The pathogenesis of alcoholic liver injury remains one of the most important unsolved problems relating to the consequences of chronic alcoholism. To study this problem the development of a suitable model of ethanol-dependent liver cell necrosis in a laboratory species that is readily amenable to experimental manipulation is crucial. This is the aim of work carried out in the past and that is proposed in the present renewal application. Chronic ethanol administration to rats is associated with the reproducible appearance of a number of alterations in the structure and function of liver mitochondria. The overall objective of this proposal is to test the hypothesis that these mitochondrial alterations render the hepatocytes susceptible to the effects of other toxic chemicals that also interfere with mitochondrial function. this hypothesis will be explored through the pursuit of three specific aims: (1) An evaluation of the sensitivity of cultured hepatocytes isolated from the livers of rats chronically adapted to ethanol to a number of chemicals that interfere with mitochondrial function in defined ways; (2) The determination of the mechanism of the cell injury produced by the mitochondrial toxins as a result of the studies performed under Specific Aim #1; and (3) An attempt to reproduce the increased sensitivity of isolated hepatocytes to the same agents in the intact animal to the same agents.
