الفهرس 
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Abstract
This study explains the hepatotoxicity effects of methotrexate (MTX) on liver. We select the liver for studying the methotrexate (MTX) induced toxicity as it was considered as a vital organ. MTX is widely used in chemotherapy, organ transplantation and as immune suppressant. MTX-induced hepatotoxicity restricts its use in clinics. MTX accumulate in liver cells and interact with folate in an unwanted manner, resulting in oxidative stress, apoptosis, and inflammation that lead to hepatotoxicity damage, its hepatotoxicity effects were detected via some findings including ALT, AST, albumin and GSH. We also detected the concentration of MDA and activity of CAT and Bcl2, Nrf2, HO-1, NF-kB, TNFα, P53, Bax, and caspase9. We aimed to study the effect of Hesperidin and Quercetin on liver signaling in MTX induced hepatotoxicity. This study was applied on Sixty male albino Wistar rats were distributed into six groups (n=10): Control group: rats received only distilled water for 30 day and a single intraperitoneal injection of (0.9%) physiological saline, MTX group: rats received a single intraperitoneal dose of MTX (20 mg/kg) on the 27th day, HD group: rats received oral dose of (50 mg/kg/day ) for 30 days, HD+MTX group: rats received oral dose of (50 ml/kg/day) of HD for 30 days + a single intraperitoneal dose of MTX (20 mg/kg) on the 27th day, Quercetin group: rats received oral dose of( 50 mg/kg/day) for 30 days, QC+ MTX group: rats received orally given( 50 mg/kg )of Quercetin for 30 days+ a single intraperitoneal dose of MTX (20 mg/kg) on the 27th day. The results were recorded in 4 tables and 15 figures. In MTX group, ALT and AST significantly increased and also albumin, GSH concentration and CAT activity decreased, but significant increase in MDA concentration, NF-kB, TNFα, Bax, P53, caspase9 and decrease in Bcl2 and HO-1. In other treated groups the potent antioxidant effect of HD and QC was indicated by increase albumin, GSH, CAT, Bcl2, HO-1, and significant decrease in AST, ALT, MDA, NF-kB, Bax, caspase, and P53. These results were confirmed by histopathological findings which showed severe infiltration, congestion and Pyknosis in liver tissue in MTX and these features were improved with HD and QC administration. This study showed that MTX induced liver toxicity to rats. It also emphasized the critical role of HD and QC in protecting liver tissue from toxicity induced by MTX and put forward the importance of HD and QC in health, therefore, considering the extensive use of medicines and pharmaceuticals that contains MTX may exert adverse effect on liver capacity. Further investigations concerning the actual effect and mechanism of MTX on cellular shift of liver should be done.