The goal of this study was to evaluate the possible protective effects of sphingosylphosphorylcholine (SPC) against cholestatic oxidative stress and liver damage in the common bile duct ligated rats. Fifty-six animals were included in each of the following 7 groups: control, SPC control, phosphate-buffered solution control, sham operated, bile duct ligation (BDL), BDL plus phosphate-buffered solution, and BDL plus SPC. Sphingosylphosphorylcholine was administered 14 days at a daily dose of 2 mu m/mL intraperitoneally. The severity of cholestasis and hepatic injury was determined by changes in the plasma enzyme activities of aspartate aminotransferase, alanine aminotransferase, gama glutamin transferase, and levels of total bilirubin and direct bilirubin. Malondialdehyde, nitric oxide, and superoxide dismutase were determined to evaluate the oxidative status in the liver tissue. Myeloperoxidase activity and levels of tissue hydroxyproline were determined to assess neutrophil activation and collagen accumulation, respectively. Treatment with SPC markedly reduced serum transaminase activities as compared to BDL rats. Sphingosylphosphorylcholine also inhibited the increase in liver malondialdehyde; nitric oxide levels significantly and also attenuated the depletion of superoxide dismutase in the liver after BDL. Similarly, the increase in tissue myeloperoxidase activity and hydroxyproline owing to BDL was also attenuated by the SPC treatment. These data were supported by histopathologic findings. The a-smooth muscle actin-positive cells in the BDL were observed to be reduced with the SPC treatment. In conclusion, these findings suggested that SPC can attenuate hepatic damage in extrahepatic cholestasis by prevention of oxidative stress, and inflammatory process. All these findings suggest that SPC may be a promising new therapeutic agent for cholestatic liver injury. (C) 2009 Elsevier Inc. All rights reserved.