• biomarkers
• kidney
• oxidative stress
• supplementation
• upper limit of toxicity
• vitamin E

• co-supplementation
• immune response
• interactions
• metabolic syndrome
• micronutrients
• vitamin E

• carboxylation
• cartilage
• joint
• menaquinone
• phylloquinone

• Biomarkers
• Calcium/metabolism
• Dietary Supplements
• Disease Susceptibility
• Humans
• Osteoarthritis/epidemiology
• Osteoarthritis/etiology
• Population Surveillance
• Vitamin K/metabolism
• Vitamin K Deficiency/complications
• Vitamin K Deficiency/etiology
• Vitamin K Deficiency/metabolism

• FRGS/1/2018/SKK10/UKM/03/1 Ministry of Higher Education, Malaysia

• Dietary vitamins
• drugs based on vitamins and minerals
• micronutrients
• vitamins

• menaquinone-4
• menaquinone-7 distribution
• phylloquinone
• vitamin E
• vitamin K metabolism

• bone metabolism
• phylloquinone
• vitamin E
• vitamin K
• α-tocopherol

Reactive oxygen species (ROS) are known to stimulate the activation of nuclear factor-erythroid 2-related factor-2 (Nrf2), the key regulator of the antioxidant and cytoprotective defense system in the body. The hypothesis underlying this study was that high dietary concentrations of vitamin E suppress Nrf2 activation, and thus could weaken the body’s antioxidative and cytoprotective capacity. As the effect of vitamin E on Nrf2 pathway might be influenced by concentrations of fatty acids susceptible to oxidation in the diet, we used also diets containing either soybean oil as a reference oil or salmon oil as a source of oil rich in n-3 polyunsatuated fatty acids.

Seventy-two rats were divided into 6 groups of rats which received diets with either 25, 250 or 2500 mg vitamin E/kg, with either soybean oil or salmon oil as dietary fat sources according to a bi-factorial experimental design. Electron spin resonance spectroscopy was used to determine ROS production in the liver. qPCR analysis and western blot were performed to examine the expression of Nrf2 target genes in the liver of rats.

Rats fed the salmon oil diet with 25 mg vitamin E/kg showed a higher production of ROS in the liver than the 5 other groups of rats which did not differ in ROS production. Relative mRNA concentrations of NFE2L2 (encoding Nrf2), KEAP1 and various Nrf2 target genes, protein concentrations of glutathione peroxidase (GPX), heme oxygenase 1 (HO-1), NAD(P)H quinone dehydrogenase 1 (NQO1) and activities of the antioxidant enzymes GPX, superoxide dismutase and catalase were not influenced by the dietary vitamin E concentration. The dietary fat had also less effect on Nrf2 target genes and no effect on protein concentrations of GPX, HO-1, NQO1 and activities of antioxidant enzymes. Dietary vitamin E concentration and type of fat moreover had less effect on mRNA concentrations of genes and concentrations of proteins involved in the unfolded protein response, a pathway which is closely linked with activation of Nrf2.

We conclude that excess dietary concentrations of vitamin E do not suppress Nrf2 signaling, and thus do not weaken the endogenous antioxidant and cytoprotective capacity in the liver of rats.

• Liver
• Nuclear factor-erythroid 2-related factor-2
• Rat
• Reactive oxygen species
• Unfolded protein response
• Vitamin E

Bioavailability of vitamin E is influenced by several factors, most are highlighted in this review. While gender, age and genetic constitution influence vitamin E bioavailability but cannot be modified, life-style and intake of vitamin E can be. Numerous factors must be taken into account however, i.e., when vitamin E is orally administrated, the food matrix may contain competing nutrients. The complex metabolic processes comprise intestinal absorption, vascular transport, hepatic sorting by intracellular binding proteins, such as the significant α-tocopherol-transfer protein, and hepatic metabolism. The coordinated changes involved in the hepatic metabolism of vitamin E provide an effective physiological pathway to protect tissues against the excessive accumulation of, in particular, non-α-tocopherol forms. Metabolism of vitamin E begins with one cycle of CYP4F2/CYP3A4-dependent ω-hydroxylation followed by five cycles of subsequent β-oxidation, and forms the water-soluble end-product carboxyethylhydroxychroman. All known hepatic metabolites can be conjugated and are excreted, depending on the length of their side-chain, either via urine or feces. The physiological handling of vitamin E underlies kinetics which vary between the different vitamin E forms. Here, saturation of the side-chain and also substitution of the chromanol ring system are important. Most of the metabolic reactions and processes that are involved with vitamin E are also shared by other fat soluble vitamins. Influencing interactions with other nutrients such as vitamin K or pharmaceuticals are also covered by this review. All these processes modulate the formation of vitamin E metabolites and their concentrations in tissues and body fluids. Differences in metabolism might be responsible for the discrepancies that have been observed in studies performed in vivo and in vitro using vitamin E as a supplement or nutrient. To evaluate individual vitamin E status, the analytical procedures used for detecting and quantifying vitamin E and its metabolites are crucial. The latest methods in analytics are presented.

• Vitamin E metabolism
• Long-chain metabolites of vitamin E
• Vitamin E bioavailability
• Vitamin E transport

• Cell Culture
• Intestinal Absorption
• Intestine
• Scavenger Receptor
• Transgenic Mice
• Vitamin K