assayed levels of proapoptotic members of the Bcl-2 family or ATP levels which may regulate a possible switch between apoptosis and necrosis in the CYP2E1 KI mice, nor conducted time courses of ethanol feeding to assess if an early apoptosis switches to necrosis. Future experiments will evaluate the ability of an inhibitor of JNK activation such as SP600125 to prevent the chronic ethanol-induced liver injury in the CYP2E1 KI mice. SP600125 was effective in preventing the CYP2E1 potentiation of LPS or TNF-α liver injury [33]. We speculate the elevated oxidative/nitrosative stress in ethanol-fed KI mice may play a role in the activation of JNK e.g. the upstream MAPKKK ASK-1 is activated when its inhibitor thioredoxin-1 is oxidized by ROS, and dissociates off ASK-1, which then allows ASK-1 to activate downstream MAPKKs and subsequently JNK [63,64]. ROS also inactivate MAPK phosphatases which dephosphorylate activated MAPK such as JNK [65]. The activation status of JNK will be assessed in the above proposed experiments evaluating the effects of antioxidants on the ethanol-induced liver injury in KI mice. Although other models of hepatotoxicity produced by overexpression of CYP2E1 have been reported e.g. a transgenic model of CYP2E1 overexpression [18,19], or administration of an adenovirus
