The order of antioxidant effectiveness of low concentrations of vitamin E analogues, in preventing cumene hydroperoxide-induced hepatocyte lipid peroxidation and cytotoxicity, was 2,2,5,7,8-pentamethyl-6-hydroxychromane (PMC) > troglitazone > Trolox C > α-tocopherol > γ-tocopherol > δ-tocopherol. However, vitamin E analogues, including troglitazone at higher concentrations, induced microsomal lipid peroxidation when oxidized to phenoxyl radicals by peroxidase/H2O2. Ascorbate or GSH was also cooxidized, and GSH cooxidation by vitamin E analogue phenoxyl radicals was also accompanied by extensive oxygen uptake and oxygen activation. When oxidized by nontoxic concentrations of peroxidase/H2O2, vitamin E analogues except PMC also caused hepatocyte cytotoxicity, lipid peroxidation, and GSH oxidation. The prooxidant order of vitamin E analogues in catalyzing hepatocyte cytotoxicity, lipid peroxidation, and GSH oxidation was troglitazone > Trolox C > δ-tocopherol > γ-tocopherol > α-tocopherol > PMC. A similar order of effectiveness was found for GSH cooxidation or microsomal lipid peroxidation but not for ascorbate cooxidation. Except for troglitazone, the toxic prooxidant activity of vitamin E analogues was therefore inversely proportional to their antioxidant activity. The high troglitazone prooxidant activity could be a contributing factor to its hepatotoxicity. We have also derived equations for three-parameter quantitative structure-activity relationships (QSARs), which described the correlation between antioxidant and prooxidant activity of vitamin E ananlogues and their lipophilicity (log P), ionization potential (EHOMO), and dipole moment.

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Journal Chemical Research in Toxicology
Tafazoli, S. (Shahrzad), Wright, J.S, & O'Brien, P.J. (Peter J.). (2005). Prooxidant and antioxidant activity of vitamin E analogues and troglitazone. Chemical Research in Toxicology, 18(10), 1567–1574. doi:10.1021/tx0500575