Protection against Carbon Tetrachloride-Induced Hepatotoxicity by Pretreating Rats with the Hemisuccinate Esters of Tocopherol and Cholesterol

• Published in: Environmental health perspectives Vol. 101; no. 6; pp. 528 - 536
• Main Authors: Fariss, Marc W., Bryson, Kay F., Hylton, Elizabeth E., Lippman, H. Robert, Stubin, Charles H., Zhao, Xiao-Guang
• Format: Journal Article
• Language: English
• Published: United States National Institute of Environmental Health Sciences. National Institutes of Health. Department of Health, Education and Welfare 01.11.1993
• Subjects: Animals; Carbon Tetrachloride Poisoning - prevention & control; Chemical and Drug Induced Liver Injury; Cholesterol Esters - therapeutic use; Cholesterols; Cytoprotection; Esters; Hepatocytes; Hepatotoxicity; Human resources; Liver; Liver Diseases - prevention & control; Male; Necrosis; Rats; Rats, Sprague-Dawley; Tocopherols; Vehicles; Vitamin E - analogs & derivatives; Vitamin E - therapeutic use
• ISSN: 0091-6765; 1552-9924
• DOI: 10.1289/ehp.93101528

Previous studies have demonstrated that α-tocopheryl hemisuccinate (TS) protects hepatocyte suspensions from chemical-induced toxicity. It has been suggested that TS cytoprotection is related to unique properties of the TS molecule or is dependent on the cellular release and activity of unesterified α-tocopherol (T). To test the unique cytoprotective nature of TS in vivo, the protective ability of T and tocopherol esters against carbon tetrachloride ( CCl4)-induced hepatotoxicity in rats was examined. Hepatoprotection [determined by serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels and histopathology] was not observed after T (or tocopheryl acetate and tocopheryl nicotinate) administration, even though this treatment resulted in a fivefold elevation in hepatic T content. Only pretreatment with TS (100 mg/kg, intraperitoneally) resulted in partial hepatoprotection against CCl4(2.9 g/kg, orally) toxicity. These findings suggest that hepatoprotection results not from the cellular accumulation of T but rather from the intact TS molecule. To test this hypothesis, the hepatoprotective capacity of cholesteryl hemisuccinate (CS), unesterified cholesterol, and cholesteryl acetate (CA) was examined against CCl4toxicity. As observed with the tocopherol derivatives, pretreatment with unesterified cholesterol or CA demonstrated no protective ability. However, when rats were pretreated with CS (100 mg/kg), the hepatotoxic effects of CCl4(elevated serum AST and ALT levels and centrilobular necrosis) were completely prevented. The prevention of CCl4-induced hepatotoxicity by CS and TS do not appear to result from an alteration in hepatic drug metabolism. These data clearly demonstrate that CS and TS are unique and powerful cytoprotective agents against CCl4hepatotoxicity in vivo. Furthermore, the protection observed is not the result of cellular T accumulation, but rather appears to depend on the hepatocellular accumulation of the intact TS molecule.