Thesis (Ph.D.) - Cairo University - Faculty of Pharmacy - Department of Pharmacology and Toxicology

Free radical-mediated oxidative stress has been implicated in the pathogenesis and progression of acute liver injury in both experimental and clinical studies. Tamoxifen is widely used for treatment of breast cancer. It showed a degree of hepatic carcinogenesis. This study investigated the hepatoprotective effects of both zafirlukast and vincamine and their possible role in the treatment of tamoxifen-induced liver injury in rats. Female Wistar rats were divided into five groups (10 rats each). Groups I and II received 1% Tween 80 and served as normal and tamoxifen controls, respectively. Groups III, IV and V were treated with zafirlukast (80 mg/kg), vincamine (10 mg/kg) and a combination of zafirlukast (80 mg/kg) and vincamine (10 mg/kg), respectively for 10 successive days. Tamoxifen was given orally to all groups, except for 1st group, in the dose of 45 mg/kg for 10 days to induce liver injury. Subsequently, rats were sacrificed for biochemical, histopathological, Immunohistochemistry, PCR and western blot assessment. Tamoxifen-induced liver injury was reflected by alterations in estimated biochemical parameters, activation of JNK/ERK pathway, increased expression of NF-mB, liver oxidative stress and inflammatory markers parallel to histopathological changes in liver tissue. Treatment of rats with zafirlukast and vincamine ameliorated tamoxifen induced hepatic cell injury via suppressing oxidative stress, inflammatory markers, caspases-3, p-JNK/ p-ERK and NF-mB pathways. Zafirlukast and vincamine may be regarded as potential therapeutic strategies with antioxidant and anti-inflammatory activities against tamoxifen-induced oxidative damage in rat liver

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