All About The Vitamin E’s
*This article is not medical advice. Before starting on any health related regimen, seek the advice of your Primary Care Physician or an M.D.
Vitamin E: Tocopherols and Tocotrienols
Vitamin E occurs in two major forms, Tocopherols, and Tocotrienols, with each form having 4 major groups (alpha, beta, delta, gamma). This article will review each of these 8 types of Vitamin E, where they play a role physiologically, and the basic physiological mechanisms it is involved with while highlighting impacts to brain/neuronal health, mitochondria, cell membranes, micro glia, the krebs cycle, the electron transport chain, cardiolipin, ion channels, endothelial health, cholesterol, and NMDA excitotoxicity.
“Gamma Tocotrienols are by far the most potent form of Vitamin E in terms of lowering cholesterol, while Alpha Tocotrienols offer the best neuro-protection. Gamma Tocopherols offer unique protection against nitrative stress (for my ADH5 and NOS2/iNOS friends).”
Basic Types Of Vitamin E
Alpha Tocopherol : Major circulating vitamin E, antioxidant, protects LDL/membranes
Beta Tocopherol : General antioxidant, less bioactive
Delta Tocopherol : Anti-cancer, anti-inflammatory
Gamma Tocopherol : Potent anti-inflammatory, scavenges peroxynitrite (RNS)
Alpha Tocotrienols: Neuroprotection, antioxidant, micro-glial protection
Beta Tocotrienols: General antioxidant, weak activity
Delta Tocotrienols: Anti-cancer, anti-proliferative, mitochondrial (SDH/Cardiolipin)/metabolic regulation
Gamma Tocotrienols: Anti-inflammatory, cholesterol-lowering, anti-cancer, mitochondrial (SDH/Cardiolipin) protection
Alpha Tocopherol - Common / Plasma Lipid Peroxidation Protection
Strongest antioxidant in plasma, weaker anti-inflammatory
Nrf2, COX-2, lipid peroxidation defense
Scavenges lipid peroxyl radicals, inhibits lipid oxidation
High doses may impair vitamin K clotting, hemorrhage risk
Brain: Major membrane antioxidant in CNS; protects PUFA-rich neuronal membranes; supports myelin integrity.
Micro Glial: Moderate inhibition of NF-κB-driven cytokines; reduces lipid peroxidation that fuels microglial activation.
Ion Channels: Indirect dampening of TRPA1/TRPV1 signaling by lowering oxidized lipids/eicosanoids; no strong direct modulation data.
NMDA Excitotoxicity: Limits lipid peroxidation during glutamate stress; weaker than α-T3 for excitotoxicity.
Endothelial: Improves LDL oxidation profile; modestly supports eNOS via reduced oxidative load; may lower VCAM-1/ICAM-1 via NF-κB restraint.
Gene Impact: NFE2L2, PTGS2(COX-2), RELA(NF-κB), NOS3, ICAM1, VCAM1
CYP4F2 variants: CYP4F2 loss-of-function (e.g., rs2108622 Met/Met) ↓ω-hydroxylation → higher α-tocopherol levels; consider lower doses and monitor bleeding/INR if on anticoagulants.
Beta Tocopherol - Relatively Weak
Similar to α but lower α-TTP transport
Weaker scavenging, membrane antioxidant
Brain: General antioxidant with lower bioactivity; limited CNS-specific data.
Micro Glial: Limited direct data; likely similar but weaker anti-inflammatory effects than α.
Ion Channels: No specific evidence; only indirect antioxidant effects.
NMDA Excitotoxicity: No specific evidence beyond generic antioxidant buffering.
Endothelial: Generic antioxidant benefits; limited isoform-specific endothelial data.
Gene Impact: General anti oxidant list
CYP4F2 variants: Also a CYP4F2 substrate; LOF may raise levels modestly; limited clinical data.
Delta Tocopherol - Potent Anti-Cancer
Induces apoptosis, suppresses inflammation
NF-κB, STAT3, apoptosis pathways
Bleeding risk, GI upset, anticoagulant interactions
Brain: Antioxidant with emerging neuroprotective data; less characterized than γ/α.
Micro Glial: Suppresses NF-κB/STAT3; potential to reduce microglial cytokines.
Ion Channels: No direct data; indirect antioxidant effects may reduce TRP activation..
NMDA Excitotoxicity: Indirect antioxidant protection; limited direct NMDA evidence.
Endothelial: Anti-proliferative/anti-inflammatory; potential vascular benefits.
Gene Impact: RELA, STAT3, NFE2L2, CASP3/9
CYP4F2 variants: Likely CYP4F2 substrate; LOF → higher exposure; clinical significance uncertain.
Gamma Tocopherol - Potent Reactive Nitrogen Scavenger (ONOO)
Neutralizes RNS, modulates eicosanoids, anti-inflammatory
Inhibits NF-κB, iNOS, COX-2, eicosanoids
Stronger anti-inflammatory than α, moderate antioxidant
Bleeding risk, GI upset, anticoagulant interactions
Brain: Excellent scavenger of reactive nitrogen species (peroxynitrite) in neural tissue; may protect synapses from nitrosative stress.
Micro Glial: Inhibits NF-κB/iNOS; lowers NO•/ONOO−-driven microglial activation.
Ion Channels: By reducing RNS/ROS and eicosanoids, likely calms TRPA1/TRPV1; direct channel data limited.
NMDA Excitotoxicity: Protects against nitrosative potentiation of NMDA signaling by scavenging peroxynitrite.
