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* German Institute of Human Nutrition, Bergholz-Rehbrücke, Germany; and
Department of Nutrition and Food Management, Linus Pauling Institute, Oregon State University, Corvallis, Oregon 97330, USA
1Correspondence: German Institute of Human Nutrition, Arthur Scheunert-Allee 114–116, D-14558 Bergholz-Rehbrücke, Germany.
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ABSTRACT |
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 TOP ABSTRACT BACKGROUNDFUNCTIONSNONANTIOXIDANT FUNCTIONS?METABOLISMSUMMARY AND OUTLOOKREFERENCES |
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-tocopherol has the highest
biological activity. Due to the potent antioxidant properties of
tocopherols, the impact of -tocopherol in the prevention of chronic
diseases believed to be associated with oxidative stress has often been
studied, and beneficial effects have been demonstrated. Recent
observations that the -tocopherol transfer protein in the liver
specifically sorts out RRR--tocopherol from all
incoming tocopherols for incorporation into plasma lipoproteins, and
that -tocopherol has signaling functions in vascular smooth muscle
cells that cannot be exerted by other forms of tocopherol with similar
antioxidative properties, have raised interest in the roles of vitamin
E beyond its antioxidative function. Also, 
-tocopherol might have
functions apart from being an antioxidant. It is a nucleophile able to
trap electrophilic mutagens in lipophilic compartments and generates a
metabolite that facilitates natriuresis. The metabolism of vitamin E is
equally unclear. Excess -tocopherol is converted into -CEHC and
excreted in the urine. Other tocopherols, like - and 
-tocopherol,
are almost quantitatively degraded and excreted in the urine as the
corresponding CEHCs. All rac -tocopherol compared to
RRR--tocopherol is preferentially degraded to
-CEHC. Thus, there must be a specific, molecular role of
RRR--tocopherol that is regulated by a system that
sorts, distributes, and degrades the different forms of vitamin E, but
has not yet been identified. In this article we try to summarize
current knowledge on the function of vitamin E, with emphasis on its
antioxidant vs. other properties, the preference of the organism for
RRR--tocopherol, and its metabolism to
CEHCs.—Brigelius-Flohé, R., Traber, M. G. Vitamin E:
function and metabolism. |
BACKGROUND |
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TOPABSTRACTBACKGROUNDFUNCTIONSNONANTIOXIDANT FUNCTIONS?METABOLISMSUMMARY AND OUTLOOKREFERENCES |
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, ß, , ) and four tocotrienols
(, ß, , ); see Fig. 1
A, B (1)
. One form, -tocopherol, is the most abundant form
in nature (2)
, has the highest biological activity based on fetal
resorption assays (3
4
5)
, and reverses vitamin E deficiency symptoms in
humans (6
7
8
9
10)
. The molecular functions fulfilled specifically by
-tocopherol have yet to be fully described, but it is unlikely they
are limited to general antioxidant functions.
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In 1922, Evans and Bishop (11)
discovered vitamin E—a micronutrient
essential for reproduction in rats. It was rediscovered in the 1950s as
factor 2 by Klaus Schwarz (12)
and placed in the context of cellular
antioxidant systems, together with sulfur amino acids (factor 1) and
selenium (factor 3). Vitamin E subsequently proved to be effective in
preventing lipid peroxidation and other radical-driven oxidative events
(13
14
15)
.
The antioxidant activity of vitamin E has persuaded many groups to
study its ability to prevent chronic diseases, especially those
believed to have an oxidative stress component such as cardiovascular
diseases, atherosclerosis, and cancer. Epidemiological studies (16
, 17)
have reported that high vitamin E intakes are correlated with a reduced
risk of cardiovascular diseases, whereas intakes of other dietary
antioxidants (such as vitamin C and ß-carotene) are not, suggesting
that vitamin E plays specific roles beyond that of its antioxidant
function.
The possibility that vitamin E has an ameliorative effect in chronic
disease has spurred interest in determining its specific molecular
functions and whether these are related to its antioxidant function.
