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 properties of the TS molecule or is dependent on the cellular release and activity of unesterified alpha-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 CCl4 toxicity. 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 CCl4 hepatotoxicity in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)
Fariss
M W
MW
Department of Pathology, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298-0662.
Bryson
K F
KF
Hylton
E E
EE
Lippman
H R
HR
Stubin
C H
CH
Zhao
X G
XG
D000818:Animals; D002252:Carbon Tetrachloride Poisoning / Q000517:prevention & control*; D056486:Chemical and Drug Induced Liver Injury; D002788:Cholesterol Esters / Q000627:therapeutic use*; D008107:Liver Diseases / Q000517:prevention & control*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D024505:Tocopherols; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000627:therapeutic use
D002788:Cholesterol Esters; D014810:Vitamin E; D024505:Tocopherols; C013440:cholesteryl succinate