Vitamin E Deficiency and Toxicity
I.
Introduction
A) Classification
Vitamins are divided into two categories based on their chemical
interactions with solvents they encounter. First, there are the water-soluble vitamins:
biotin, folate, niacin, pantothenic acid, riboflavin, thiamin, and vitamins B6, B12, and
C. These vitamins have little or no similarity in overall structure, but they do carry
ionizable groups. The ionizable groups and other polar moieties on these compounds
will promote their solubility in water. This allows them to be excreted readily by the
kidneys.
The second class of vitamins is fat-soluble. This includes vitamins A, D,
E, and K. Unlike the water soluble vitamins, the fat soluble have similar structures
(with aromatic rings and aliphatic chains) because their syntheses are similar to each
other. This makes these vitamins more soluble in nonpolar solvents than in water.
The nonpolar fats and oils in adipose tissues provide a congenial environment for
these fat-soluble vitamins. Also, rather than being excreted renally like the watersoluble vitamins, the fat-soluble vitamins are eliminated in feces; the process takes
longer as well.
VITAMIN
FUNCTION
DISEASE ASSOCIATED WITH
DEFICIENCY
A
Vision, cellular differentiation
Night blindness
D
Calcium metabolism
Rickets, osteomalacia
E
Lipid antioxidant
Lipid peroxidation
K
Blood coagulation enzymes
Inability to clot blood
Isomerization of methylmalonyl CoA to
succinyl CoA; conversion of homocysteine to
methionine
Carboxylation reactions
Pernicious anemia; megaloblastic
anemia; homocysteinuria; CNS
degeneration
Deficiency
rarely
occurs;
dermatitis, alopecia
Scurvy
FAT SOLUBLE
WATER SOLUBLE
B12 (cobalamin)
Biotin
C (Ascorbic acid)
Folic acid
Niacin
Hydroxylation reactions; biosynthesis of
collagen
Wide variety of reactions involving H- and Ctransfers
REDOX reactions
Megaloblastic anemia
Pellagra
Pantothenic acid
Deficiency rarely occurs
Pyridoxine (B6)
Synthesis of Coenzyme A, acyl carrier in fatty
acid metabolism
Transaminations
Riboflavin (B2)
REDOX reactions
Deficiency rarely occurs
Thiamine (B1)
Oxidative decarboxylation reactions
Beri-beri
Anemia
B) Structures and Chemistry
Nomenclature
Vitamin E is the generic term used for all of the compounds in this
group. The vitamin can exist as two types of structures: the tocopherol and
tocotrienol structures. Both structures are similar except the tocotrienol structure
has double bonds on the isoprenoid units. There are many derivatives of these
structures due to the different substituents possible on the aromatic ring at
positions 5, 6, 7, and 8.
*Structure of both tocopherol and tocotrienol and find source with derivatives and
their importance
Chemistry
Tocopherols (Vitamin E) are equipped to perform a unique function.
They can accept free radicals making them have antioxidant properties. The free
hydroxyl group on the aromatic ring is responsible for its antioxidant properties. The
hydrogen from this group is donated to free radicals (p. 168 Rucker).
*Find source on chemistry of free radical reactions and how specifically vitamin E
acts as an antioxidant.
C) Importance of Vitamin E
The chief function of vitamin E is to preserve our tissues from any harm
they may receive by oxidative substance. This involves the maintenance of
biological membranes, skeletal and smooth muscle, epidermal and nerve tissue
(Rucker p.176-7). Oxidative metabolites therefore can have deleterious effects
on us if they are not removed from our tissues.
Vitamin E has also been shown to be protective in both preventing
oxidative damage and in reducing damage associated with concomitant disease states.
Conditions associated with oxidative damage would include the following:
Aging
There is a potential link between oxidative damage and aging.
According to the free-radical theory of aging, the damage done by the oxidative
metabolites cause “adverse effects on gene expression, diminished immune function,
and enhanced programmed cell death.” (Combs p.207)
Air pollution
Adverse effects of air pollutants have been attributed to a lack of
vitamin E in cells. Vitamin E may provide extra protection to individuals who live in
urban environments.
