986). The effect of supplementing the diet with trace metals has been inadequately explored as a method of preventing carbon disulphide-induced neurotoxicity (Beauchamp et al., 1983).

2. Carbon disulphide (or the oxidative metabolites) can react directly with the amine and thiol groups on proteins and hence disrupt normal protein function and metabolism (Davidson and Feinleib, 1972; Bus, 1985; BUA, 1991).

3. Carbon disulphide can react with the free amine group pyridoxamine and produce a neuropathy similar to that observed in vitamin B6 deficiency (Bus, 1985).

Liver toxicity is thought to be connected with the formation of reactive sulphur from carbon disulphide, which can bind onto sulphydryl groups and thus inactivate enzymes and other SH-proteins. Although the mechanism is not fully understood it is known that this reactive sulphur is responsible for reducing cytochrome P450 activity (BUA, 1991).

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