Natural forms of vitamin E: metabolism, antioxidant, and anti-inflammatory activities and their role in disease prevention and therapy

Abstract

The vitamin E family consists of four tocopherols and four tocotrienols. α-Tocopherol (αT) is the predominant form of vitamin E in tissues and its deficiency leads to ataxia in humans. However, results from many clinical studies do not support a protective role of αT in disease prevention in people with adequate nutrient status. On the other hand, recent mechanistic studies indicate that other forms of vitamin E, such as γ-tocopherol (γT), δ-tocopherol, and γ-tocotrienol, have unique antioxidant and anti-inflammatory properties that are superior to those of αT in prevention and therapy against chronic diseases. These vitamin E forms scavenge reactive nitrogen species, inhibit cyclooxygenase- and 5-lipoxygenase-catalyzed eicosanoids, and suppress proinflammatory signaling such as NF-κB and STAT3/6. Unlike αT, other vitamin E forms are significantly metabolized to carboxychromanols via cytochrome P450-initiated side-chain ω-oxidation. Long-chain carboxychromanols, especially 13'-carboxychromanols, are shown to have stronger anti-inflammatory effects than unmetabolized vitamins and may therefore contribute to the beneficial effects of vitamin E forms in vivo. Consistent with mechanistic findings, animal and human studies show that γT and tocotrienols may be useful against inflammation-associated diseases. This review focuses on non-αT forms of vitamin E with respect to their metabolism, anti-inflammatory effects and mechanisms, and in vivo efficacy in preclinical models as well as human clinical intervention studies.

Keywords: 5-Lipoxygenase; Asthma; Cancer; Cyclooxygenase; Free radicals; Inflammation; Long-chain carboxychromanol; Lung injury; Tocopherol; Tocotrienol.

Figure 1. Natural forms of vitamin E

Figure 2

A - Transport and metabolism of vitamin E forms in the liver. With exception of αT, large portions of other vitamin E forms such as γT, δT and γTE are metabolized by CYP4F2-initiated ω-oxidation to form terminal metabolite CEHCs. In contrast, αT and small amounts of other vitamin E forms are incorporated into lipoproteins by α-TTP with assistance of ABCA1 before being transported to other tissues via circulation. The crisscross arrows (light blue) indicate relatively minor events taking place for αT (catabolism) and other forms of vitamin E (binding to α-TTP) in the liver. B – Molecular mechanism of vitamin E metabolism (representatively shown by γT). Vitamin E forms are metabolized by CYP4F2-mediated ω-hydroxylation and ω-oxidation in endoplasmic reticulum. 13’-COOHs are then further metabolized via β-oxidation in peroxisome and mitochondria to generate series of shorter-chain carboxychromanols. Under the condition of high vitamin E intake, sulfation of carboxychromanols in the cytosol may take place in parallel with β-oxidation. It is currently not clear whether sulfated forms can be further metabolized via β-oxidation (dash arrows).

Figure 2

A - Transport and metabolism of vitamin E forms in the liver. With exception of αT, large portions of other vitamin E forms such as γT, δT and γTE are metabolized by CYP4F2-initiated ω-oxidation to form terminal metabolite CEHCs. In contrast, αT and small amounts of other vitamin E forms are incorporated into lipoproteins by α-TTP with assistance of ABCA1 before being transported to other tissues via circulation. The crisscross arrows (light blue) indicate relatively minor events taking place for αT (catabolism) and other forms of vitamin E (binding to α-TTP) in the liver. B – Molecular mechanism of vitamin E metabolism (representatively shown by γT). Vitamin E forms are metabolized by CYP4F2-mediated ω-hydroxylation and ω-oxidation in endoplasmic reticulum. 13’-COOHs are then further metabolized via β-oxidation in peroxisome and mitochondria to generate series of shorter-chain carboxychromanols. Under the condition of high vitamin E intake, sulfation of carboxychromanols in the cytosol may take place in parallel with β-oxidation. It is currently not clear whether sulfated forms can be further metabolized via β-oxidation (dash arrows).

Figure 3. Antioxidant activities of vitamin E forms (representatively shown by γT)

Tocopherols and tocotrienols are potent lipophilic antioxidants by scavenging lipid peroxyl radicals via donating hydrogen from the phenolic group on the chromanol ring. Vitamin E forms with an un-substituted 5-position including γT may trap electrophiles such as NO₂ or peroxynitrite to form 5-nitro-γ-tocopherol (5-NγT). This figure is modified based on ref [1].

Figure 4. Anti-inflammatory activities and mechanisms of vitamin E forms and long-chain carboxychromanols

In epithelial cells, macrophages and neutrophils, γT, δT and γTE modestly inhibit PGE₂ and LTB₄ without inhibiting COXs and 5-LOX activity. 13’-COOHs potently inhibit COX-1/COX-2 and 5-LOX enzyme activity (red cross marks). In neutrophils, vitamin E forms suppress ionophore- or S1P (sphingosine 1-phosphare)-stimulated calcium influx and its downstream signaling. In lung epithelial cells, macrophages and some cancer cells, γTE inhibits activation of NF-κB and STAT6/3 as well as their regulated genes including cytokines and chemokines.