Effect of trazodone and nefazodone on hepatic injury induced by carbon tetrachloride

Abstract

The present study aimed to evaluate the effect of the serotonin antagonists and reuptake inhibitors trazodone and nefazodone on liver injury induced by treatment with carbon tetrachloride (CCl(4)) in rats. Liver damage was induced in rats by oral administration of CCl(4) (2.8 mL/kg in olive oil). Nefazodone (5, 10, or 20 mg/kg), trazodone (5, 10, or 20 mg/kg), silymarin (25 mg/kg), or saline (control) was orally administered once daily in association with CCl(4) and for one week thereafter. Liver damage was assessed by determining serum enzyme activities and hepatic histopathology. In CCl(4)-treated rats, treatment with trazodone (5, 10, 20 mg/ kg), reduced serum alanine aminotransferase (ALT) levels by 24, 38.6, and 49.3%. Serum aspartate aminotransferase (AST) levels were decreased by 18.1, 37.9, and 42.2%, and alkaline phosphatase (ALP) levels decreased by 25.7, 32.6, and 39.7%, respectively. Nefazodone (5, 10, 20 mg/kg) in a dose-dependent manner reduced the elevation of ALT levels by 15.6, 36.5, and 45.9%, AST levels by 16.7, 17.3, and 43%, and ALP by 30.5, 37.5, and 42.9%, respectively. Silymarin treatment reduced the levels of ALT, AST, and ALP by 56.1-62.8, 56.0-64.0, and 50.1-58.2%, respectively. The administration of CCl(4) decreased levels of reduced glutathione in blood compared to the vehicle-treated group. In CCl(4)-treated rats, reduced glutathione levels increased after trazodone in a dose-dependent manner. Reduced glutathione was increased by nefazodone at concentrations of 5 and 10 mg/kg, but not after 20 mg/kg nefazodone. Reduced glutathione levels were increased by the administration of silymarin to near normal values. The administration of CCl(4) resulted in a marked increase in nitric oxide levels in serum (the concentrations of nitrite/nitrate) as compared to the control group. Treatment with trazodone or nefazodone caused a dose-dependent decrease in serum nitric oxide levels compared with the CCl(4) control group. Histopathological and histomorphometric examinations also indicated that CCl(4)-induced liver injury was less severe in trazodone and nefazodone-treated groups than in the CCl(4) control groups. Metabolic perturbations caused by CCl(4) in the form of decreased intracellular protein and mucopolysaccharide content in hepatocytes were improved by treatment with trazodone and nefazodone. It is concluded that administration of serotonin antagonists and reuptake inhibitors trazodone and nefazodone is associated with a reduction in experimental liver injury induced by CCl(4).