THE 5-LIPOXYGENASE (5-LO) INHIBITOR ZILEUTON (ZI) AFFECTS THE EXPRESSION OF EARLY GENES INVOLVED IN RAT LIVER REGENERATION.

FLORENCIA LORENZETTI; MARINA CECILIA VERA; JUAN ALBERTO MONTI; MARÍA PAULA CEBALLOS; JUAN PABLO PARODY; GERARDO BRUNO PISANI; MARÍA TERESA RONCO; MARÍA CRISTINA CARRILLO; ARIEL DARÍO QUIROGA; MARÍA DE LUJÁN ÁLVAREZ

Congreso; LXI REUNIÓN ANUAL DE LA SOCIEDAD ARGENTINA DE INVESTIGACIÓN CLÍNICA (SAIC) LXIV REUNIÓN ANUAL DE LA SOCIEDAD ARGENTINA DE INMUNOLOGÍA (SAI) XLVIII REUNIÓN ANUAL DE LA SOCIEDAD ARGENTINA DE FARMACOLOGÍA EXPERIMENTAL (SAFE) VII REUNIÓN ANUAL DE LA SOCIEDAD; 2016

Leukotrienes (LTs) are inflammatory eicosanoids synthesizedvia the 5-LO pathway. The main LTs -LTB4 and LTC4- are involvedin cell proliferation and the liver plays a central role in their synthesisand metabolism. Previous studies from our lab showed thatZi treatment (a 5-LO inhibitor) caused a decrease in LTs contentand a reduction in liver proliferation after partial hepatectomy (PH)in rats. Objectives: 1) to study the impact of Zi treatment on theexpression of liver regeneration-associated early genes in rats,and 2) to analyze the effect of Zi in cell proliferation using humanhepatoma cell lines. Methods and Results: In vivo studies: Adultmale Wistar rats were subjected to sham surgery or PH (70% live rremoval). 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 inZi treated PH group than in vehicle-treated PH group. NF-kB activitywas 80%* lower in Zi-treated PH compared to vehicle-treatedPH rats. Immunoblot analysis of nitric oxide synthase-2 (NOS-2),a critical player for tissue permeabilization and vascularizationduring liver regeneration, showed a 52%* reduction in Zi-treatedPH rats compared to the vehicle-treated PH animals. In vitrostudies:HepG2 and HuH7 human hepatoma cell lines were treatedwith Zi 30 and 50 μg/mL for 48 hours. MTT assays showed thatZi at a dose 50 μg/mL reduced the proliferation of HepG2 andHuH7 cells in 16%* and 37%* respectively. Furthermore, the presenceof LTB4 increased the viability of HuH7 cells treated with Zi(*p