Arthritis
Arthritic pain may be associated with lipids in the joint that are
reacting with oxidative metabolites. This process causes the joint to stiffen. Vitamin
E supplementation may inhibit this process and thus alleviate the swelling associated
with arthritis.
Cardiovascular Disease
In study with patients who with atherosclerosis,
supplementation with vitamin E reduced heart attack risk significantly compared to
patients not taking the supplement. This may be due to the vitamin’s oxidative
properties with low-density lipoproteins (LDL). Research has demonstrated that
oxidative damage to LDLs can lead to or increase the risk of developing
arthrosclerosis.
Cigarette Smoking
Smokers may benefit from the antioxidative properties of
vitamin E. They are at high risk of developing cancers associated with oxidative
damage.
Diabetes
Supplementation with vitamin E may prevent hemoglobin
damage in non-insulin dependent diabetes. This is due to the reduction in lipid
peroxidation in diabetic’s erythrocytes.
Exercise
After intense exercise, our bodies make more mitochondria.
Mitochondria produce oxidative metabolites during ATP production.
More
mitochondria mean more oxidative metabolites that produce more cell damage. Cell
damage due to oxidants can be prevented by vitamin E.
D) The Physiological Aspects of Vitamin E
Absorption
The process of absorption is passive and does not require the use of a protein
carrier to bring in the vitamin ( Rucker 169). It occurs in the small intestine and the vitamin can
only be absorbed if it has been cleaved by esterases located in the stomach lining. It is then
transformed into very low-density lipoproteins (VLDL) by the addition of lipid-like substances.
VLDLs enter the lymphatics and eventually released into the bloodstream.
The absorption process occurs best under hydrophilic conditions than in a
nonpolar environment. The amount absorbed decreases with increasing concentrations in the
intestine. The alpha-tocotrienol appears to be better absorbed than the other tocopherol forms
(Combs p.194).
Transport
Once again vitamin E does not have a specific protein used to transport it to the
bloodstream but it is transferred by hepatic and lymphatic mechanisms. When it is first absorbed
into the hepatic portal vein it is contained inside a lipid like structure called a chylomicron. This
structure is then converted hepatically to three distinct lipoprotein structures: high-density
lipoprotein (HDL), low-density lipoprotein, and as already mentioned VLDLs.
The alpha-tocotrienol is the most preferred form taking precedence over the
other tocopherol forms. Interestingly the R,R,R form or the natural form is also preferred over the
other racemetric tocopherol forms (Rucker p. 170).
The transport process is an important aspect in the delivery of vitamin E to our
blood system. Without the protective barrier of the lipoproteins (HDL, LDL, and VLDL), the
vitamin would be exposed to the oxidative radicals circling through our bodies. This would
prevent vitamin E from performing its number one duty, antioxidizing oxidative substances.
Uptake
After transport by lipoproteins in the blood system, vitamin E is ready to meet
its destinations. Tissue uptake occurs by one of two ways: by lipases digesting the lipoprotein
types or by “receptor mediated uptake” by binding of the lipoprotein to a specific tissue receptor
site (Combs p.195). This allows for the vitamin to enter the tissue.
Vitamin E enters a variety of different tissue types with adipose and the adrenal
gland having the highest levels. (insert table on p. 198 of Combs) It location within the cell is
found in mitochondria and since most of the mitochondria are located in the membrane of the cell,
three-fourths of the vitamin can be found there as well.
The storage capacity of the vitamin is worth noting. The vitamin can be stored
in tissue for long periods of time (years) due to its exceedingly slow turnover rate. “Owing to the
very slow rates of turnover, the amounts of vitamin E in tissue can be nearly normal even in
animals showing clinical signs of vitamin E deficiency” (Combs p.197).
Metabolism
Vitamin E is considered to be metabolized after it has performed its antioxidant
function. It is converted from a tocopherol to a tocopherylquione. The elimination of this end
product is primarly through the feces but a small fraction is removed by urine (less than 1 percent).