Endothelial: Anti-inflammatory in endothelium; may lower adhesion molecules (VCAM-1/ICAM-1); improves NO bioavailability by reducing ONOO−.
Gene Impact: RELA(NF-κB), NOS2(iNOS), PTGS2, NFE2L2
CYP4F2 variants: CYP4F2 metabolizes γ as well; LOF can increase γ-tocopherol exposure; monitor for additive anticoagulant effects at high doses.
Alpha Tocotrienol - Potent Neuroprotection
Neuroprotection, antioxidant
Crosses BBB, prevents glutamate excitotoxicity, strong neuro-protection
12-LOX, c-Src, NF-κB, neuronal survival
Bleeding risk at high doses, anticoagulant interactions
Electron Transport Chain: Protects Complex I and IV from excitotoxic ROS
Cardiolipin: Preserves neuronal mitochondrial membranes
Krebs Cycle: Preserves aconitase (ACO2) by ROS defense
Brain: Strong neuroprotection; blocks glutamate-induced neurodegeneration via 12-LOX and c-Src inhibition; high membrane mobility.
Micro Glial: Downregulates microglial NF-κB and 12-LOX-derived lipid mediators; reduces cytokines.
Ion Channels: By lowering 12-LOX products and oxidized lipids, indirectly reduces TRPV1/TRPA1 sensitization.
NMDA Excitotoxicity: Robust protection against glutamate excitotoxicity upstream of NMDA-driven ROS; preserves mitochondrial function.
Endothelial: Protects endothelial mitochondria/cardiolipin; may enhance NO bioavailability via reduced ROS.
Gene Impact: ALOX12(12-LOX), SRC, RELA, NFE2L2
CYP4F2 variants: Tocotrienols undergo CYP4F2 ω-hydroxylation; LOF variants may increase exposure/tissue levels; use divided, lower dosing if bleeding risk.
Beta Tocotrienol - General antioxidant, weak activity
Not a lot of compelling research on this Tocotrienol; weak activity.
Delta Tocotrienol - Strongest anti-cancer; potent metabolic effects
Anti-cancer, anti-proliferative, metabolic regulation
Strong apoptosis induction, insulin-sensitizing
NF-κB, STAT3, PI3K/Akt, caspases, insulin pathways
GI upset, interacts with statins/anticoagulants
Electron Transport Chain: Protects Complex II (SDH) and III, supports ATP synthase
Cardiolipin: Potent cardiolipin stabilization, anti-apoptotic
Krebs Cycle: Protects α-KGDH (OGDH), SDH, improves insulin-linked metabolism
Brain: Neuroprotective potential with strong anti-inflammatory/anti-proliferative signaling; stabilizes mitochondrial membranes.
Micro Glial: Inhibits NF-κB/STAT3; may reduce NLRP3 activation under oxidative stress.
Ion Channels: Indirectly calms TRP sensitization by reducing oxidized lipids/eicosanoids.
NMDA Excitotoxicity: Indirect NMDA protection via mitochondrial and redox support
Endothelial: Improves endothelial function; insulin-sensitizing; reduces inflammatory adhesion molecules.
Gene Impact: RELA, STAT3, PIK3CA/AKT1, CASP3/9, ICAM1/VCAM1
CYP4F2 variants: Likely most affected among T3s due to slower clearance; CYP4F2 LOF → higher δ-T3; monitor if combined with anticoagulants.
Gamma Tocotrienol - cholesterol-lowering is prominent
Anti-inflammatory, cholesterol-lowering, anti-cancer
Suppresses HMG-CoA reductase, induces apoptosis, blocks angiogenesis
Inhibits HMGCR, NF-κB, STAT3, PI3K/Akt, caspases
Most versatile: strong anti-inflammatory + lipid lowering
GI upset, interacts with statins/anticoagulants
Electron Transport Chain: Stabilizes Complex I & III, reduces ROS leakage
Cardiolipin: Strong cardiolipin protection, reduces lipid peroxidation
Krebs Cycle: Protects Fe-S clusters in aconitase and SDH; Nrf2 activation
Brain: Neuroprotective via anti-inflammatory/RNS suppression; supports mitochondrial integrity under stress.
Micro Glial: Strong inhibition of NF-κB/STAT3 and iNOS; reduces microglial cytokines and nitrosative stress.
Ion Channels: By reducing oxidized lipids/RNS, likely diminishes TRPA1/TRPV1 sensitization; direct channel data limited.
NMDA Excitotoxicity: Indirectly mitigates NMDA overactivation via RNS control and mitochondrial protection.
Endothelial: Cardiometabolic & endothelial benefits: suppresses HMGCR; lowers adhesion molecules; improves NO bioavailability.
Gene Impact: HMGCR, RELA, STAT3, PIK3CA/AKT1, CASP3/9, NOS2
CYP4F2 variants: CYP4F2 LOF may increase γ-T3 exposure despite lower α-TTP binding; watch coagulation with high-dose use.
Across both groups of Vitamin E - Tocopherols and Tocotrienols we can see specific benefits. Although, the standard Alpha Tocopherol, is the most common, potent effects from Gamma Tocopherols (nitrative stress), Alpha Tocotrienols (neural protection), Gamma Tocotrienols (lowers cholesterol and Metabolic), and Delta Tocotrienols (Metabolic) offer some strong benefits. There are a variety of Tocopherol and Tocotrienol supplements on the market - some are more transparent than others in terms of what is the specific make up of the different Tocotrienols and Tocopherols. I have had some clients respond with very pronounced effects (e.g. ‘game changer’) when i lined up the specific effect i was looking for against the higher doses of the specific Tocotrienol.