The cytotoxicity of vitamin E is both vitamer- and cell-specific and involves a selectable trait

During a study of the effect of vitamin E in activated mouse macrophages, we observed a reduction in the viability of cells treated with various forms of vitamin E. We show in this report that some tocopherols (both gamma- and delta-tocopherol) are cytotoxic to some but not all cell types. Mouse macrophages were especially sensitive (40 micromol/L), whereas human hepatocytes and bovine endothelial cells were almost completely refractory (90 micromol/L). The fully methylated tocopherol, alpha-tocopherol (alpha-Toc), was not cytotoxic in any cell type tested. The cytotoxicity observed with delta-tocopherol (delta-Toc) was associated with 2 markers of apoptosis. Vitamer-specific cytotoxicity was not due to differences in cellular uptake/accumulation because both alpha-Toc and delta-Toc accumulated equally in any cell type tested. In contrast, the cell-specific cytotoxicity was related in part to uptake/accumulation of the tocopherols. Macrophages accumulated nearly 5 times more tocopherol compared with hepatocytes cultured under similar conditions. To address the hypothesis that uptake accounted for the cell-specific sensitivity, we developed a macrophage "subtype" that was markedly resistant (>150 micromol/L) to delta-Toc. Under many different cell culture conditions (including human serum) uptake/accumulation of tocopherols was reduced in this subtype by approximately 50%. Further selection and evaluation of this phenotype, however, demonstrated no cytotoxicity even when cellular levels were elevated. Our results show that undermethylated tocopherols are cytotoxic to macrophages and that there are independent and selectable processes that determine cellular tocopherol uptake/accumulation and delta-Toc cytotoxicity.