This paper seeks to describe the current knowledge of vitamin E
function: What are its specific antioxidant functions, its role in cell
signaling, its recognition by the -tocopherol transfer protein, and
its metabolism? These important functions are discussed in relationship
to human vitamin E deficiency, normal metabolism, and chronic disease.
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FUNCTIONS |
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TOPABSTRACTBACKGROUNDFUNCTIONSNONANTIOXIDANT FUNCTIONS?METABOLISMSUMMARY AND OUTLOOKREFERENCES |
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, 14
, 18
19
20
21)
.
To induce lipid peroxidation, Ham and Liebler (22)
perfused male
Sprague-Dawley rat livers with 2 mM tert-butylhydroperoxide
(t-BuOOH)2
for 10
min. t-BuOOH induced oxidation of -tocopherol to -tocopherol
quinone, -tocopherol hydroquinone, 2,3-epoxy--tocopherol quinone,
and 5,6-epoxy--tocopherol quinone (Fig. 2
). Isolated mitochondria from these livers exhibited increased state 3
and state 4 respiration and a decline in the respiratory control ratio.
However, in livers from rats given supplementary vitamin E (which
contained 7- to 10-fold higher vitamin E levels than controls), lipid
peroxidation and metabolic changes induced by t-BuOOH were decreased;
t-BuOOH-induced increase in state 4 respiration did not occur and the
respiratory control ratio was maintained. The relative extent of
-tocopherol oxidation, oxidation products formed, and distribution
in whole liver and isolated mitochondria was similar in the vitamin
E-supplemented and unsupplemented animals. These data suggest that the
`extra' vitamin E prevented mitochondrial dysfunction in the face of
severe oxidative stress.
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In vivo antioxidant activity
In 1996, the Cambridge Heart Antioxidant Study (CHAOS) (23)
reported in over 2000 patients with angiographically proven coronary
atherosclerosis that vitamin E supplementation (400–800 IU/day) for
slightly under 2 years significantly (P<0.005) reduced the
incidence of cardiovascular death and nonfatal myocardial infarction by
77%. Decreases in lipid peroxidation of low density lipoproteins (LDL)
have been assumed to be the mechanisms for this result. However, tissue
responses to oxidative stress may be important. In a Japanese trial of
60 patients with coronary spastic angina, treatment for 30 days with a
daily dose of 300 mg -tocopherol resulted in a significant
improvement (P<0.001) of impaired endothelium-dependent
vasodilation concomitant with a reduction of plasma TBARS
(thiobarbituric acid-reactive substrate), a marker of lipid
peroxidation (24)
.
Demonstration of free radical damage and its prevention by vitamin E
in vivo have lagged because of a lack of sensitive
analytical techniques. This, however, has recently changed;
quantification of F2-isoprostanes, isomers of
prostaglandin F2, has been suggested by a number
of investigators as a reliable index of in vivo free radical
generation and oxidative lipid damage.
F2-isoprostanes are formed in membranes from
arachidonyl-containing lipids by cyclooxygenase enzymes, as well as
during free radical-catalyzed lipid peroxidation (25
26
27)
. In studies
using experimental animals, F2-isoprostanes
increased in plasma and tissues as a result of vitamin E deficiency
(28)
. Furthermore, in an animal atherosclerosis model (the
apoE-deficient mouse), vitamin E supplementation not only suppressed
F2-isoprostane production but also decreased
atherosclerotic lesion formation (29)
.
8-epi-prostaglandin F2
(8-iso-PGF2) is one of the more abundant
F2-isoprostanes produced in vivo in
humans (30)
. 8-iso-PGF2 excretion is depressed
in humans by antioxidant vitamins (31
, 32)
, but not by the nonspecific
cyclooxygenase inhibitor, aspirin (32)
. In hypercholesterolemic
subjects, 8-iso-PGF2 and
11-dehydro-thromboxane B2 (a marker of platelet
activation) were elevated, but urinary excretion was unaffected by
low-dose aspirin and indobufen, a reversible cyclo-oxygenase inhibitor,
whereas these agents decreased thromboxane biosynthesis (33)
. In
contrast, vitamin E supplementation resulted in a dose-dependent
reduction in 8-iso-PGF2 excretion and
decreased sensitivity of LDL to in vitro oxidation (33)
.
