Mechanisms of Pathogenesis in Drug Hepatotoxicity Putting the Stress on Mitochondria

Interplay of signal transduction and mitochondria in acetamin-ophen-induced liver injury. Acetaminophen is metabolized by CYP2E1 to produce the reactive intermediate NAPQI, which modifies mitochondrial proteins and depletes mitochondrial GSH (first hit). The latter leads to increased ROS production, which activates ASK-1, thereby leading to JNK activation. Mitochondrial ROS may also be involved in GSK-3β activation, which in turn helps activate JNK, possibly through MAPKKK. Once activated, both GSK-3β and JNK translocate to mitochondria, thereby providing a sustained second hit. Mcl-1, an important anti-apoptotic protein in mitochondrial membranes, is phosphorylated by GSK-3β, which promotes its degradation. The translocation of GSK-3β and JNK to mitochondria promotes the mitochondrial permeability transition pore opening, full collapse of mitochondrial function, and hepatocyte death. See text for details.