In order for tocopherylquione to be excreted, it first has to be converted to
tocopherylhydroquinone, a partially reduced form (Combs p. 197). This form can then combine
with glucoronic acid so that it can mix with bile. Bile is removed from our system through feces
which results in the removal of vitamin E’s end product tocopherylquinone. This allows for new
vitamin E to replenish the already plentiful tissue pools of the vitamin.
E) Sources of vitamin E from nutrition
Foods derived from wheat are a good source of vitamin E. These foods vary in their
content of vitamin E based on the source and processing involved. Wheat germ oil is the richest source of
natural vitamin E (Combs p. 192). If the wheat product is processed to make other foods such as margine,
the content of vitamin E is reduced due to the presence of lipid peroxides, methods involved in formulation,
and exposure to chemicals (acids and bases) that can destroy vitamin E. The only usable form of vitamin
E is the alpha tocopherol form that is concentrated highly in wheat germ oil. Other than wheat containing
products, the amount of vitamin E varies widely. For a more complete list, visit the web site under the
FAQ section.
II. Vitamin E deficiency
A) Causes of the deficiency
Deficiency of vitamin E can be attributed to either poor diet or inability to absorb the
vitamin due to disease or physiologic malformation. Deficiency due to diet is seldom seen except
in poorly developed countries and in “individuals practicing bizarre food faddism which entails
consumption of low vitamin E foods” (DeLuca p.160). Diseases associated with vitamin E
deficiency are cystic fibrosis and malabsorption syndromes. Cystic fibrosis results in deficiency
due to lack of pancreatic enzymes that are needed in order to emulsify fat for systemic absorption
(a process in which vitamin E is absorbed). Malabsorption syndromes result in deficiency because
of defects in the organs involved in the uptake of vitamin E. Table 4 p.175 Rucker
B) Symptoms of the deficiency
Many animal studies have been performed on recognition of the symptoms. Of those that
are important in relation to humans are the studies that involve mammals. These include
studies of the rodent, pigs, and monkeys. In these studies these symptoms were reversible by
the addition of vitamin E, selenium, and an antioxidant. Vitamin E has a combined function
with selenium. Selenium is important in the destruction of peroxides.
Almost all of the symptoms were reversed by vitamin E. Some symptoms were only
reversed by the addition of selenium. This would include myopathies associated with white
muscle. The addition of an antioxidant reversed several but not all of the associated
symptoms.
Specific symptoms
Reproductive effects
A lack of vitamin E can result in shrinkage of reproductive organs including the
uterus and scrotum sack. These changes are not well understood. Birth defects also occur in
embryos of vitamin E deficient females. The vascular system is affected and anemia is
developed.
Muscular related effects
As already mentioned muscular defects can be corrected by vitamin E and only
with selenium for others. Progressive muscular weakness and deformity of the muscle tissue
occurs in deficient animals. Wasting also occurs latter which is noted by the increase in
urinary creatine (p. 149 DeLuca). This occurs of the muscle unable to retain creatine.
Liver related effects
Liver tissue necrosis occurs in the “terminal stages” of the deficient
creature (p.152 DeLuca).
Fat related effects
Most noted due to the oxidative reactions that occur are fat related effects of
vitamin E deficiency. Vitamin E’s principal role in preventing the production of harmful
peroxide products is thwarted. This results in “ceroid” production or brown insoluble fat
production (p.154 DeLuca).
Deficiencies in Man
Deficiency in man “depends on (1) the amount of biologically active vitamin E
being consumed (2) the levels of prooxidants and antioxidants in the diet, (3) the adequacy of
dietary selenium and (4) the dietary intake of sulfur amino acids and other factors which may
alter the vitamin E requirements of man” (p.160 DeLuca).
In terms of deficiency observed in children is noted in poor transfer of vitamin E
to the fetus. The level of vitamin E in breast milk is the other consideration. Pregnant women
have higher levels of vitamin E than nonpregnant women but overall dietary intake dictates
how much will be present in the breast milk.