Davi et al. (33)
suggest that pharmacological vitamin E doses in humans
may decrease an aspirin-insensitive prothrombotic factor involved in
myocardial infarction. This hypothesis provides an alternative
mechanism for the beneficial effects of vitamin E seen in the CHAOS
study (23)
.
Pro-oxidant activity
The antiatherogenic results conflict with pro-oxidative vitamin E
effects observed in vitro. It has to be considered that
vitamin E, like every redox-active compound, may exert anti- and
pro-oxidative effects depending on the reaction partners present.
Pro-oxidative functions of -tocopherol have been demonstrated in LDL
isolated from healthy volunteers (34)
and a patient with a defect in
the -TTP gene (35)
. The importance of a pro-oxidant role of vitamin
E in vivo has yet to be demonstrated. Certainly in the
presence of other coantioxidants, including ascorbic acid and
ubiquinol, vitamin E does not have a prooxidant function. This topic is
more fully discussed in the review by Upston et al. (36)
.
Specific chemical role for -tocopherol?
A role distinct from oxygen radical scavenging has been proposed
for -tocopherol. In contrast to -tocopherol, -tocopherol is a
powerful nucleophile that traps electrophilic mutagens in lipophilic
compartments (37
38
39)
. It thus complements glutathione, which similarly
scavenges electrophilic mutagens in the aqueous phase of the cell. An
electrophilic mutagen prone to react with -tocopherol is
peroxynitrite. Thus, -tocopherol may protect lipids, DNA, and
proteins from peroxynitrite-dependent damage.
Hoglen et al. (40)
have shown that the reaction of peroxynitrite with
-tocopherol in vitro results in the formation of four
major products:
2,7,8-trimethyl-2-(4,8,12-trimethyldecyl)-5-nitro-6-chromanol (NGT),
2,7,8-trimethyl-2-(4,8,12-trimethyldecyl)-5,6-chromaquinone
(tocored), and two diastereomers of 8 -(hydroxy)--tocopherone.
However, when -tocopherol was reacted with the nitrating agent
NO2+
BF4-, the major product detected
was -tocopheryl quinone, a product that was not detected in
reactions involving peroxynitrite. Since the product distribution after
oxidation with NO2+
BF4- differed substantially from that after
oxidation with peroxynitrite,
NO2+ appears not to be the
principal species involved in NGT formation. Nitration of
-tocopherol may involve either peroxynitrite or some
peroxynitrite-derived oxidant other than
NO2-. Because of its stability
and formation as a novel product of the reaction between -tocopherol
with peroxynitrite, Hoglen et al. (40)
suggest that NGT may be a useful
in vivo marker for peroxynitrite interactions with
-tocopherol.
Vitamin E deficiency, antioxidant function, and neurological
dysfunction
In humans, severe vitamin E deficiency leads to
neuromuscular abnormalities characterized by spinocerebellar ataxia (8
, 41
42
43
44)
and myopathies (9
, 45)
. The peripheral neuropathy likely occurs
due to free radical damage to the nerves and a dying back of the
sensory neurons (46)
. Similarly, vitamin E deficiency anemia occurs,
largely in premature infants, as a result of free radical damage (47)
.
Diminished erythrocyte life span (48
, 49)
and increased susceptibility
to peroxide-induced hemolysis are apparent not only in severe
deficiency, but also in marginal vitamin E deficiency in
hypercholesterolemic subjects (50)
.
Overt vitamin E deficiency occurs only rarely in humans and virtually
never as a result of dietary deficiencies. Vitamin E deficiency does
occur as a result of genetic abnormalities in the -tocopherol
transfer protein (-TTP) and as a result of various fat malabsorption
syndromes, as reviewed in ref 51
. The frequency of human vitamin E
deficiency as a result of -TTP defects is unknown.
