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

LORENZETTI, FLORENCIA; VERA, MARINA C.; MONTI, JUAN A.; CEBALLOS, MARÍA P.; PARODY, JUAN P.; PISANI,GERARDO B.; RONCO, MARÍA T.; CARRILLO, MARÍA C.; QUIROGA, ARIEL D.; ALVAREZ, MARÍA DE LUJÁN

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Congreso; LXI REUNIÓN ANUAL DE LA SOCIEDAD ARGENTINA DE INVESTIGACIÓN CLÍNICA (SAIC); 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