Induction and regulation of hepatocyte apoptosis by oxidative stress

Reactive oxygen intermediates (ROI) have been implicated in the induction of hepatocyte apoptosis that results from a variety of forms of liver injury. Exogenous oxidants induce hepatocyte apoptosis and may mediate death during inflammatory liver injury. Lethal levels of intracellularly generated ROI resulting from hepatotoxin metabolism, or the induction of enzymes in the cytochrome P450 family, are also important inducers of apoptosis. In addition, ROI production may mediate death from a number of diverse factors, including tumor necrosis factor-alpha, bile acids, ischemia, and transforming growth factor-beta1. Oxidants alter many redox-sensitive cellular signaling pathways, including mitogen-activated protein kinases and transcription factors such as activator protein-1 and nuclear factor-kappaB. The mechanisms of oxidant-induced hepatocyte apoptosis remain unclear, but probably involve effects on cell signaling, as well as direct chemical interactions. The delineation of stimulus-specific mechanisms of oxidant-dependent hepatocyte apoptosis is important to the design of effective therapies for a number of forms of liver injury.