Patients with familial isolated vitamin E deficiency, an inborn genetic
defect in the gene for the -tocopherol transfer protein (52
, 53)
,
have dramatically reduced plasma vitamin E levels and neurological
disorders characteristic of vitamin E deficiency such as cerebellar
ataxia, dysarthria, absence of deep tendon reflexes, vibratory and
proprioceptive sensory loss, and positive Babinski sign (52)
.
The deficiency symptoms associated with this syndrome can be
ameliorated when these patients are given doses of vitamin E of up to
2000 mg per day (8
9
10)
. Also, symptoms of vitamin E deficiency caused
by chronic liver disease, fat malabsorption, or abetalipoproteinemia
are ameliorated by high doses of vitamin E (7
, 54)
. None of the
curative dosages can be achieved by an optimized dietary regimen; the
patients must consume vitamin E supplements.
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NONANTIOXIDANT FUNCTIONS? |
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TOPABSTRACTBACKGROUNDFUNCTIONSNONANTIOXIDANT FUNCTIONS?METABOLISMSUMMARY AND OUTLOOKREFERENCES |
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. -Tocopherol inhibits smooth muscle cell proliferation
(56)
, decreases protein kinase C activity (57)
, increases
phosphoprotein phosphatase 2A activity (58)
, and controls expression of
the -tropomyosin gene (55)
. These functions are not related to
vitamin E antioxidant action because ß-tocopherol, which has a
similar antioxidant activity, does not perform any of these functions;
it actually abrogates the -tocopherol effect.
-Tocopherol effects on protein kinase C inhibition have also been
reported in human platelets (59)
, diabetic rat kidney (60
, 61)
, and
human monocytes (62)
. The mechanism of protein kinase C inhibition by
-tocopherol may be attributable in part to its attenuation of the
generation of membrane-derived diacylglycerol, a lipid that activates
protein kinase C translocation and activity (63
, 64)
. Cachia et al.
(65)
have also suggested that the inhibition of protein kinase C
activity is not due directly to the antioxidant capacity of
-tocopherol, but requires the integration of -tocopherol into a
membrane structure, and is likely due to the direct interaction between
-tocopherol and protein kinase C in the cell membrane.
-Tocopherol modulates the in vitro expression of some
significant proteins/enzymes in various cell types involved in
atherogenesis (66)
. Vitamin E enrichment of endothelial cells
down-regulates the expression of intercellular cell adhesion protein
and vascular cell adhesion molecule-1, thereby reducing the oxidized
LDL-induced adhesion of white cells to the endothelium (67)
.
Recent advances in the area of the arachidonic acid cascade have also
demonstrated that -tocopherol can regulate these pathways, and its
effect is not always shared by other vitamin E forms; see review (66)
.
Vitamin E up-regulates the activities of cytosolic phospholipase A2
(68
, 69)
and cyclooxygenase (69)
. The enhanced activity of these two
rate-limiting enzymes in the arachidonic acid cascade provides a
mechanism for the observation that vitamin E dose-dependently enhances
release of prostacyclin, a potent vasodilator and inhibitor of platelet
aggregation (70
71
72
73
74)
.
Infertility
Vitamin E prevents loss of spermatogenesis in males and the
failure to retain zygotes in female rats (11)
. Male infertility also
results from selenium deficiency, and could thus be envisaged to
support a general antioxidant function of vitamin E in the reproductive
system. A synergistic effect of vitamin E and selenium in the
protection of biomembranes from oxidative attack has been widely
discussed. Vitamin E is known to readily reduce alkyl peroxy radicals
of unsaturated lipids (75)
, thereby generating hydroperoxides that are
reduced by the selenoperoxidases, in particular by phospholipid
hydroperoxide glutathione peroxidase (76
, 77)
. Correspondingly, vitamin
E and selenium can substitute for each other or at least act
synergistically in pathogenic phenomena arising from oxidative stress
(78)
. Surprisingly, however, vitamin E was not able to replace selenium
in the prevention of functional and structural alterations of
spermatozoa (79)
. This observation suggests distinct roles for both
micronutrients. The specific role of selenium in spermatogenesis
appears to be related to phospholipid hydroperoxide glutathione
peroxidase, which is expressed depending on the developmental state of
spermatids (80)
and seems to be converted into a structural component
in the midpiece of mature spermatozoa (81)
. The molecular role of
-tocopherol in this context remains undefined.
