title: Administration of the tris salt of alpha-tocopheryl hemisuccinate inactivates CYP2E1, enhances microsomal alpha-tocopherol levels and protects against carbon tetrachloride-induced hepatotoxicity.
abstract: A series of tocopherol compounds were examined for their capacity to protect against carbon tetrachloride (CCl4)-induced hepatotoxicity in rats. Of the tocopherol compounds tested in our study, only the tris salt of d-alpha-tocopheryl hemisuccinate (TS-tris) protected against CCl4-induced hepatotoxicity. The administration of d-alpha-tocopherol (alpha-T) and the nonhydrolyzable tocopherol ether, d-alpha-tocopheryloxybutyrate tris salt (TSE-tris), failed to protect against CCl4-induced hepatotoxicity. TS-tris was the only tocopherol which significantly decreased CYP2E1 activity after 18 h. This decrease in CYP2E1 activity is likely to limit the activation of CCl4 and protect against CCl4-induced hepatotoxicity. Our results also suggest that TS-tris protection against CCl4-induced hepatotoxicity correlates with the enhanced capacity of TS-tris to deliver alpha-T and increase the antioxidant status of hepatocytes. TSE-tris did not increase cellular alpha-T levels, while administration of TS-tris produced large increases in alpha-T levels in liver homogenates as well as in liver nuclei, microsomes, mitochondria and plasma membranes. This enhanced ability to deliver tocopherol equivalents to parenchymal liver cells may be related in part to the ability of TS-tris to form liposomes in aqueous solutions. TS-tris administration protected against CCl4-induced microsomal lipid peroxide formation and inactivation of the microsomal enzyme glucose-6-phosphatase (G6Pase). Supplementation of animals with alpha-T protected against microsomal lipid peroxide formation but not against the inactivation of G6Pase. Based on our findings, we propose that high cellular levels of alpha-T protect against CCl4-induced hepatotoxicity by scavenging CCl4 radicals as well as protecting against lipid peroxidation. Our results do not support the importance of microsomal lipid peroxidation as an early event in acute CCl4-induced hepatic necrosis.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University, Pullman 99164-6510, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Tirmenstein
authors.forename: X
authors.initials: X
authors.lastname: Ge
authors.forename: C R
authors.initials: CR
authors.lastname: Elkins
authors.forename: M W
authors.initials: MW
authors.lastname: Fariss
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002251:Carbon Tetrachloride / Q000633:toxicity*; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D005952:Glucose-6-Phosphatase / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D024505:Tocopherols; D014325:Tromethamine / Q000494:pharmacology; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D014325:Tromethamine; D014810:Vitamin E; D002251:Carbon Tetrachloride; D000410:Alanine Transaminase; D005952:Glucose-6-Phosphatase; D024505:Tocopherols