Neutral sphingomyelinase-induced ceramide accumulation by oxidative stress during carbon tetrachloride intoxication

Abstract

Ceramide is a biologically active lipid causing apoptosis in a variety of cells. In this study, we examined the effect of CCl 4 on the ceramide metabolism and indicators of oxidative stress. After 12 h of oral administration of CCl 4 (4 ml/kg body weight as a 1:1 mixture of CCl 4 and mineral oil) to rats, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were increased. Antioxidants such as vitamins C and E were decreased in the liver and kidney. In addition, the ratio of GSH/GSSG in the liver, plasma, kidney, and brain decreased at 2 h. The total ceramide in the liver significantly increased as early as 2 h after CCl 4 administration. After 24 and 36 h, the total ceramide in plasma and the kidney was also augmented. In the brain, the total ceramide dramatically increased at 36 h. These results suggested that the increased ceramide in plasma was transferred to the kidney and the brain. The activity of neutral sphingomyelinase (SMase), which was reported to be enhanced by the decrease of GSH, was significantly increased after CCl 4 treatment in the liver, kidney, and brain. However, acid SMase activities were not increased in the liver and kidney. Thus, the activation of neutral SMase via oxidative stress induced the increase of ceramide during CCl 4 intoxication in not only the liver but also other tissues. These results suggested that the excess accumulation of ceramide causes damage in other organs including the kidney and brain during fulminant hepatic failure.