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METABOLISM |
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TOPABSTRACTBACKGROUNDFUNCTIONSNONANTIOXIDANT FUNCTIONS?METABOLISMSUMMARY AND OUTLOOKREFERENCES |
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-tocopherol, provided either unesterified or usually as the ester of
acetate, succinate, or nicotinate. Supplements can contain either the
natural RRR- or the synthetic (all rac)
-tocopherol. all rac -tocopherol consists of all eight
possible stereoisomers arising from the three chiral centers, the C2 in
the chroman ring and C4' and C8' in the phytyl tail (82)
(Fig. 3
). None of forms are bioequivalent; the stereoisomers have been tested
in the rat resorption-gestation test and showed highly different
biological activities (83)
. Taking the activity of the
RRR--tocopheryl acetate as 100%, the other forms had the
following activities: RRS 90%, RSS 73%,
SSS 60%, RSR 57%, SRS 37%,
SRR 31%, and SSR 21% (83)
. Nonetheless,
analysis of tissue stereoisomers demonstrated that the 2R forms were
predominant (5
, 84)
.
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In humans given an equimolar mixture of free and esterified
-tocopherol labeled with different amounts of deuterium, the
concentrations of -tocopherol derived from the both forms were equal
in plasma and red blood cells (85)
. These results show that in humans,
free and esterified -tocopherol have the same bioavailability.
Determinants of biological activity
The biological activity of natural RRR--tocopherol
is higher than that of the synthetic all rac -tocopherol
and other natural forms of vitamin E. Differences in absorption,
however, do not satisfactorily explain the differences in the specific
activities of the isomers. Instead, the following possibilities and
facts may account for their differential therapeutic profiles:
1) distinct biological activity of the isomers themselves or
their metabolites; 2) different rates and/or modes of
metabolism; 3) compartmentalization by transport mechanisms
specific for RRR--tocopherol; and 4) specific
interaction of individual isomers with particular receptors.
Vitamin E is absorbed in the intestine and enters the circulation via
the lymphatic system. It is absorbed together with lipids, packed into
chylomicrons, and transported to the liver with the chylomicrons and
the remnants derived thereof (reviewed in (51)
). This process is
similar for all forms of vitamin E tested. Only after passage through
the liver does -tocopherol preferentially appear in the plasma (51)
.
Most of the ingested ß-, -, and -tocopherol is secreted into
bile or not taken up and excreted in the feces (86)
.
The reason for the plasma preference for -tocopherol is its specific
selection by the hepatic -tocopherol transfer protein (-TTP)
(87)
. -TTP not only specifically sorts out the form of all
tocopherols but also has a preference for 2R-stereoisomers.
Supplementation studies with differentially deuterated -tocopherols
revealed that the 2R epimers compared with the 2S
epimers are preferentially retained in all tissues except the liver
(88
, 89)
. Moreover, use of chiral HPLC techniques has demonstrated that
plasma and tissues after supplementation with all rac
-tocopherol contain the 2R epimers (5
, 84
, 90)
.
Plasma RRR--tocopherol incorporation is a saturable
process. Plasma levels on vitamin E supplementation cease to increase
at ~80 µM despite increasing dosages of up to 800 mg
RRR- (91
, 92)
or 1320 mg all rac -tocopherol
(93)
per day. A dose response study using deuterated
RRR--tocopherol demonstrated that the limitation in
plasma -tocopherol concentration appears to be a result of the rapid
replacement of circulating with newly absorbed -tocopherol (94)
.
