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OCR for page 23
V· · .~
stamen ~
Vitamin E was recognized more than 60 years ago as a
factor required for normal gestation in rats fed diets
containing rancid fat (Evans and Bishop, 1922~. This
factor, named tocopherol from the Greek tokos (child-
birth) and Therein (to bring forth), was also found to be
required for prevention of encephalomalacia in chicks
and nutritional myopathies in several species (Goettsch
and Pappenheimer, 1931; Pappenheimer and Goettsch,
1931~. Evans et al. (1936) isolated the vitamin from
wheat germ oil; Fernholz (1938) elucidated its chemical
structure; and Karrer et al. (1938) achieved its synthesis
shortly thereafter.
NUTRITIONAL ROLE
Dietary Requirements of Various Species
After vitamin E was recognized as an essential nutri-
ent, numerous interrelationships were identified be-
tween it and other dietary factors, such as selenium and
synthetic antioxidants, in preventing many varied ani-
mal diseases. (See reviews by Mason and Horwitt, 1972;
Scott, 1978; Combs, 1981; Machlin, 1980, 1984.) These
diseases include those prevented by vitamin E or certain
synthetic antioxidants (e.g., encephalomalacia in
chicks, fetal death and resorption in rats, depigmenta-
tion of incisor enamel in rats, and muscular dystrophy in
rabbits); those prevented by vitamin E or selenium (e.g.,
dietary liver degeneration in rats, exudative diathesis in
chicks, and nutritional muscular dystrophies in lambs,
calves, ducks, and turkeys); and those prevented only
by vitamin E (e.g., testicular degeneration in rats, ham-
sters, guinea pigs, dogs, monkeys, and chickens. and
~. - . . . . . . .
. .
nutritional muscular dystrophies In rats, guinea pigs,
rabbits, pigs, and dogs). The dietary requirements for
vitamin E estimated for most animal species are in the
range of 5 to 50 IU/kg of diet. The role of vitamin E in
human health is most apparent in conditions of poor
enteric absorption of lipids, for example, biliary atresia,
cystic fibrosis, and neonatal prematurity. Similar condi-
tions of lipid malabsorption in animals, such as pancrea-
titis or bile stasis, may be expected to impair the
utilization of dietary vitamin E.
Biochemical Functions
Because synthetic antioxidants, such as ethoxyquin,
diphenyl-p-phenylenediamine (DPPD), and butylated
hydroxytoluene (BHT) prevent many vitamin E-
deficiency syndromes and because vitamin E functions
in vitro as a very good antioxidant, hypotheses for this
nutrient's mode of action held that it was a biologically
specific lipid-soluble antioxidant (Tappet, 1962~. How-
ever, the metabolic basis for the nutritional interrela-
tionships of vitamin E and selenium was not understood
until Rotruck et al. (1972) discovered that selenium eras
an essential component of an enzyme, glutathione
peroxidase, which was involved in the metabolism of
hydroperoxides. Investigations of this interrelationship
have led to the present understanding that vitamin E
and selenium (via glutathione peroxidase) function as
parts of a multicomponent antioxidant defense system.
This system protects the cell against the adverse effects
of reactive oxygen and other free radical initiators of the
oxidation of polyunsaturated membrane phospholipids,
critical proteins, or both (Chow, 1979~. This function of
vitamin E is thought to be the basis of its role in nutrition
and in protection against the toxic effects of certain pro-
oxidant drugs (Combs, 1981~.
The different types of vitamin E-deficiency syn-
dromes that are manifested in different animals have
been taken to indicate that, in various species and organ
systems, lesions in different aspects of the cellular aIlti
23
OCR for page 24
24 Vitamin Tolerance of Animals
oxidant defense system may occur. Vitamin E is thought
to be involved specifically in the protection against
peroxidative deterioration of polyunsaturated phospho-
lipids in cellular membranes. Lipid peroxidation initi-
ated within the membrane is not presumed to be
affected by the selenium-dependent glutathione perox-
idase, which is present only in the cytosol and mitochon-
drial matrix space. Lesions of this nature are thought to
result in the deficiency syndromes described above that
respond only to vitamin E or to fat-soluble synthetic
antioxidants capable of entering membranes. Lesions
that involve both the membrane and soluble compo-
nents of cells are believed to result in the previously
noted deficiency syndromes that respond to either vita-
min E or selenium.
FORMS OF THE VITAMIN
Vitamin E is the generic descriptor for derivatives of
6-chromanol with the qualitative biological activity of
or-tocopherol,thatis,5,6,7-trimethyltocoltsee Figure 71.
