Antioxidant-independent activities of alpha-tocopherol

Alpha-tocopherol (vitamin E) is a plant-derived dietary lipid that is essential for the health of most animals, including humans. Originally discovered as a fertility factor in rodents, the primary health-promoting properties of the vitamin in humans was shown to be protection of neuromuscular functions. Heritable vitamin E deficiency manifests in spinocerebellar ataxia that can be stabilized by timely supplementation with high-dose α-tocopherol. The molecular basis for α-tocopherol's biological activities has been attributed primarily to the vitamin's efficacy in preventing lipid peroxidation in membranes and lipoproteins, but the possibility that the vitamin possesses additional biological activities has been postulated and debated in the literature without conclusive resolution. We designed and synthesized a novel analog of α-tocopherol, 6-hydroxymethyl α-tocopherol (6-HMTC), which retains most of the vitamin's structural, physical, and biochemical properties, yet lacks measurable radical-trapping antioxidant activity. 6-HMTC bound to the tocopherol transfer protein with high (nanomolar) affinity, like that of the natural vitamin, attesting to the analog's preservation of structural integrity. Yet, 6-HMTC did not inhibit lipid peroxidation or associated ferroptotic cell death. Notably, 6-HMTC modulated the expression of some genes in a manner essentially identical to that exhibited by α-tocopherol. These findings support the notion that α-tocopherol modulates gene expression via an antioxidant-independent mechanism.