These data are consistent with kinetic analyses demonstrating that the
entire plasma pool of -tocopherol is replaced daily (95)
.
Degradation
Products with chroman ring oxidation
Due to the great interest in the antioxidant function of vitamin
E, studies of metabolism have concentrated on metabolites resulting
from oxidation of the chroman moiety. The main hepatic oxidation
product was described as -tocopheryl quinone derived from the
reaction of the tocopheroxyl radical with a peroxyl radical (Fig. 2)
(96)
. -Tocopheryl quinone can be reduced to -tocopheryl
hydroquinone by NAD(P)H-dependent microsomal and mitochondrial enzymes
(97)
. The quinone and the hydroquinone have both been found in
biological membranes treated with azo-bis(amidinopropane, a peroxyl
radical generator (98)
.
For decades, the only known urinary metabolites of -tocopherol were
the so-called Simon metabolites, first described in 1956 (99
, 100)
.
These metabolites, -tocopheronic acid and its lactone, were
found in increased amounts in the urine of subjects who consumed 3–5 g
all rac -tocopherol (Fig. 4
).
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The chroman ring is opened in the Simon metabolites. Ring opening
starts with the formation of the -tocopheroxyl radical (96)
, i.e.,
when -tocopherol has exerted its antioxidant function. The Simon
metabolites were therefore taken as indicators that vitamin E had
reacted as an antioxidant. It was paradoxical, however, why a high
intake of vitamin E increased its oxidative destruction.
Metabolites with an intact chroman structure
-CEHC
Searching for urinary metabolites of
vitamin E, another metabolite of -tocopherol,
2,5,7,8-tetramethyl-2(2'-carboxyethyl)-6-hydroxychroman
(-CEHC), was identified (91
, 101)
(Fig. 4)
. -CEHC
excretion was found to increase when a certain plasma level of
RRR--tocopherol was exceeded (91)
. The intact chroman
structure of this metabolite indicates that -CEHC is derived from
-tocopherol that has not reacted as an antioxidant.
Therefore, it was concluded that the excretion of -CEHC could be
taken as an indicator of an adequate or excess -tocopherol supply
(91)
.
To test why -CEHC was not detected in the experiments of Simon et
al. (100)
, the sample processing procedure was analyzed. When care was
taken to avoid oxygenation during sample preparation, -CEHC was
detected in the sample (91
, 101)
; in the absence of argon or nitrogen
protection, tocopheronolactone (e.g., Simon metabolite) appeared. In
addition, when oxygen was bubbled through an -CEHC solution, it was
converted into tocopheronolactone within 8 h (91)
. Therefore,
metabolites previously identified in the urine after a high intake of
-tocopherol have probably derived during sample processing from
-CEHC. This appears to be a more reasonable explanation of why a
higher excretion of the Simon metabolites is observed after a high
intake of -tocopherol than the explanation of an increased
antioxidant function.
-Tocopherol contains three chiral centers, one at the connection of
the phytyl tail and the chroman ring (C2) and two in the phytyl tail
itself. Because -CEHC results from a tail shortening, it was of
interest to investigate the conversion of all rac
-tocopherol compared with the conversion of
RRR--tocopherol to the vitamin E metabolite. Therefore,
six volunteers consuming equimolar doses of differentially deuterated
RRR- and all rac -tocopheryl acetate were
studied (102)
. After dosing, the plasma concentrations of deuterated
RRR--tocopherol were twice those of deuterated all
rac -tocopherol, whereas urinary excretion of -CEHC derived
from the all rac form exceeded that of -CEHC derived from
the RRR form by a factor of 3 or 4 (102)
.
The plasma factor of 2 in favor of the RRR form has been
observed in humans several times (89
, 90
, 102
103
104
105)
and far exceeds the
accepted ratio of biological activity of 1.36. This observation can
only be explained by a preferential incorporation of those forms of
-tocopherol having the R-configuration at C2, which is 100% in the
RRR form and 50% in the all rac form,
respectively.
