NOVEL MECHANISMS IN CHEMICALLY-INDUCED HEPATOTOXICITY

This review focuses on cellular events that modulate hepatotoxicity su bsequent to initial liver insult. Cellular events that determine the n ature and extent of hepatotoxic injury and the ultimate outcome of tha t injury are also discussed. The roles of cell types other than hepato cytes, hepatocyte organelle-specific processes, and regeneration in pr ogression or recovery from liver injury are emphasized. Leukocyte acti vities are key events in two distinct hepatotoxicities. Neutrophil-med iated, periportal inflammation appears to play a primary role in progr ession of alpha-naphthylisothiocyanate-induced cholangiolitic hepatiti s. However, a humorally mediated autoimmune response to protein adduct s that occurs after anesthesia is critical in onset of halothane-induc ed hepatitis. New insights into specific events at the hepatocyte leve l are also emerging. Although reducing gap junctional communication be tween hepatocytes can protect against progression of liver injury, dow n-regulation of the subunit proteins (connexins) can isolate neoplasti c cells from growth regulation. Acidic intracellular pH characteristic of hypoxia is protective against both hypoxic and toxicant-induced ce ll injury. In oxidative injury, a pH-mediated mitochondrial permeabili ty transition causes mitochondrial uncoupling and ATP loss and leads t o cell death. The ultimate outcome of hepatotoxic injury depends on th e extent of tissue repair. Stimulation of tissue repair after a sublet hal dose of CCl4 appears to be the central mechanism in protection aga inst death from a subsequent large dose. Taken together, these example s illustrate the importance of events subsequent to initial liver inju ry as determinants of extent of liver damage.-Mehendale, H. M., Roth, R. A., Gandolfi, A. J., Klaunig, J. E., Lemasters, J. J., Curtis, L. R . Novel mechanisms in chemically induced hepatotoxicity.