Halomethane-induced inhibition of protein synthesis in isolated hepatocytes

The effect of several halomethanes on protein synthesis has been studied in isolated hepatocytes. When cells are added to medium preequilibrated with CCl₄ or CBrCl₃, protein synthesis is inhibited after a lag period of 4 to 10 min. The concentrations of CBrCl₃, CCl₄, and CHCl₃ which cause a 50% inhibition of protein synthesis are about 6 μM, 400 μM, and 4mM, respectively. This order of potency parallels the rate at which these compounds are metabolized by the hepatic mixed function oxidase, suggesting that metabolism is required for toxicity. The inhibitory effect caused by 18 min of exposure to CBrCl₃ is not reversed when the toxin is removed, indicating that inhibition involves some irreversible modification of cellular material. Unexpectedly, the inhibitory effect caused by 18 min of exposure of CCl₄ is about 30–40% reversed when the toxin is removed. This suggests that CCl₄ causes inhibition not only by a metabolism-dependent (irreversible) pathway, but by a metabolism-independent (reversible) mechanism as well. Extracellular Ca²⁺ is not required for CCl₄ inhibition of protein synthesis.