-CEHC
The American diet contains large amounts of
-tocopherol compared with the European diet due to the high
consumption of soybean and corn oils by Americans. Despite the high
intake of -tocopherol, plasma -tocopherol is ~10-fold higher
than -tocopherol, again demonstrating the preference of the sorting
mechanism for -tocopherol. Moreover, plasma -tocopherol has been
shown to be replaced when the intake of -tocopherol is increased
(106
, 107)
.
Urinary -tocopherol excretion had not been investigated until the
detection of a -tocopherol metabolite with an intact chroman
structure and a shortened side chain. This metabolite was named LLU-
by Wechter et al. (108)
for Loma Linda University metabolite-, but
it corresponds exactly to the -tocopherol-derived -CEHC (91)
and
therefore is referred to as -CEHC in the following discussion.
-CEHC was first detected as an endogenous natriuretic factor (108)
in uremic patients, but is also found in normal human urine (109)
. The
stereochemistry has been unequivocally established as S(+) by X-ray
crystallography (108
, 110)
, meaning that it was derived from
2R--tocopherol without any epimerization at C-2. This
finding is consistent with the metabolites formed from - and
-tocopherols (91
, 111
, 112)
. The lack of an opening of the chroman
ring can be taken as further evidence that oxidation of tocopherols is
not a necessary step for urinary excretion of tocopherol metabolites.
Despite the usual higher - to -tocopherol ratio in human plasma,
urinary -CEHC excretion was higher than that of -CEHC (102)
. It
has even been suggested that all of the ingested -tocopherol is
converted to -CEHC (109)
, as has been shown for -tocopherol (see
below). This is in contrast to -CEHC excretion, which represents
only a small part of the ingested -tocopherol and shows that
alternative routes of excretion may exist for -tocopherol if it is
not reincorporated into plasma. -CEHC may represent the part of
-tocopherol that cannot be incorporated into VLDL either because of
saturation or due to a stereochemistry that cannot be selected by
-TTP.
-CEHC
-CEHC was the first urinary vitamin E metabolite
to be detected that did not result from oxidative destruction of the
chroman ring (111)
. -CEHC was found in the urine of rats given
tritium-labeled -tocopherol intravenously. About 50% of the given
dose appeared as -CEHC in the urine. This means that a substantial
portion of -tocopherol is degraded into -CEHC.
As originally suggested for -CEHC (111)
, CEHCs are probably formed
according to the following degradation pathway: shortening of the side
chain to three carbons by 
-oxidation and subsequent ß-oxidation
(91
, 101)
. The chroman ring is maintained during the metabolic process.
The enzyme systems that degrade the side chains have yet to be
identified. The reason for a suggested higher degradation of
-tocopherol compared with -tocopherol was explained by steric
hindrance of the methyl group. But in view of today's knowledge
concerning the function of -TTP, it is likely that -tocopherol is
salvaged and its metabolism and excretion are prevented by the function
of -TTP, while preferential degradation of unselected forms occurs.
This hypothesis is supported by the observation that synthetic
all rac -tocopherol is more readily converted to -CEHC
than is natural RRR--tocopherol.
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SUMMARY AND OUTLOOK |
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|
TOPABSTRACTBACKGROUNDFUNCTIONSNONANTIOXIDANT FUNCTIONS?METABOLISMSUMMARY AND OUTLOOKREFERENCES |
|---|
-Tocopherol, the
prominent component of the vitamin E complex, is unique in many
respects. A sorting process exists only for the natural
RRR--tocopherol; -TTP-preferentially incorporates only
the natural RRR--tocopherol into plasma. - and
-tocopherols can practically substitute for -tocopherol in
in vitro antioxidant action and partially in the
resorption-gestation assay, the differences being primarily due to the
-tocopherol-specific sorting system. An analogous in vivo
lack of equivalence exists between RRR--tocopherol and
all rac -tocopherol. The sorting process is highly
specific and does not tolerate the alteration in stereochemistry at C2.
