Mode of action

The toxicity of carbon tetrachloride has been extensively studied and is widely recognised to be due to the reductive halogenation of carbon tetrachloride catalysed by cytochrome P450 in the liver. This leads to free radical formation and lipid peroxidation (Recknagel et al., 1989; IPCS, 1999), which results in hepatic and renal toxicity. A cascade of secondary reactions then occurs resulting in plasma membrane disruption and cell death. However the exact nature and relative importance of these interactions with various tissues has not been fully elucidated (Dianzani, 1984).

Cleavage of the CCl3-Cl bond occurs after binding of carbon tetrachloride to cytochrome P450 apoprotein in the mixed function oxidase system. This results in the formation of the reactive trichloromethyl radical (•CCl3), which may be further oxidised to form the trichloromethylperoxy free radical (Cl3COO^). The trimethylperoxy free radical species is considered to be much more reactive than the trichloromethyl radical (Slater, 1985; Recknagel et al., 1989).

Cytochrome P450 is encased in lipid and the free radicals formed by the cleavage initiate peroxidative decomposition of the polyenoic lipids of the endoplasmic reticulum and generation of secondary free radicals (Recknagel, 1983; IPCS, 1999). This destructive lipid peroxidation leads to breakdown of membrane structure and function, and, if a sufficient quantity of carbon tetrachloride has been absorbed, the intracellular cytoplasmic calcium concentration increases, causing disruption of intracellular calcium homeostasis, resulting in cell death (Recknagel, 1983; Kalf et al., 1987; Recknagel et al., 1989). Lipid peroxidation produces a variety of substances that have high biological activities, including effects on cell division (Slater et al., 1985). Coincidental with structural disorganisation of the endoplasmic reticulum, there is loss of microsomal enzyme function, including the cytochrome P450 monooxygenase system and glucose-6-phosphatase (Recknagel et al., 1989).

The trichloromethyl radical can undergo anaerobic reactions resulting in the formation of a variety of toxins including chloroform and carbon monoxide (Ahr et al., 1980), and under aerobic conditions may react to form trichloromethanol, a precursor of phosgene (Kalf et al., 1987; ATSDR, 1992a). Phosgene may play a role in carbon tetrachloride-induced hepatotoxicity (Kubic and Anders, 1980; Kalf et al., 1987).

An alternative hypothesis involves covalent binding of carbon tetrachloride metabolites to critical macromolecules leading to cell damage. Binding of carbon tetrachloride metabolites to hepatic nuclear DNA, proteins and lipids has been demonstrated and this could be relevant to carbon tetrachloride induced liver tumours and hepatotoxic effects (Diaz Gomez and Castro, 1980a,b). It appears that aerobic covalent binding and hepatotoxicity may be accounted for by the trichloromethyl free radical or the trichloromethylperoxy free radical, whereas carbenes (R3C:) may play a more important role when oxygen tension is low (Slater, 1982).

The fatty changes that are characteristic of carbon tetrachloride hepatotoxicity are due to the accumulation of triglycerides, but the mechanism is not yet clear. The mechanism is not the same as that producing liver necrosis, but metabolism of carbon tetrachloride is definitely required and lipid peroxidation may play a role (Reid, 2001).

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