α‐Tocopherol Long‐Chain Metabolite α‐T‐13′‐COOH Exhibits Biphasic Effects on Cell Viability, Induces ROS‐Dependent DNA Damage, and Modulates Redox Status in Murine RAW264.7 Macrophages

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SCOPE: The α-tocopherol long-chain metabolite α-tocopherol-13'-hydroxy-chromanol (α-T-13'-COOH) is a proposed regulatory intermediate of endogenous vitamin E metabolism. Effects of α-T-13'-COOH on cell viability and adaptive stress response are not well understood. The present study aims to investigate the concentration-dependent effects of α-T-13'-COOH on cellular redox homeostasis, genotoxicity, and cytotoxicity in murine RAW264.7 macrophages as a model system. METHODS AND RESULTS: Murine RAW264.7 macrophages are exposed to various dosages of α-T-13'-COOH to determine its regulatory effects on reactive oxygen species (ROS) production, DNA damage, expression of stress-related markers, and the activity of ROS scavenging enzymes including superoxide dismutases, catalase, and glutathione-S-transferases. The impact on cell viability is assessed by analyzing cell proliferation, cell cycle arrest, and cell apoptosis. CONCLUSION: α-T-13'-COOH influences ROS production and induces DNA damage in a dose-dependent manner. The metabolite modulates the activity of ROS-scavenging enzymes, with significant changes observed in the activities of antioxidant enzymes. A biphasic response affecting cell viability is noted: sub-micromolar doses of α-T-13'-COOH promote cell proliferation and enhance DNA synthesis, whereas supraphysiological doses lead to DNA damage and cytotoxicity. It hypothesizes an adaptive stress response, characterized by upregulation of ROS detoxification mechanisms, enhanced cell cycle arrest, and increased apoptosis, indicating a correlation with oxidative stress and subsequent cellular damage.

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