Eight or more compounds in this category are found
widely distributed in nature. The compound with great
CH~
CH3 ~CH3
CH ~cow -Tocotrienol
CH3
HO ~ ~=
OCR for page 25
Vitamin E 25
TABLE 7 Relative Biopotencies of Vitamin E-Active Compounds and Analogues
Trivial Names
d-~-Tocopherol 2R-(4 'R. 8 'R), 5, 7, 8-Trimethyltocol
Chemical Names
Biopotencies
(lU/mg)a Sources
1.49 Wheat germ,
other
vegetable
oils (some
synthetic)
Chemical
esterification
Synthetic
Synthetic
d-c`-Tocopheryl acetate
I-~-Tocopherol
2-l-c'-Tocopherol
(2-epi-~-tocopherol)
dl-~-Tocopherol
(all-rac-cx-tocopherol)
dl-~-Tocopheryl
2R-(4'R, 8'R)-5,7,8-Trimethyltocol 1.36
acetate
2S-(4'RS, 8'RS)-5,7,8-Trimethyltocol 0.36
2S-(4'R, 8'R)-5, 7,8-Trimethyltocol 0.36
2RS-(4'RS,8'RS)-5,7,8-Trimethyltocol 1.1
2RS-(4'RS,8'RS)-5,7,8-Trimethyltocol 1.0
acetate
Synthetic
Synthetic
2-dl-cx-Tocopherol 2RS-(4'R,8'R)-5,7,8-Trimethyltocol 1.1 Synthetic
2-dl-cY-Tocopheryl acetate 2RS-(4'R, 8 'R)-5, 7, 8-Trimethyltocol 1.0 Synthetic
acetate
d-,B-Tocopherol 2R-(4'R, 8'R)-5,8-Dimethyltocol
0.12
Wheat germ,
other
vegetable
oils
d-~-Tocopherol 2R-(4'R,8'R)-7,8-Dimethyltocol 0.05 Corn oil
d-~-Tocotrienol trans-2R-5,7,8-Trimethyltocotrienol 0.32 Wheat oil
d-,B-Tocotrienol trans-2R,5,8-Dimethyltocotrienol 0.05 Plant oils
d-^y-Tocotrienol trans-2R,7,8-Dimethyltocotrienol Plant oils
d-~-Tocotrienol trans-2R,8-Methyltocotrienol Plant oils
aBased largely on prevention of resorption-gestation in the rat.
SOURCE: Scott (1978).
intestinal lumen. Its enteric absorption, like that of
other fat-soluble nutrients, therefore is dependent upon
its micellar solubilization. Consequently, impairment of
pancreatic function or bile production will result in im-
paired absorption of vitamin E. The efficiency of ab-
sorption of tocopherols is relatively low at 20 to 40
percent (Gallo-Torres, 1980a). Absorption is increased
by medium-chain triglycerides and is decreased by high
levels of linoleic acid. In mammals, absorbed tocopherol
is transported by chylomicrons via the lymphatic circu-
lation to the liver and subsequently to the general circu-
lation in very low density lipoproteins (VLDL). In birds
and fish, absorbed lipids are conveyed via the portal
vein to the liver. The liver and virtually all extrahepatic
tissues take up vitamin E from VLDL. It is present in
tissues as free tocopherol.
In most tissues of animals fed nutritionally adequate
amounts of vitamin E, c~-tocopherol is detectable. Most
species show normal plasma o`-tocopherol concentra-
tions in the range of 1-5 ~g/ml. The species have twice
these levels in the liver and heart but only half the levels
in the skeletal muscle. Although tocopherol is associ-
ated with the lipid phase of cells, tissue tocopherol con-
centrations do not relate directly to tissue lipid levels.
The basis for the variation of tocopherol concentrations
between tissues is poorly understood; nevertheless, all
tissues show linear increases in tocopherol concentra-
tions with increases in tocopherol intake.
Tocopherol acts in the transfer of hydrogen for the
reduction of free radicals within the cell. It does so by
acting as a donor of the hydrogen of its 6-OH group,
resulting in the formation of 8-`x-hydroxy-tocopherone
or 8-cx-alkoxy-or-tocopherone; upon subsequent hydroly-
sis, the tocopherones are irreversibly converted to to-
copheryl quinones. Other metabolites have been
reported; these have been reviewed by Gallo-Torres
(1980b).
HYPERVITAMINOSIS
Vitamin E is generally considered to be one of the
least toxic of the vitamins. However, several studies
have demonstrated adverse effects of very high levels of
vitamin E in animals and humans (Table 8~.
