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-Tocopherol1 ,2
Institute of Biochemistry and Molecular Biology, University of Bern, 3012 Bern, Switzerland
3To whom correspondence should be addressed.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONAntioxidant Capacity Can Coexist...Molecular Mechanisms of {alpha}...Regulation of Integrated...Possible Links between In...Final Considerations.REFERENCES |
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-tocopherol, some
of which are independent of its antioxidant/radical-scavenging ability,
have been revealed. Absorption of -tocopherol from the gut is a
selective process. Other tocopherols are not absorbed or are absorbed
to a lesser extent. At the post-translational level, -tocopherol
inhibits protein kinase C and 5-lipoxygenase and activates protein
phosphatase 2A and diacylglycerol kinase. Some genes [platelet
glycoprotein IV/thrombospondin receptor/class B scavenger receptor
(CD36), -tocopherol transfer protein (-TTP), -tropomyosin,
connective tissue growth factor and collagenase] are affected by
-tocopherol at the transcriptional level. -Tocopherol also
inhibits cell proliferation, platelet aggregation, monocyte adhesion
and the oxygen burst in neutrophils. Other antioxidants, such as
ß-tocopherol and probucol, do not mimic these effects, suggesting a
nonantioxidant, -tocopherol–specific molecular mechanism.
KEY WORDS: • vitamin E • -tocopherol • antioxidant • cell proliferation • protein kinase C • gene expression
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONAntioxidant Capacity Can Coexist...Molecular Mechanisms of {alpha}...Regulation of Integrated...Possible Links between In...Final Considerations.REFERENCES |
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to describe a dietary factor in animal nutrition
important for reproduction. It took >40 years (2)
before
vitamin E was associated with an antioxidant property and another 25
years to begin to consider the nonantioxidant properties of
-tocopherol (3
,4)
. -Tocopherol is the member of the
vitamin E group of compounds (- ß- 
- and 
- tocopherols and
tocotrienols) that possess extensive biological properties
(5)
and are found most prevalently in mammalian tissues
(6)
.
Emulsified together with the fat-soluble components of the food,
tocopherols passively reach the blood stream and eventually the liver.
In the hepatocyte, the specific -tocopherol transfer protein
(-TTP)4
mediates the selective transfer of -tocopherol into lipoproteins
(7
,8)
. A tocopherol-associated protein (TAP), capable
of specific tocopherol binding was found recently to be present in a
large number of tissues (9)
. TAP, by analogy with the
homologous phosphatidylinositol-transfer protein (SEC14),
may be a candidate responsible for the regulation of tissue
-tocopherol levels or of signal transduction–related reactions.
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Antioxidant Capacity Can Coexist with Additional Functions of
-Tocopherol.
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TOPABSTRACTINTRODUCTIONAntioxidant Capacity Can Coexist...Molecular Mechanisms of {alpha}...Regulation of Integrated...Possible Links between In...Final Considerations.REFERENCES |
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-tocopherol as an
antioxidant (10
,11)
, but this antioxidant activity is
unrelated to its determination of secondary sexual characters. The
principal function of all-trans-retinol in rhodopsin and
vision is not related to its antioxidant properties (12)
.
The sleep-wake regulation by melatonin in humans occurs through a
receptor-mediated signaling function (13)
and not
through its free radical-scavenging properties (14)
.
All-trans retinoic acid binds to nuclear retinoid
receptors, major regulators of gene expression (15)
, but
it is also an antioxidant (16)
. Carotenoids (also a family
of antioxidants) up-regulate connexin43 gene expression in
fibroblasts and inhibit carcinogen-induced neoplastic
transformation (17)
via an antioxidant-independent
mechanism.
The protective effect of -tocopherol against LDL oxidation
(18)
and other free radical–induced damage is only one
side of the coin. In fact, both a prooxidant effect (19)
and an antityrosine nitrating action (20
,21)
of
-tocopherol have been described. Furthermore, the nonantioxidant
action of -tocopherol appears to be of particular relevance at a
cellular level (3
,4
,22
23
24
25
26)
.
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Molecular Mechanisms of -Tocopherol Action at Cellular Level.
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TOPABSTRACTINTRODUCTIONAntioxidant Capacity Can Coexist...Molecular Mechanisms of {alpha}...Regulation of Integrated...Possible Links between In...Final Considerations.REFERENCES |
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-tocopherol at the
cellular level, with a particular focus on the nonantioxidant
properties of the molecule (Table 1
).
|
-tocopherol have been associated with increased risk
for coronary artery disease and increased intake has been shown to be
protective. Thus, scientific interest has gone beyond recognition of
the role of oxidized LDL in atherogenesis, toward the understanding of
the -tocopherol response of crucial cells in the progress of
atherosclerosis. Inhibition of smooth muscle cell proliferation,
preservation of endothelial function, inhibition of
monocyte-endothelial adhesion, inhibition of monocyte reactive
oxygen species and cytokine release, and inhibition of platelet
adhesion and aggregation are some examples of the cellular events that
are regulated by -tocopherol. These cellular complex events are
associated with effects at a molecular level, both
post-transcriptional and transcriptional. Post-translational regulation of cellular reactions.
