Causal role of oxidative stress in liver preconditioning by thyroid hormone in rats

Hepatic ischemia–reperfusion (IR) injury, a major clinical drawback during surgery, is abolished by l-3,3′,5-triiodothyronine (T3) administration. Considering that the triggering mechanisms are unknown, the aim of this study is to assess the role of oxidative stress in T3 preconditioning using N-acetylcysteine (NAC) before T3 administration. Male Sprague–Dawley rats given a single dose of 0.1 mg of T3/kg were subjected to 1 h ischemia followed by 20 h reperfusion, in groups of animals pretreated with 0.5 g of NAC/kg 0.5 h before T3 or with the respective control vehicles. At the end of the reperfusion period, blood and liver samples were taken for analysis of serum aspartate aminotransferase (AST) and hepatic histology, glutathione (GSH) and protein carbonyl contents, and nuclear factor-κB (NF-κB) and activating protein 1 (AP-1) DNA binding. The IR protocol used led to a 4.5-fold increase in serum AST levels and drastic changes in liver histology, with significant GSH depletion and enhancement of protein carbonyl levels and of the protein carbonyl/GSH content ratio, whereas NF-κB and AP-1 DNA binding was decreased and enhanced, respectively. In a time window of 48 h, T3 exerted protection against hepatic IR injury, with 88% reduction in the protein carbonyl/GSH ratio and normalization of NF-κB and AP-1 DNA binding, changes that were suppressed by NAC administration before T3. Data presented suggest that a transient increase in the oxidative stress status of the liver is an important trigger for T3 preconditioning, evidenced in a warm IR injury model through antioxidant intervention.