Chemopreventive effects of α-tocopherol and its long-chain metabolites α-13'-hydroxy- and α-13'-carboxychromanol in LT97 colon adenoma cells.

Anticancer effects of vitamin E (tocopherols) have been studied extensively. While in vitro and animal studies showed promising results regarding anticancer effects of tocopherols, human intervention studies failed to reproduce these results. In vivo, α-tocopherol (α-TOH) is metabolized to the long-chain metabolites (LCM) 13'-hydroxychromanol (α-13'-OH) and 13'-carboxychromanol (α-13'-COOH), which likely reach the large intestine. The LCM showed antiproliferative effects in different colon cancer cell lines, but the exact mechanism of action remains unclear. To further clarify the chemopreventive action of the LCM, premalignant LT97 colon adenoma cells were treated with α-TOH, α-13'-OH and α-13'-COOH to study their impact on growth, apoptosis, antigenotoxicity, and ROS-scavenging capacity as well as expression of selected genes involved in detoxification and the cell cycle. Growth inhibitory potential was observed for α-13'-OH (IC50: 37.4 µM) and α-13'-COOH (IC50: 5.8 µM) but not for α-TOH in the tested concentrations. Levels of caspase-3 activity and expression of genes regulating the cell cycle and detoxification remained unchanged. However, α-TOH, α-13'-OH and α-13'-COOH exhibited antigenotoxic and partly ROS-scavenging capacity. The results indicate that the LCM exert chemopreventive effects via ROS-scavenging capacity, the protection against DNA damage and the induction of cell death via caspase-independent mechanisms in premalignant colon cells.

α-Tocopherol-13'-Carboxychromanol Induces Cell Cycle Arrest and Cell Death by Inhibiting the SREBP1-SCD1 Axis and Causing Imbalance in Lipid Desaturation.

α-Tocopherol-13'-carboxychromanol (α-T-13'-COOH) is an endogenously formed bioactive α-tocopherol metabolite that limits inflammation and has been proposed to exert lipid metabolism-regulatory, pro-apoptotic, and anti-tumoral properties at micromolar concentrations. The mechanisms underlying these cell stress-associated responses are, however, poorly understood. Here, we show that the induction of G0/G1 cell cycle arrest and apoptosis in macrophages triggered by α-T-13'-COOH is associated with the suppressed proteolytic activation of the lipid anabolic transcription factor sterol regulatory element-binding protein (SREBP)1 and with decreased cellular levels of stearoyl-CoA desaturase (SCD)1. In turn, the fatty acid composition of neutral lipids and phospholipids shifts from monounsaturated to saturated fatty acids, and the concentration of the stress-preventive, pro-survival lipokine 1,2-dioleoyl-sn-glycero-3-phospho-(1'-myo-inositol) [PI(18:1/18:1)] decreases. The selective inhibition of SCD1 mimics the pro-apoptotic and anti-proliferative activity of α-T-13'-COOH, and the provision of the SCD1 product oleic acid (C18:1) prevents α-T-13'-COOH-induced apoptosis. We conclude that micromolar concentrations of α-T-13'-COOH trigger cell death and likely also cell cycle arrest by suppressing the SREBP1-SCD1 axis and depleting cells of monounsaturated fatty acids and PI(18:1/18:1).

Vitamin E and Metabolic Health: Relevance of Interactions with Other Micronutrients.

A hundred years have passed since vitamin E was identified as an essential micronutrient for mammals. Since then, many biological functions of vitamin E have been unraveled in both cell and animal models, including antioxidant and anti-inflammatory properties, as well as regulatory activities on cell signaling and gene expression. However, the bioavailability and physiological functions of vitamin E have been considerably shown to depend on lifestyle, genetic factors, and individual health conditions. Another important facet that has been considered less so far is the endogenous interaction with other nutrients. Accumulating evidence indicates that the interaction between vitamin E and other nutrients, especially those that are enriched by supplementation in humans, may explain at least some of the discrepancies observed in clinical trials. Meanwhile, increasing evidence suggests that the different forms of vitamin E metabolites and derivates also exhibit physiological activities, which are more potent and mediated via different pathways compared to the respective vitamin E precursors. In this review, possible molecular mechanisms between vitamin E and other nutritional factors are discussed and their potential impact on physiological and pathophysiological processes is evaluated using published co-supplementation studies.