PROTECTION AGAINST CARBON TETRACHLORIDE-INDUCED HEPATOTOXICITY BY PRETREATING RATS WITH THE HEMISUCCINATE ESTERS OF TOCOPHEROL AND CHOLESTEROL

Previous studies have demonstrated that alpha-tocopheryl hemisuccinate (TS) protects hepatocyte suspensions from chemical-induced toxicity. It has been suggested that TS cytoprotection is related to unique prop erties of the TS molecule or is dependent on the cellular release and activity of unesterified alpha-tocopherol (T). To test the unique cyto protective nature of TS in vivo, the protective ability of T and tocop herol esters against carbon tetrachloride (CCl4)-induced hepatotoxicit y in rats was examined. Hepatoprotection [determined by serum aspartat e aminotransferase (AST) and alanine aminotransferase (ALT) levels and histopathology] was not observed after T (or tocopheryl acetate and t ocopheryl nicotinate) administration, even though this treatment resul ted in a fivefold elevation in hepatic T content. Only pretreatment wi th TS (100 mg/kg, intraperitoneally) resulted in partial hepatoprotect ion against CCl4 (2.9 g/kg, orally) toxicity. These findings suggest t hat hepatoprotection results not from the cellular accumulation of T b ut rather from the intact TS molecule. To test this hypothesis, the he patoprotective capacity of cholesteryl hemisuccinate (CS), unesterifie d cholesterol, and cholesteryl acetate (CA) was examined against CCl4 toxicity. As observed with the tocopherol derivatives, pretreatment wi th unesterified cholesterol or CA demonstrated no protective ability. However, when rats were pretreated with CS (100 mg/kg), the hepatotoxi c effects of CCl4 (elevated serum AST and ALT levels and centrilobular necrosis) were completely prevented. The prevention of CCl4-induced h epatotoxicity by CS and TS do not appear to result from an alteration in hepatic drug metabolism. These data dearly demonstrate that CS and TS are unique and powerful cytoprotective agents against CCl4 hepatoto xicity in vivo. Furthermore, the protection observed is not the result of cellular T accumulation, but rather appears to depend on the hepat ocellular accumulation of the intact TS molecule.