Inhibition of γ-glutamyl transpeptidase ameliorates ischemia- reoxygenation tissue damage in rats with hepatic steatosis.

BACKGROUND AND AIMS Hepatic steatosis may accompany with increased γ-glutamyl transpeptidase (γ-GT) levels. Ischemia-reoxygenation (IR) injury is a pathological condition with several deleterious effects. We evaluated the protective effects of a specific inhibitor of γ-GT in experimentally induced IR injury in rats with obesity and steatosis. METHODS Otsuka Long-Evans Tokushima Fatty (OLETF) rats with hepatic steatosis were used in the current study. The portal vein and hepatic artery of left lateral and median lobes were clamped to induce ischemia. Before clamping, 1 ml of saline (IR group) or 1 ml saline containing 1 mg/kg body weight of GGsTop (γ-GT inhibitor) (IR-GGsTop group) was injected into the liver from inferior vena cava. The blood flow was restored at 30 min after the start of ischemia. Blood was collected before and at 30 min after ischemia, and at 2 h and 6 h after reoxygenation. All the animals were euthanized at 6 h and the livers were collected. RESULTS Treatment with GGsTop resulted in significant reduction of serum ALT, AST, and γ-GT levels and hepatic γ-GT, malondialdehyde, 4-hydroxy-2-nonenal, and HMGB1 at 6 h after reoxygenation. Inhibition of γ-GT retained normal hepatic glutathione levels. There was prominent hepatic necrosis in IR group, which is significantly reduced in IR-GGsTop group. CONCLUSIONS Treatment with GGsTop significantly increased hepatic glutathione content, reduced hepatic MDA, 4-HNE, and HMGB1 levels, and remarkably ameliorated hepatic necrosis after ischemia-reoxygenation. The results indicated that GGsTop could be an appropriate therapeutic agent to reduce IR-induced liver injury in obesity and steatosis.