Gamma-tocopherol, a major form of vitamin E in diets: Insights into antioxidant and anti-inflammatory effects, mechanisms, and roles in disease management

Qing Jiang, Suji Im, James G Wagner, Michelle L Hernandez, David B Peden

Free Radic Biol Med . 2022 Jan;178:347-359. doi: 10.1016/j.freeradbiomed.2021.12.012. Epub 2021 Dec 9.


γ-Tocopherol (γT) is a major form of vitamin E in the US diet and the second most abundant vitamin E in the blood and tissues, while α-tocopherol (αT) is the predominant vitamin E in tissues. During the last >25 years, research has revealed that γT has unique antioxidant and anti-inflammatory activities relevant to disease prevention compared to αT. While both compounds are potent lipophilic antioxidants, γT but not αT can trap reactive nitrogen species by forming 5-nitro-γT, and appears to show superior protection of mitochondrial function. γT inhibits ionophore-stimulated leukotrienes by blocking 5-lipoxygenase (5-LOX) translocation in leukocytes, decreases cyclooxygenase-2 (COX-2)-catalyzed prostaglandins in macrophages and blocks the growth of cancer cells but not healthy cells. For these activities, γT is stronger than αT. Moreover, γT is more extensively metabolized than αT via cytochrome P-450 (CYP4F2)-initiated side-chain oxidation, which leads to formation of metabolites including 13′-carboxychromanol (13′-COOH) and carboxyethyl-hydroxychroman (γ-CEHC). 13′-COOH and γ-CEHC are shown to be the predominant metabolites found in feces and urine, respectively. Interestingly, γ-CEHC has natriuretic activity and 13′-COOH inhibits both COX-1/-2 and 5-LOX activity. Consistent with these mechanistic findings of γT and metabolites, studies show that supplementation of γT mitigates inflammation and disease symptoms in animal models with induced inflammation, asthma and cancer. In addition, supplementation of γT decreased inflammation markers in patients with kidney diseases and mild asthma. These observations support that γT may be useful against inflammation-associated diseases.

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The α-tocopherol-derived long-chain metabolite α-13′-COOH mediates endotoxin tolerance and modulates the inflammatory response via MAPK and NFκB pathways

Martin Schubert, Stefan Kluge, Elena Brunner, Simona Pace, Marc Birringer, Oliver Werz, Stefan Lorkowski

Free Radic Biol Med . 2022 Jan;178:83-96. doi: 10.1016/j.freeradbiomed.2021.11.032. Epub 2021 Nov 27.


Scope: The long-chain metabolites of (LCM) vitamin E are proposed as the active regulatory metabolites of vitamin E providing, with their anti-inflammatory properties, an explanatory approach for the inconsistent effects of vitamin E on inflammatory-driven diseases. We examined the modulation of cytokine expression and release from macrophages, a fundamental process in many diseases, to gain insights into the anti-inflammatory mechanisms of the α-tocopherol-derived LCM α-13′-COOH.

Methods and results: Suppressed gene expression of C-C motif chemokine ligand 2 (Ccl2), tumor necrosis factor (Tnf), and interleukin (Il) 6 in response to lipopolysaccharides by 24 h pre-treatment with α-13′-COOH in RAW264.7 macrophages was revealed using quantitative reverse transcription PCR. Further, reduced secretion of IL1β and CCL2 was found in this setup using flow cytometry. In contrast, 1 h pre-treatment suppressed only CCL2. Consequent gene expression analysis within 24 h of α-13′-COOH treatment revealed the induction of mitogen-activated protein kinases (MAPK) and nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) negative feedback regulators including the ‘master regulators’ dual-specificity phosphatase 1 (Dusp1/Mkp1) and tumor necrosis factor induced protein 3 (Tnfaip3/A20). Approaches with immunoblots and chemical antagonists suggest a feedback induction via activation of extracellular-signal regulated kinase (ERK), p38 MAPK and NFκB pathways.

Conclusions: CCL2 is suppressed in murine macrophages by α-13′-COOH and the indirect suppression of MAPK and NFκB pathways is likely a relevant process contributing to anti-inflammatory actions of α-13′-COOH. These results improve the understanding of the effects of α-13′-COOH and provide a basis for new research strategies in the context of inflammatory diseases.

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Label-Free Electrochemical Biosensors to Evaluate the Antioxidant Effect of Tocopherol in Ultraviolet Radiation

Lixia Gao, Yong Teng

Methods Mol Biol . 2022;2343:241-246. doi: 10.1007/978-1-0716-1558-4_16.


Electrochemical biosensors offer a sensitive, specific, and rapid detection platform for in situ real-time monitoring of intracellular and extracellular metabolites. These sensors have been widely used to evaluate the efficacy of preclinical drugs, especially for natural products with antioxidant potency. Ultraviolet (UV) radiation causes oxidative stress in cells and induces cells to release reactive oxygen species. Tocopherol is a fat-soluble vitamin found in vegetable oils as well as in grains, seeds, and nuts, which plays an important protective role as an antioxidant in resisting oxidative stress caused by UV radiation. Here, we describe a protocol using a glass carbon electrode functionalized with nanotube@DNA-Mn3(PO4)2 composite to monitor and quantify the production of superoxide ions in UV-irradiated melanoma cells in the presence or absence of tocopherol. This study demonstrates the advantages and potential application of label-free electrochemical sensors in the measurement of natural antioxidants from plant materials.

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