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Title: $Apoptosis—the mechanism of cell death in dimethylnitrosamine‐induced hepatotoxicity
Abstract: Abstract Dimethylinitrosamine (DMN) induces an acute haemorrhagic centrilobular necrosis when given as a single dose to rats. In this study, the progression of the lesion was studied at the ultrastructural level in order lo elucidate the precise mechanisms of hepatic injury. Within 3h of a single dose of DMN there was disruption of endothelial lining cells. In areas of endothelial cell loss, the exposed hepatocyte sinusoidal membranes became simplified and flattened. In the centrilobular area, hepatocytes became apoptotic and by 16 h apoptotic bodies, formed from degenerate hepatocytes, were engulfed by intact hepatocytes or by circulating macrophages. This progressive degeneration of hepatocytes and endothelial cells gave rise, by 24 h, to the classically recognized centrilobular haemorrhagic necrosis. The damage to the endothelial cells was concurrent with, or in some areas prior to, significant morphological changes in adjacent hepatocytes. This contrasts with other hepatotoxins such as carbon tetrachloride where the primary target is the hepatocyte, giving rise to hydropic degeneration and coagulative neerosis. DMM, however, results in apoptosis, a mechanism of cell death not normally associated with chemically induced injury.