Patofyzilogie a význam vitamínu E

BUD13

• Variation in the blood carriage capacity - BUD13 [5]

Cluster of the differentiation (CD36)

• Gene variants in SEC14L2, CYP3A, CETP, and CD36 did not reach genome-wide significance

Cytochrome p450, family 3, subfamily A (CYP3A)

CYP4F2

Rs2108622 in CYP4F2

• Reported to be associated with
• Altered fatty acid metabolism
• But not with TG (P values ranging from 0.39 to 0.97) in meta-analyses
• Supporting a potential nonlipid transport function for CYP4F2 in vitamin E metabolism
• I.e., by catalyzing tocopherol phytyl side-chain oxidation [5]

Colesteryl ester transfer protein (CETP)

Gamma-tocopherol

• Most common form of vitamin E in the American diet
• Its plasma and tissue concentrations are generally significantly lower than those of alpha-tocopherol
• More gamma-tocopherol is excreted in urine than alpha-tocopherol
• Suggesting less gamma-tocopherol is needed for use by the body [10]
• Gamma-tocopherol and its major metabolite, gamma-carboxyethyl hydroxychroman (gamma-CEHC)
• May play a role in protecting the body from free radical-induced damage in various conditions of oxidative stress and inflammation
• Two recent randomized, placebo-controlled studies [10]
• Supplementation of smokers with gamma-tocopherol [10]
• Potentiated short-term benefits of smoking cessation (with or without nicotine replacement therapy) on vascular endothelial function [10]

NKAIN3

• Na+/K+ transport membrane protein [5]
• SNP in NKAIN3, the observed association with serum alpha-tocopherol in the supplemented state
• May be partly explained by the role vitamin E plays in
• Preventing loss of Na/K-ATPase activity
• A plasma membrane-bound enzyme essential for the maintenance of cell viability
• And lipid peroxidation [5]
• NKAIN3, rs7834588, was not associated with lipids in recent GWAS meta-analyses [5]

Polymorphisms of the cluster of differentiation 36 (CD36)

• Might modestly influence plasma alpha-tocopherol concentrations
• Especially in people with low triglyceride concentrations (Lecompte et al., 2011)

Single-nucleotide polymorphisms in SCARB1

• Cohort of 128 volunteers
• Gene coding for scavenger receptor B type 1 (SR-BI)
• Related to plasma alpha-tocopherol concentration
• Effect of these variants on alpha-tocopherol distribution in the body (Borel et al., 2007)

SEC14 like protein 2 - CEC14L2

Tocotrienols - especially delta-tocotrienol

• Numerous preclinical studies - might be beneficial in the prevention of chronic diseases
• Shown greater anti-proliferative and pro-apoptotic effects than tocopherols in malignant cell lines
• Dose, formulation, and type of study population [10]
• Affect the bioavailability of tocotrienols
• May undermine their putative efficacy in humans [10]
• Currently no data available on the effectiveness of supplemental tocotrienols in humans [10]

ZNF259

Adhese krevní destiček

• Supplementation with ‘vitamin E’ for two weeks up to 400 IU/day
• Equivalent to 267 mg/day of alpha-tocopherol
• Significant dose-dependent decrease in platelet adhesion (Richardson and Steiner, 1993)
• Oral supplementation with alpha-tocopherol (267–805 mg/day)
• Increase in platelet alpha-tocopherol concentration
• Correlated with a marked inhibition of platelet aggregation (Freedman et al., 1996) [2]
• Limited data on other functions of alpha-tocopherol
• Considers that markers of these functions are not specific to effects of alpha-tocopherol [2]

Antinarodovy

• Induce cell death and reduce cell proliferation [5]

Antioxidant (oxidace)

• Scavenger peroxylových radikálů, singletový kyslík, superoxdové radikály
• Peroxyl radical scavenger
• Especially protects polyunsaturated fatty acids (PUFAs) within membrane phospholipids and plasma lipoproteins [2]
• Inhibice řetězových reakcí lipoperoxidace
• Pro antiox. vlastností tokoferolů důležitá hydroxylová skupina (OH)
• Darují atom vodíku (H) volným radikálům
• Důležité je, že neutralizace volného lipidového radikálu tokoferoly a stop řetězpové rakci proběhne rychleji než oxidace volných MK a okolních proteinů
• Vznikají tokoferolové radikály a dále reagují:
• S dalším tokoferylovým radikálem za vzniku dimeru [1]

