Abdel Salam O Me, Sleem A A, Shafee N
Department of Pharmacology, National Research Centre, Cairo, Egypt.
Drug Discov Ther. 2010 Aug;4(4):285-97.
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).
本研究旨在评估5-羟色胺拮抗剂及再摄取抑制剂曲唑酮和奈法唑酮对四氯化碳（CCl₄）诱导的大鼠肝损伤的影响。通过给大鼠口服CCl₄（2.8 mL/kg溶于橄榄油）诱导肝损伤。与CCl₄联合，每日一次口服给予奈法唑酮（5、10或20 mg/kg）、曲唑酮（5、10或20 mg/kg）、水飞蓟宾（25 mg/kg）或生理盐水（对照），并持续一周。通过测定血清酶活性和肝脏组织病理学评估肝损伤。在CCl₄处理的大鼠中，曲唑酮（5、10、20 mg/kg）治疗使血清丙氨酸氨基转移酶（ALT）水平分别降低了24%、38.6%和49.3%。血清天冬氨酸氨基转移酶（AST）水平分别降低了18.1%、37.9%和42.2%，碱性磷酸酶（ALP）水平分别降低了25.7%、32.6%和39.7%。奈法唑酮（5、10、20 mg/kg）以剂量依赖方式使ALT水平升高分别降低了15.6%、36.5%和45.9%，AST水平分别降低了16.7%、17.3%和43%，ALP分别降低了30.5%、37.5%和42.9%。水飞蓟宾治疗使ALT、AST和ALP水平分别降低了56.1 - 62.8%、56.0 - 64.0%和50.1 - 58.2%。与溶媒处理组相比，CCl₄给药降低了血液中还原型谷胱甘肽水平。在CCl₄处理的大鼠中，曲唑酮使还原型谷胱甘肽水平呈剂量依赖性增加。奈法唑酮在浓度为5和10 mg/kg时使还原型谷胱甘肽增加，但在20 mg/kg奈法唑酮后未增加。给予水飞蓟宾使还原型谷胱甘肽水平升高至接近正常水平。与对照组相比，CCl₄给药导致血清中一氧化氮水平（亚硝酸盐/硝酸盐浓度）显著升高。与CCl₄对照组相比，曲唑酮或奈法唑酮治疗使血清一氧化氮水平呈剂量依赖性降低。组织病理学和组织形态计量学检查还表明，曲唑酮和奈法唑酮治疗组中CCl₄诱导的肝损伤比CCl₄对照组轻。曲唑酮和奈法唑酮治疗改善了CCl₄以肝细胞内蛋白质和粘多糖含量降低形式引起的代谢紊乱。结论是，给予5-羟色胺拮抗剂及再摄取抑制剂曲唑酮和奈法唑酮与减轻CCl₄诱导的实验性肝损伤有关。
