Metabolic interactions

The metabolism of carbon tetrachloride is catalysed by cytochrome P450-dependent monooxygenases. Agents which induce such enzymes will enhance the toxicity of carbon tetrachloride. Conversely, agents inhibiting the drug-metabolising activity of the cytochrome P450 enzyme system will diminish the hepatotoxic effects of carbon tetrachloride.

Alcohols

The toxicity of carbon tetrachloride is enhanced by concomitant ingestion of alcohol (Alswang, 1979). Low molecular weight aliphatic alcohols can induce production of mixed-function oxidase enzymes, thereby potentiating the formation of carbon tetrachloride toxic intermediates and metabolites (Cornish and Adefuin, 1967; Traiger and Plaa, 1971; ATSDR, 1992a). The potentiating effect of these alcohols appears to be most effective when administered 18 to 24 hours prior to carbon tetrachloride exposure (Traiger and Plaa, 1971).

The consumption of ethanol prior to or during exposure to carbon tetrachloride vapours may increase the toxicity of carbon tetrachloride (Cornish and Adefuin, 1966, 1967; Cornish et al., 1977; Sturbelt et al., 1978). Studies in mice have shown an increased incidence of hepatotoxic effects in animals receiving ethanol prior to exposure to carbon tetrachloride, compared to those exposed to carbon tetrachloride alone (Cornish et al., 1977). This additive effect may result from ethanol-induced induction of CYP2E1, the main enzyme involved in the metabolism of carbon tetrachloride (Cornish and Adefuin, 1967; Allis et al., 1996). Initially, there is a synergistic depression of the CNS. In some cases this is followed by pulmonary oedema, kidney and liver lesions. Sturbelt et al. (1978), extrapolating from studies on rats, concluded that the moderate amounts of ethanol commonly ingested by many individuals, may be enough to increase the hepatotoxic effects of halogenated hydrocarbons such as carbon tetrachloride. Consequently, chronic ethanol ingestion may put workers more at risk of toxicity if subsequently exposed to carbon tetrachloride. Manno et al. (1996) reported that in a group of workers exposed to a carbon tetrachloride containing fire extinguisher, signs of toxicity only developed in those with a previous history of high ethanol intake.

• Isopropanol

Isopropanol has an even greater ability than ethanol to potentiate the hepatotoxic effects of carbon tetrachloride (Louria and Bogden, 1980). This interaction is highlighted in several reports of industrial accidents involving isopropanol and carbon tetrachloride (Folland et al., 1976; Deng et al., 1987). Three workers in a colour printing factory were admitted to community hospitals with acute hepatitis, one worker also developed acute renal failure and pulmonary oedema. An investigation was carried out to determine the aetiology of the outbreak. Seventeen of 25 workers at the plant had abnormal liver function tests (LFTs) 10 days after the outbreak. It was found that there was a strong correlation between abnormal LFTs and the combined use of carbon tetrachloride and isopropanol in a cleaning process (Deng et al.,

1987). A similar incident was reported by Folland et al. (1976). Fourteen of 43 workers developed nonspecific illness when carbon tetrachloride was used to clean equipment close to an isopropanol packaging line. They developed symptoms of nausea, vomiting, headache, weakness and abdominal pain. Dizziness, blurred vision and diarrhoea were also reported. The illness lasted an average of 7 days. Two workers had signs of liver and renal toxicity. The onset and prevalence of illness was related to proximity to the area where the agents were being used. The potentiating interaction in these cases may also be related to the presence of acetone, the main metabolite of isopropanol. Acetone is known to induce the CYP2E1 enzyme (Morgott, 2001), and induction of this pathway contributes to the increased toxicity in a combined carbon tetrachloride and isopropanol exposure.

Methanol exposure induces cytochrome P450 CYP2E1, which leads to increased metabolism and hence increased hepatotoxicity of carbon tetrachloride (Allis et al., 1996). Methanol is thought to be a more effective potentiating agent that ethanol (Cornish and Adefuin, 1967; Traiger and Plaa, 1971).

Other interactions

Acetone is considered a major potentiator of carbon tetrachloride toxicity (Folland et al., 1976; IPCS, 1999). This may be related to acetone induced enzyme induction, increasing the production of the reactive metabolites of carbon tetrachloride.

• Carbon disulphide

Exposure to carbon disulphide decreases the toxicity of carbon tetrachloride. Rats dosed simultaneously with carbon disulphide and carbon tetrachloride displayed hepatic effects resembling those due to carbon disulphide alone, rather than to effects caused by carbon tetrachloride alone (ATSDR, 1994). This is thought to be due to the destruction of the hepatic P450 metabolic system by carbon disulphide, such that activation of carbon tetrachloride to toxic metabolites is much reduced. Similar results have been reported in workers exposed to an 80:20 mixture of carbon tetrachloride and carbon disulphide used to fumigate grain (Peters et al., 1986). The neurological effects observed in these individuals resembled those caused by carbon disulphide alone, and there was no evidence of carbon tetrachloride induced hepatotoxicity (Peters et al., 1986; ATSDR, 1994).

• Diet and nutritional status

It is suggested that diets sufficiently low in protein to reduce mixed function oxidase activity will have a protective effect, as there will be a reduced ability to bioactivate carbon tetrachloride to its toxic metabolites. However, more prolonged protein deprivation, in the presence of residual mixed function oxidase activity, may lead to more severe liver damage because of the loss of protective sulphydryl compounds such as glutathione (Plaa, 1986). Diabetes and certain nutritional deficiencies have been implicated in enhanced toxic effects from carbon tetrachloride (Capurro, 1973; ATSDR, 1992a; Torkelson, 1994).

Drugs that are known to induce the cytochrome P450 enzymes will lead to greater metabolism of carbon tetrachloride and hence potentiate its toxic effects, e.g., phenobarbital (Mahieu et al., 1983).

• Trichloroethylene

Carbon tetrachloride induced hepatotoxicity in rats is enhanced by the simultaneous administration of trichloroethylene and this response is potentiated by pre-treatment with acetone (Charbonneau et al.,

1988). This may be relevant for people who work with a mixture of solvents.

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