This preference prevents -tocopherol from rapid -oxidation and
thus keeps the excretion of the -CEHC degradation product low. Only
excess -tocopherol seems to be converted to -CEHC, whereas
ingested - and -tocopherol may be almost quantitatively converted
to their CEHCs and excreted in the urine. These findings suggest that
there is a specific, molecular role for RRR--tocopherol.
-Tocopherol also appears unique in regulating phosphorylation
cascades. Such a role may be important in heart disease where cell
adhesion, proliferation, and oxidant production may all be modified
through vitamin E-sensitive pathways.
-Tocopherol is unique in being a potent nucleophile and generating a
metabolite, -CEHC, with an intriguing pharmacological function,
natriuresis. The former may contribute to the scavenging of
electrophilic mutagens, the latter to the prevention of cardiovascular
disease by lowering blood pressure.
In view of the significant differences in metabolism and, as a result, biopotency of the individual tocopherols, it is not surprising that many epidemiological and intervention studies aiming to elucide presumed vitamin E effects that did not take into account the metabolic differences between tocopherols remained inconclusive. Definite recommendation on the uses and dosages of tocopherols can only be expected from prospective intervention studies of individual tocopherols with defined isomers and stereochemistry.
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FOOTNOTES |
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-CEHC,
2,5,7,8-tetramethyl-2(2'-carboxyethyl)-6-hydroxychroman; CHAOS,
Cambridge Heart Antioxidant Study; 8-iso-PGF2,
8-epi-prostaglandin F2; NGT,
2,7,8-trimethyl-2-(4,8,12-trimethyldecyl)-5-nitro-6-chromanol; t-BuOOH,
tert-butylhydroperoxide; -TTP, -tocopherol transfer protein. 
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REFERENCES |
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TOPABSTRACTBACKGROUNDFUNCTIONSNONANTIOXIDANT FUNCTIONS?METABOLISMSUMMARY AND OUTLOOKREFERENCES |
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1-tocopherol and 5-methyltocol. Br. J. Nutr. 15,253-257[Medline]
-tocopheryl acetate. IV. USP units and -tocopherol equivalents of all-rac-, 2-ambo- and RRR--tocopherol evaluated by simultaneous determination of resorption-gestation, myopathy and liver storage capacity in rats. Int. J. Vit. Nutr. Res. 56,45-56
-tocopherol transfer protein deficiency. J. Pediatr. 134,240-244[Medline]
-Tocopherol detoxification of nitrogen dioxide: superiority to -tocopherol. Proc. Natl. Acad. Sci. USA 90,1771-1775-Tocopherol traps mutagenic electrophiles such as NOx and complements -tocopherol: physiological implications. Proc. Natl. Acad. Sci. USA 94,3217-3222-tocopherol. Chem. Res. Toxicol. 10,401-407[Medline]
-tocopherol transfer protein. Nat. Genet. 9,141-145[Medline]
-Tocopherol (vitamin E) regulates vascular smooth muscle cell proliferation and protein kinase C activity. Arch. Biochem. Biophys. 286,264-269[Medline]
-Tocopherol specifically inactivates cellular protein kinase C alpha by changing its phosphorylation state. Biochem. J. 334,243-249
-tocopherol inhibits the respiratory burst in human monocytes. Attenuation of p47(phox) membrane translocation and phosphorylation. J. Biol. Chem. 273,32801-32805-tocopheryl acetate. Characterization of the samples by physico-chemical methods and determination of biological activities in the rat resorption-gestation test. Int. J. Vit. Nutr. Res. 51,100-113
-tocopheryl acetate. II. Biopotencies of all eight stereoisomers, individually or in mixtures, as determined by rat resorption-gestation tests. Int. J. Vit. Nutr. Res. 52,351-370
-tocopherol and -tocopheryl acetate as sources of vitamin E in rats and humans. Lipids 23,834-840[Medline]
-tocopherols in the male rat. Lipids 22,163-172[Medline]
