may provide a valuable model of ethanol-induced fibrosis and stellate cell activation. CYP2E1 levels and activity were about two-fold higher in the CYP2E1 KI mice compared to the wild type mice after the ethanol feeding suggesting the elevated liver injury may be due to the elevated content of CYP2E1 although the possibility that the human CYP2E1 is more reactive than the mouse CYP2E1 in promoting this injury remains to be evaluated. The elevated liver injury is associated with an elevated oxidative/nitrosative stress in the ethanol-fed CYP2E1 KI mice and we speculate that the latter plays a key role in the former. This will be evaluated in future studies examining the effects of antioxidants such as N-acetylcysteine, vitamins E and C and inhibitors of the inducible nitric oxide synthase e.g.1400W. The elevated liver injury is also associated with an increase in activation of the JNK mitogen activated protein kinase. Activation of JNK has been shown to be important in many models of hepatotoxicity [30–33], including CYP2E1 potentiation of LPS or TNF-α liver injury [34,35]. Activated JNK can phosphorylate and thereby inactivate Bcl-2 and Bcl-XL [62]. Levels of these two anti-apoptotic proteins were lowered by chronic ethanol feeding in CYP2E1 KI mice
