α-Tocopheryl hemisuccinate administration increases rat liver subcellular α-tocopherol levels and protects against carbon tetrachloride-induced hepatotoxicity

Abstract

Rats were administered a series of tocopherol analogs 18 h prior to a hepatotoxic dose of carbon tetrachloride (CCl 4). Of the compounds tested, only d- α-tocopheryl hemisuccinate (TS) provided significant protection against CCl 4-induced hepatotoxicity. No protection was observed with either d- α-tocopherol ( α-T) or a tocopherol succinate ether derivative, d- α-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 CCl 4. Homogenate and subcellular α-T levels were not significantly increased following TSE administration but were increased 2–3 fold following TS and α-T administration. Total tocopherol levels ( α-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 α-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 α-T but not TS correlates with increased protection against lipid peroxidation. These results suggest that the ability of TS to protect against CCl 4-induced hepatotoxicity relates to its enhanced hepatic accumulation and subsequent hydrolysis to α-T.