The role of lipid peroxidation in the toxicity of foreign compounds to liver cells.

The peroxidation of polyunsaturated fatty acids present in the membrane lipids has been proposed as the mechanism by which a number of foreign compounds produce structural tissue injury [1-3]. For certain chemicals, such as bromotrichloroethane and carbon tetrachloride, it is clear that lipid peroxidation may have a critical role in bringing about the tissue damage [3-5]. However, in respect to others, such as paracetamol, bromobenzene, adriamycin and paraquat, the importance of peroxidative damage is a matter of continued debate and controversy [6-12]. In a critical review of the importance of lipid peroxidation in the hepatotoxic effects of a number of toxins, Mitchell et al. [13] concluded that the lipid peroxidation which occurred during paracetamol and bromobenzene hepatocellular necrosis was due to the depletion of glutathione (GSH) from dying cells and had little to do with the initiation of liver damage. In short, the measured lipid peroxidation was a consequence rather than a cause of cell death. Recently, however, a report [14] has appeared in which the authors conclude that lipid peroxidation is an early important event in the toxicity of bromobenzene to monolayer cultures of rat hepatocytes. The major piece of evidence which supports this conclusion is the finding that the antioxidant N,N ' diphenyl-p-phenylenediamine (DPPD) delays, but does not prevent, the toxicity of bromobenzene to the cultured hepatocytes [14]. Once again, therefore, the importance of peroxidation vs arylation in bromobenzene hepatotoxicity has become a matter of debate. During the past few years we, along with other colleagues in our laboratory, have performed detailed studies on the mechanism of bromobenzene-induced cytotoxicity, using suspensions of freshly isolated rat hepatocytes as the experimental model [15-21]. These studies show that freshly isolated hepatocytes metabolize bromobenzene to reactive intermediate(s) which are inactivated by conjugation with GSH. Increased cell damage is observed with GSH-depleted cells which, in turn, are protected by facilitated GSH resynthesis [15-20]. More recently, we [21] have tried to further evaluate the importance of lipid peroxidation in bromobenzene-induced cytotoxicity. By utilizing two