The 5-lipoxygenase (5-LO) inhibitor zileuton (Zi) affects the expression of early genes involved in rat liver regeneration

LORENZETTI FLORENCIA; VERA MC; MONTI J A; CEBALLOS M P; PARODY J P; PISANI G; RONCO M T; CARRILLO M C; QUIROGA A D; ALVAREZ ML

Mar del Plata

Congreso; LXI Reunión Científica Anual de la Sociedad Argentina de Investigación Clínica (SAIC); 2016

SAIC

Leukotrienes (LTs) are inflammatory eicosanoids synthesized via the 5-LO pathway. The main LTs -LTB4 and LTC4- are involved in cell proliferation and the liver plays a central role in their synthesis and metabolism. Previous studies from our lab showed that Zi treatment (a 5-LO inhibitor) caused a decrease in LTs content and a reduction in liver proliferation after partial hepatectomy (PH) in rats. Objectives: 1) to study the impact of Zi treatment on the expression of liver regeneration-associated early genes in rats, and 2) to analyze the effect of Zi in cell proliferation using human hepatoma cell lines. Methods and Results: In vivo studies: Adult male Wistar rats were subjected to sham surgery or PH (70% live removal). Two hours before surgery, animals received Zi 40 mg/kg BW or vehicle. Rats were sacrificed 1 and 5 hours post-PH.Lipid peroxides levels-determined by TBARS- were 43%* lower in Zi treated PH group than in vehicle-treated PH group. NF-kB activity was 80%* lower in Zi-treated PH compared to vehicle-treated PH rats. Immunoblot analysis of nitric oxide synthase-2 (NOS-2), a critical player for tissue permeabilization and vascularization during liver regeneration, showed a 52%* reduction in Zi-treatedPH rats compared to the vehicle-treated PH animals. In vitro studies:HepG2 and HuH7 human hepatoma cell lines were treated with Zi 30 and 50 μg/mL for 48 hours. MTT assays showed that Zi at a dose 50 μg/mL reduced the proliferation of HepG2 and HuH7 cells in 16%* and 37%* respectively. Furthermore, the presenceof LTB4 increased the viability of HuH7 cells treated with Zi (*p