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.