• Peroxyl radicals react 1 000 times faster with alpha-tocopherol than with PUFAs (Buettner, 1993)
• Protecting PUFAs within membrane phospholipids
• Preserves intracellular and cellular membrane integrity and stability
• Stability of erythrocytes
• Conductivity in central and peripheral nerves [2]

• Phenolic hydrogen at position 6
• Is the active site for scavenging radicals [2]

• Alpha-Tocopherol scavenges free radicals
• Primarily by hydrogen atom transfer reaction to yield a:
• Non-radical product
• Alpha-tocopherol radical [2]

• Alpha-Tocopherol may also scavenge radicals by
• Electron is transferred from alpha-tocopherol to give a vitamin cation radical
• Undergoes rapid deprotonation to provide an alpha-tocopherol radical [2]

• Alpha-tocopherol scavenges
• Lipid peroxyl radicals
• Lipid hydroperoxide
• Alpha-tocopherol radicals are formed (Niki et al., 1993; Yamauchi, 2007; Niki, 2014) [2]

Tocotrienols and gamma-tocopherol

• Thought to be better scavengers of peroxyl radicals and reactive nitrogen species, respectively, than alpha-tocopherol [10]

The alpha-tocopherol radical

• May react with another radical to give stable products
• Attack lipids
• React with a reducing agent such as ascorbate or ubiquinol to regenerate the vitamin (Packer et al., 1979; Niki et al., 1982)

Vit.C a Selen

• In vivo role is sustaining the antioxidant capacity of alpha-tocopherol
• Interaction of alpha-tocopherol and vitamin C
• Function of oxidised alpha-tocopherol is continuously restored by other antioxidants
• Antioxidant network depends on the supply of aqueous antioxidants and the metabolic activity of cells [2]

Regenerace antioxidační schopnosti (redukce)

• Reduktanty vitamínu E (regenerace vit. E) jsou:
• Ubiquinol,
• Polyfenoly,
• vit. C (nejvýznamnější cesta)
• Význam synergie jednotlivých vitamínů [1]

Separate cluster of the differentiation gene (CD4)

rs3741920 in CD4

• Was associated with a high level of significance [5]
• P = 4.2 × 10-6 [5]

Immunoregulatory potential

• Able to boost host protection against bacterial infection [8]
• Mediation of genetic factors on immune responses after VE supplementation in healthy humans
• Production of cytokines and/or related with the cytokine genes
• TNF,
• IL-6,
• IL-1B

• May influence the activity of membrane proteins and enzymes [10]
• Improve the formation of an adhesive junction (known as immune synapse)
• Between naive T lymphocytes and antigen-presenting cells (APC)
• Eventually prompted T cell activation and proliferation [10]

• Alpha-Tocopherol enhance specifically the T cell-mediated immune response
• That declines with advancing age [10]
• T cell impaired response has been partly associated with
• Reduced capacity of naive T cells to be activated during antigen presentation
• And to produce interleukin-2 (IL-2)
• Proliferate as a result [10]

• Small intervention study in older adults (mean age, 70 years)
• Supplementation with 200 mg/day of all-rac-alpha-tocopherol (equivalent to 100 mg of RRR-alpha-tocopherol) 3 months significantly improved
• Natural killer (NK) cytotoxic activity
• Neutrophil chemotaxis
• Phagocytic response
• Enhanced mitogen-induced lymphocyte proliferation
• Interleukin-2 (IL-2) production compared to baseline [10]

• Daily supplementation of healthy older adults (nad 65 years of age) with 200 mg of all-rac-alpha-tocopherol for 235 days
• Improved T lymphocyte-mediated immunity
• Measured with the delayed-type hypersensitivity (DTH) skin test
• Increased the production of antibodies in response to hepatitis B and tetanus vaccines [10]

• Lower alpha-tocopherol doses
• Failed to improve the DTH response compared to a placebo in another study in healthy participants (ages, 65-80 years) [10]

• A randomized, placebo-controlled trial in 617 nursing home residents (nad 65 years of age)
• Daily supplementation with 200 IU of synthetic alpha-tocopherol (90 mg of RRR-alpha-tocopherol) for 1 year
• Significantly lowered the risk of contracting upper respiratory tract infections
• Especially the common cold
• Had no effect on lower respiratory tract (lung) infections [10]

