alpha-Tocopheryl hemisuccinate administration increases rat liver subcellular alpha-tocopherol levels and protects against carbon tetrachloride-induced hepatotoxicity.
Rats were administered a series of tocopherol analogs 18 h prior to a hepatotoxic dose of carbon tetrachloride (CCl4). Of the compounds tested, only d-alpha-tocopheryl hemisuccinate (TS) provided significant protection against CCl4-induced hepatotoxicity. No protection was observed with either d-alpha-tocopherol (alpha-T) or a tocopherol succinate ether derivative, d-alpha-tocopheryloxybutyric acid (TSE). None of the tocopherol analogs significantly inhibited CYP2E1 activity as measured by oxidation of p-nitrophenol. Liver homogenates and subcellular fractions (cytosol, nuclei, plasma membranes, mitochondria and microsomes) were collected 18 h after tocopherol analog administration in the absence of CCl4. Homogenate and subcellular alpha-T levels were not significantly increased following TSE administration but were increased 2-3 fold following TS and alpha-T administration. Total tocopherol levels (alpha-T+ TS + TSE) in liver homogenates and subcellular fractions were highest in rats supplemented with TS. In these animals, TS was detected in all subcellular fractions and total tocopherol levels were increased from 6-23 fold over those seen in controls and 2-9 fold over alpha-T treated rats. In vitro studies in which liver homogenates and subcellular fractions were peroxidized with ascorbate and ADP/Fe suggest that increasing levels of alpha-T but not TS correlates with increased protection against lipid peroxidation. These results suggest that the ability of TS to protect against CCl4-induced hepatotoxicity relates to its enhanced hepatic accumulation and subsequent hydrolysis to alpha-T.
Tirmenstein
M A
MA
Department of Pharmaceutical Sciences, College of Pharmacy and Graduate Program in Pharmacology/Toxicology, Washington State University, Pullman 99164-6510, USA.
Leraas
T L
TL
Fariss
M W
MW
D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D002251:Carbon Tetrachloride / Q000633:toxicity*; D056486:Chemical and Drug Induced Liver Injury; D019392:Cytochrome P-450 CYP2E1 / Q000187:drug effects / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008107:Liver Diseases / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D009336:Necrosis; D015388:Organelles / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013347:Subcellular Fractions / Q000378:metabolism; D024505:Tocopherols; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology
D014810:Vitamin E; D002251:Carbon Tetrachloride; D019392:Cytochrome P-450 CYP2E1; D000410:Alanine Transaminase; D024505:Tocopherols