March et al. (1973) demonstrated that feeding chicks
vitamin E levels of 1,800 IU/kg of diet did not affect
their growth. Growth was depressed by 2,200 IU kg,
however. At this growth-depressing level of intake, re-
duced hematocrit, reticulocytosis, and increased pro
OCR for page 26
26
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OCR for page 28
2~3 Vitamin Tolerance of Animals
thrombin times were observed. Vitamin K injections
corrected the prothrombin times. The high level of vita-
min E depressed bone calcification among chicks fed
either a calcium- or vitamin D-deficient diet. Skeletal
muscle mitochondria isolated from chicks fed the high
level of vitamin E showed a 33 percent reduction in
oxygen uptake. March et al. (1973) concluded that vita-
min E fed to chicks at the 2,200-IU/kg level increased
their nutritional requirements for vitamins K and D.
Murphy et al. (1981) showed an effect related to the
vitamin D function. Their research found that vitamin E
at 10,000 IU/kg of diet reduced concentrations of cal-
cium and phosphorus in plasma and of total ash in tibiae.
Nockels et al. (1976) found that dietary levels of vita-
min E of 4,000 IU/kg or more produced hepatomegaly
and reduced skin pigmentation in broiler chicks. Levels
of 8,000 IU/kg or more significantly reduced chick body
weight (BOO) and caused a waxy appearance of the
feathers. Sklan (1983) found that vitamin E at 200 IU/kg
of diet increased hepatic vitamin A stores and decreased
intraduodenal concentrations of retinyl glucuronides
with no effect on the enteric absorption of vitamin A.
Yang and Desai (1977a,b) conducted long-term stud-
ies of the effects of high dietary levels of vitamin E (all-
rac-~-tocopheryl acetate) on growth in rats. It was
evident by 8 months that levels of vitamin E of 10,000
IU/kg significantly depressed BW and increased rela-
tive heart weights (organ weight/unit BW) and by 16
months that relative spleen weights increased. That
level of vitamin E also depressed femur ash content by
16 months and decreased prothrombin times at 12
months. Hematocrit values were increased at 12 and 16
months in rats fed 25,000 IU of vitamin E/kg. Rats fed
2,500 IU of vitamin E/kg showed increased hepatic lipid
contents at 8 months, but this effect was not significant
at 16 months. Rats fed 10,000 or 25,000 IU of vitamin E/
kg showed reductions in the total lipids and cholesterol
contents of plasma by 16 months. This finding contrasts
with the report of Cho and Sugano (1978), who found
that a dietary level of 2,000 IU of vitamin E/kg tended to
cause higher plasma lipid levels in the rat.
Yang and Desai (1977a,b) found that high-level vita-
min E treatment did not significantly affect liver vita-
min A storage or urinary creatine or creatinine. [enkins
and Mitchell (1975), however, found that a dietary level
of 6,000 IU of vitamin E/kg produced significant in-
creases in liver retinal ester concentrations, both at low
and intoxicating levels of vitamin A intake. High levels
of vitamin E have been shown to reduce the hepatic
storage of vitamin A (Johnson and Baumann, 1948;
Swick and Baumann, 1951~.
lenkins and Mitchell (1975) found that a dietary vita-
min E level of 6,000 IU/kg did not affect the 8-week
growth of weanling rats. This level of the vitamin signif-
icantly reduced the relative weight of the adrenal gland
but did not affect the relative weights of liver, kidney,
spleen, or testes. Although the total protein concentra-
tion of plasma was not significantly affected, the high
level of vitamin E increased albumin concentrations and
decreased globulin concentrations. The result was a 50
percent increase in the albumin: globulin ratio.
Yang and Desai (1977a,b) observed no adverse effects
of any kind among rats fed levels of vitamin E as great as
2,500 IU/kg. Alam and Alam (1981) found the same
dietary level of vitamin E to produce no deleterious ef-
fects on ash or mineral contents of developing rat teeth.
Wheldon et al. (1983) found that dietary intakes of vita-
min E as great as 2,000 mg of all-rac-o`-tocopheryl
acetate/kg of BW/day for 104 weeks did not adversely
affect growth rate, survival, or hepatic function as indi-
cated by serum enzyme levels.
Martin and Hurley (1977) studied the effects of exces-
sive amounts of vitamin E during pregnancy and lacta-
tion in the rat. They found that the placental transfer of
vitamin E is inefficient; thus, the dietary exposure of the
dams to vitamin E had minimal effects on the progeny
before birth. They observed no teratogenic effects of
dietary intakes as great as 2,252 mg/kg of BW per day;
however, this level of vitamin E intake was associated
with a few cases of delayed deliveries (i.e., gestation
periods longer than 21 days) and a few pups with eyes
closed at 14 days of age. The dams receiving the high
level of vitamin E had enlarged livers and elevated
plasma lipids.
The acute oral LD50 value of all-rac-o`-tocopheryl ace-
tate for rats, mice, and rabbits has been estimated to be
in excess of 2 g/kg of BW (FASEB, 19751.