Reduces carcinogen production

Snížená tvorba aktivního protrombinu

• Daily supplementation with 1,000 IU (670 mg) of RRR-alpha-tocopherol for 12 weeks
• Decreased gamma-carboxylation of prothrombin
• A vitamin K-dependent factor in the coagulation cascade

Zvýšené riziko krvácení

• Individuals taking anticoagulant drugs like warfarin
• Vitamin K deficient
• Should not take vitamin E supplements without medical supervision [10]

Interakce s PUFA

• Alpha-tocopherol depletion and supplementation in men consuming diets with different PUFA content
• Effect on the percentage of hydrogen peroxide-induced haemolysis (Horwitt et al., 1956; Horwitt, 1960)(Harris and Embree; 1963)
• Minimum intake ratio needed to prevent alpha-tocopherol deficiency
• Range 0.5–0.8 mg alpha-tocopherol/g PUFAs
• Ratio of 0.6 mg alpha-tocopherol/g PUFAs (mainly linoleic acid) in the American diet
• Considered this ratio to be protective against alpha-tocopherol deficiency [2]
• 1970s, in the USA
• Ratio of milligrams of alpha-tocopherol / gram of PUFAs12 in typical breakfasts, lunches and dinners
• Ranged from 0.16 - 0.71, with a mean at 0.43 (Bieri and Evarts, 1973) [2]

• Female students consuming a repetitive series of diets over about 9 months in the USA (Witting and Lee;1975)
• Mean plasma total tocopherol concentration of 1.09 mg/dL13 for a daily mean intake of
• 17.9 g of 18:2 n-6
• 1.6 g of 18:3 n-3
• 7.5 mg RRR-alpha-tocopherol
• Authors thus proposed a ratio of 0.4 mg alpha-tocopherol/g PUFAs
• Ratios were not related to a functional outcome. [2]

• Compositional requirement for RRR-alpha-tocopherol in infant formulae
• SCF (1997) considered the results of an in vitro study (Holman, 1954) and an animal study (Witting and Horwitt, 1964)
• Relative rate of oxidation of fatty acids was 0.025: 1: 2: 4: 6: 8 for the number of double bonds in fatty acids
• Increasing from 1 to 6 [2]

• Tocopherol-deficient rats showed that the
• Relative ratio of fatty acid oxidation was slightly different: 0.3, 2, 3, 4, 5, 6
• For mono-, di-, tri-, tetra-, penta- and hexaenoic fatty acids (Witting and Horwitt, 1964) [2]

• SCF (1997) proposed the relative requirement of RRR-alpha-tocopherol in infant formulae
• According to the degree of unsaturation of PUFAs to be:
• 0.5 mg/g linoleic acid,
• 0.75 mg/alpha-linolenic acid
• 1 mg/g arachidonic acid
• 1.25 mg/g eicosapentaenoic acid
• 1.50 mg/g docosahexaenoic acid [2]

• There is little evidence to support the ratios of 0.4 mg or 0.6 mg of alpha-tocopherol per gram of dietary PUFAs
• Uncertainties in the intake measurements based on which both ratios were proposed.
• Cannot be used for deriving the requirement for alpha-tocopherol [2]

Essentiality for normal reproduction in animals

• Has never been demonstrated in humans (Brigelius-Flohe et al., 2002)
• Human case report has been published on a woman with recurrent spontaneous abortions, that successfully delivered a health baby after administration of 300 mg/day of tocopherol nicotinate (Harada et al., 2005) [2]

rs12272004 SNP

• Previously reported to be associated with serum alpha-tocopherol concentrations (P = 3.9 × 10-7) [5]
• Not highly correlated with the SNP most significantly associated with alpha-tocopherol concentrations (rs964184; linkage disequilibrium r2 = 0.20) [5]

rs1800896

• Located in IL10 gene promoter
• Modulates the production of IL-1beta.

Sirtuin 1

• protein family of NAD+-dependent histone deacetylases
• Involved in various physiological processes
• Energy metabolism
• Protects cells against oxidative stress [8]
• Decreased expression of SIRT1 is related to obesity [8]
• Dietary vitamin E and genetic variants in SIRT1 in relation to BMI
• Elevated risk to having a greater BMI was related to a higher copy number of the most common haplotype
• Alleles A of rs7895833, G of rs1467568, and G of rs497849 among subjects with low VE intake [8]
• V.s. capacity of VE to modify the association between SIRT1 variants and obesity [8]