It was shown previously that ethanol could

also increase CYP2E1 within mitochondria, although to a much smaller extent than in the microsomes.38 Alternatively, glutathione peroxidase might be the major enzyme responsible for the elimination of mitochondrial ROS. Glutathione peroxidase and glutathione homeostasis in mitochondria have been shown to be important for prevention of ethanol-induced oxidative injury MG-132 solubility dmso in the liver.4, 33 We did not detect Prx IV-SO2 in the liver of ethanol-fed Srx−/− mice. Prx IV is a luminal ER protein, and, given that thioredoxin is not present inside the ER, Prx IV does not function as a peroxidase in this organelle but rather serves as a peroxide sensor for other proteins.37 It is thus possible that ROS produced by CYP2E1 are rapidly removed by Prx I before they can cross the ER membrane. Together, our results suggest that, among the 2-Cys Prxs, Prx

I is largely responsible for the reduction of ROS generated in the liver in response to ethanol exposure because of its proximity to CYP2E1. Prx I molecules are thus converted to the inactive, sulfinylated form (Prx I-SO2). Reactivation of such hyperoxidized Prx I requires the action of Srx, the expression of which is greatly increased in the liver of ethanol-fed mice. The pivotal roles of Srx and Prx I in protection of the liver against ethanol-induced oxidative stress were apparent in Srx−/− and Prx I−/− mice. Subjection of such mice to chronic ethanol feeding thus resulted in more severe oxidative damage to the liver, as revealed by carbonylation CAL-101 nmr of soluble proteins

and by the formation of 4-HNE and 3-NT adducts in the centrilobular regions, compared with that observed in ethanol-fed wildtype mice. Additional supporting information may be found Rolziracetam in the online version of this article. “
“Potential curative therapies for hepatocellular carcinoma (HCC) include orthotopic liver transplantation, resection, and radiofrequency ablation (RFA). The intent of other therapies is to prolong survival by increasing the time to tumor progression (TTP) while not incurring significant hepatic injury. Transarterial chemoembolization (TACE) and sorafenib are the proposed treatments for intermediate and advanced HCC based on the positive results of randomized controlled trials (RCTs).1-3 Transarterial radioembolization (TARE) has gained popularity; however, enthusiasm for the procedure has been tempered by a lack of randomized controlled data. BCLC, Barcelona Clinic Liver Cancer; CP, Child-Pugh; HCC, hepatocellular carcinoma; OS, overall survival; PVT, portal vein thrombosis; RCT, randomized controlled trial; RFA, radiofrequency ablation; TACE, transarterial chemoembolization; TARE, transarterial radioembolization; TTP, time to tumor progression. TARE is a form of intra-arterial therapy that is mechanistically distinct from TACE.