Alberts et al. (1978) found that intraperitoneal admin-
istration of 85 IU of vitamin E to mice 24 hours before
intravenous treatment with adriamycin increased the
bone marrow toxicity of the drug.
Farrell and Bieri (1975) studied a population of 28
adults who consumed 100 to 800 IU of vitamin E/day for
an average of 3 years. The results of clinical blood tests
revealed no disturbances in the liver, kidney, muscle,
thyroid gland, erythrocytes, leukocytes, coagulation pa-
rameters, and blood glucose. Farrell and Bieri con-
cluded that vitamin E in this range of intake produced no
apparent toxic side effects. Nevertheless, the literature
contains reports of such effects as creatinuria (Hillman,
1957), fatigue (Roberts, 1981), depression (Kligman,
1982), thrombophlebitis (Roberts, 1978, 1981), and
other disorders ranging from hypoglycemia to hyper-
tension (Roberts, 1981~. A review by Salkeld (1979) of
more than 10,000 cases in which the minimum oral in-
take of vitamin E was greater than 200 IU/day for at
OCR for page 29
Vitamin E 29
least 4 weeks indicated that only 61 subjects reported
side effects. These effects were generally minor: nau-
sea, generalized dermatitis, and fatigue.
Tsai et al. (1978) conducted a double-blind study with
200 healthy college students who were given either 600
IU of vitamin E/day or a placebo. Their results showed
that vitamin E treatment did not significantly affect sub-
jective evaluations of work performance, sexuality, gen-
eral well-being, muscular weakness, or gastrointestinal
disturbances. It also did not affect prothrombin times,
total blood leukocyte counts, or serum creatine phos-
phokinase activities. Vitamin E treatment did produce
significant elevations in serum triglycerides in females.
It significantly decreased serum concentrations of thy-
roxine and triiodothyronine in females who were not
using oral steroid contraceptive agents and in males.
Corrigan and Marcus (1974) reported a coagulopathy,
which is characterized by severely prolonged prothrom-
bin times, in a patient receiving anticoagulant therapy
and voluntarily consuming a high level (1,200 IU/day) of
vitamin E. A model for this condition has been produced
in the dog (Corrigan, 1979~. He showed that high levels
of vitamin E do not affect coagulation mechanisms un-
less animals are made mildly vitamin K deficient by the
use of warfarin. In this case, high levels of vitamin E
produce a profound coagulopathy. A double-blind study
by Zipursky et al. (1980) found that administration of 25
IU/day of vitamin E by mouth to premature infants to 6
weeks of age did not affect coagulation factors.
PRESUMED UPPER SAFE LEVELS
For the time being, the information on hypervitamin-
osis E in animals is limited. Therefore, estimates of
maximum tolerable levels in animals should be consid-
ered tentative. Studies with rats and chicks indicate that
dietary levels of at least 1,000 IU/kg can be fed for pro-
longed periods of time without deleterious effects. For
these species, the presumed upper safe levels of vitamin
E are higher than the dietary levels by rather undefined
increments. In rats, the maximum tolerable level is
probably about 2,500 IU/kg. The studies by Yang and
Desai (1977a,b) and Alam and Alam (1981) indicate that
this level is not hazardous. The presumed upper safe
level for the chick, however, is lower (1,000 to 2,000 IU/
kg) as indicated by the studies of March et al. (19731.
The level of 1 jOOO IU/kg is taken, therefore, as the pre-
sumed upper safe level of vitamin E for the chick. In the
absence of experimental data on hypervitaminosis E for
other species, maximum tolerable levels of the vitamin
can be inferred only by extrapolation from these esti-
mates for rats and chicks. Thus, a presumed upper safe
level of about 75 IU/kg of BW/day is suggested as a
tentative guideline for safe dietary exposure to vitamin
E. Because the dietary requirements of most species for
vitamin E are in the range of 5 to 50 IU/kg of diet (or 2 to
4 IU/kg of BW/day), intakes of at least 20 times the
nutritionally adequate levels should be well tolerated.
SUMMARY
1. Vitamin E is a required nutrient for cell antioxidant
protection by all animals.
2. Hypervitaminosis E has been studied in rats,
chicks, and humans. These scant data indicate maxi
mum tolerable levels to be in the range of 1,000 to 2,000
IU/kg diet. A tentative presumed safe use level of 75 IU/
kg of BW/day is suggested.
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Alberts, D. S., Y. M. Peng, and T. E. Moon. 1978. Alpha-tocopherol
pretreatment increases adriamycin bone toxicity. Biomedicine
29:189.
Cho, S., and M. Sugano. 1978. Effect of different levels of dietary
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OCR for page 30
30 Vitamin Tolerance of Animals
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Effect of vitamin E therapy on blood coagulation in newborn infants.
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Representative terms from entire chapter:
presumed upper
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