Evaluation of the Protective Effect of Silibinin in Rats with Liver Damage Caused by Itraconazole

Abstract

Itraconazole (ITZ) belongs to the triazole group of antifungals with potent keratinophilic and lipophilic features. Hepatotoxicity is one of its most remarkable features. Silibinin (SIL) is a plant used worldwide which is used in the treatment of many liver diseases and it is especially very well known for its hepatoprotective-cytoprotective effect. The aim of our study was to research the protective effect of SIL in ITZ-induced hepatotoxicity using biochemical and pathological tests. Liver enzymes and antioxidant enzyme activities were measured spectrophotometrically by using commercial kits. ALT and AST levels in ITZ group were significantly increased compared to the group, while the activities of GSH-Px and SOD had decreased (p < 0.05). When ITZ group was compared to ITZ + SIL group, AST, ALT, and levels of NO and MPO were significantly decreased, while the activities of GSH-Px and SOD were increased (p < 0.05). Histopathological evaluation showed that SIL significantly decreased periportal inflammation and parenchymal hepatocyte apoptosis in ITZ and ITZ + SIL groups (p < 0.05). Eventhough not statistically significant, partial improvement with the use of SIL has been detected (p > 0.05) in hepatocyte degeneration and multinuclear giant cell formation. According to the evaluation performed with comet assay method, ITZ leads to DNA damage, and the use of SIL significantly decreases DNA damage (p < 0.05). We have detected that the use of ITZ increases oxidative stress (MPO, NO), decreases antioxidant activity (SOD and GSH-Px), and leads to DNA damage and histopathological liver damage, whereas the use of SIL has a cytoprotective effect on the liver by increasing the antioxidant effect (SOD, GSH-Px) and by decreasing the oxidative stress (NO, MPO). ITZ causes the generation of ROS and leads to DNA damage and liver damage. SIL has a cytoprotective effect on the liver by increasing antioxidant enzyme activities, preventing the formation of ROS.

Biomonitoring of the Genotoxic and Hepatotoxic Effects and Oxidative Stress Potentials of Itraconazole in Pregnant Rats

“…The oxidative stress damage caused by itraconazole is consistent with previous studies using different antifungals (Liu et al, 2002;Rodriguez and Buckholz, 2003;Amin and Hamza, 2005;Amin, 2008). Sozen et al (2014) found that the use of itraconazole increased oxidative stress through significant increases of myeloperoxidase and nitric oxide levels and significant decreases in the antioxidant activity of superoxide dismutase and GSH-peroxidase.…”

“…Treatment with the high dose (100 mg itraconazole/kg per day) induced bile duct hyperplasia, biliary cirrhosis, focal necrosis, and severe infiltration of neutrophils with detection of giant cells. Sozen et al (2014) found that itraconazole led to significant hepatocyte degeneration, bile duct hyperplasia, formation of bile duct plugs, inflammation of the portal/periportal area, and the presence of apoptotic cells.…”

“…Sozen et al. () found that the use of itraconazole increased oxidative stress through significant increases of myeloperoxidase and nitric oxide levels and significant decreases in the antioxidant activity of superoxide dismutase and GSH‐peroxidase.…”

“…Sozen et al. () found that itraconazole led to significant hepatocyte degeneration, bile duct hyperplasia, formation of bile duct plugs, inflammation of the portal/periportal area, and the presence of apoptotic cells.…”

Natural Products for Prevention and Treatment of Chemical‐Induced Liver Injuries

“…Wolf extract through regulating arginine and proline metabolism, primary bile acid biosynthesis, and sphingolipid metabolism (Gao et al., ). In addition, silibinin showed the ability of enhancing antioxidant enzyme activities and preventing ROS formation, when administrated to the rats suffering from liver injury caused by itraconazole, a medication for fungal infections (Sozen et al., ).…”