In 1991, inhibition of protein kinase C activity by -tocopherol was
discovered to be at the basis of the inhibition of vascular smooth
muscle cell proliferation by -tocopherol (3
,4
,22
23
24
25
26)
.
A number of reports have subsequently confirmed the involvement of
protein kinase C in the effect of -tocopherol on different cell
types, including monocytes, macrophages, neutrophils, fibroblasts and
mesangial cells (27
28
29
30
31
32
33
34)
. -Tocopherol but not
ß-tocopherol was found to inhibit thrombin-induced protein kinase
C activation and endothelin secretion in endothelial cells
(35)
. -Tocopherol (but not ß-tocopherol or Trolox)
inhibits protein kinase C activity from monocytes, followed by
inhibition of phosphorylation and translocation of the cytosolic factor
p47(phox) and impaired assembly of the NADPH-oxidase and of
superoxide production (36)
. -Tocopherol has the
important biological effect of inhibiting the release of the
proinflammatory cytokine, interleukin-1ß, via inhibition of the
5-lipoxygenase pathway (37)
.
Inhibition of protein kinase C by -tocopherol in vascular smooth
muscle cells is observed to occur at concentrations of -tocopherol
close to those measured in healthy adults (38)
.
ß-Tocopherol per se is ineffective but prevents the inhibitory effect
of -tocopherol. The mechanism involved is not related to the
radical-scavenging properties of these two molecules, which are
essentially equal (39)
. In vitro studies with recombinant
protein kinase C have shown that inhibition by -tocopherol is not
caused by a tocopherol-protein interaction. -Tocopherol does not
inhibit protein kinase C expression as well. Inhibition of protein
kinase C activity by -tocopherol occurs at a cellular level by
producing dephosphorylation of the enzyme, whereas ß-tocopherol is
much less potent (40)
. Dephosphorylation of protein kinase
C occurs via the protein phosphatase 2A (PP2A), which has
been found to be activated by treatment with -tocopherol in vitro
(40
,41)
.
King’s group (32)
reported that prevention of glomerular
dysfunction in diabetic rats can be achieved by treatment with
-tocopherol. Such a protection occurs through inhibition of protein
kinase C. In this case, however, -tocopherol would act on the
diacylglycerol pathway by activating the enzyme diacylglycerol kinase,
with consequent diminution of diacylglycerol and protein kinase C
activation. In these studies, high glucose was responsible for the
increased diacylglycerol synthesis counteracted, in the presence of
-tocopherol, by the activation of diacylglycerol kinase. The
experiments of Azzi’s group (42)
were conducted at low
glucose concentrations, and protein kinase C was found to be
deactivated by -tocopherol by means of its dephosphorylation. Other
possible effects of -tocopherol at a cellular level such as
inhibition of lipoxygenase (37
,43)
have also been
reported.
Transcriptional regulation of cellular reactions.
Recently, the possibility of regulation of gene transcription by
-tocopherol has been analyzed (44)
. Upregulation (not
mediated by protein kinase C) of -tropomyosin expression by
-tocopherol and not by ß-tocopherol (45)
once more
suggests a nonantioxidant mechanism. Long- and short-term
-tocopherol supplementation inhibits liver collagen 1(I) gene
expression (46)
. In human skin fibroblasts, an
age-dependent increase of collagenase expression can be reduced by
-tocopherol (47)
.
In rats, liver -TTP and its mRNA are modulated by dietary vitamin E
deficiency (48)
. Scavenger receptors, particularly
important in the formation of atherosclerotic foam cells, are also
modulated by -tocopherol. Both class A (SR-A) activity in
macrophages (49)
and CD36 (the oxidized LDL scavenger
receptor), in macrophage and smooth muscle cells, are
down-regulated at the transcriptional level by -tocopherol but
not by ß-tocopherol (50)
.
The following questions remain open. In some cases, differential
effects of -tocopherol and ß-tocopherol have been found, pointing
to a nonantioxidant mechanism at the basis of gene regulation
(45
,50)
. In other cases, however, only -tocopherol has
been tested, leaving the mechanism of -tocopherol action
unclarified. Furthermore, the involvement of protein kinase C has not
been assessed in many cases, and it remains to be established whether
the transcriptional regulation of certain genes by -tocopherol is a
direct or indirect consequence of protein kinase C inhibition by
-tocopherol.
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Regulation of Integrated Cellular Functions by -Tocopherol.
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TOPABSTRACTINTRODUCTIONAntioxidant Capacity Can Coexist...Molecular Mechanisms of {alpha}...Regulation of Integrated...Possible Links between In...Final Considerations.REFERENCES |
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-Tocopherol, at concentrations of 50 µmol/L,
inhibits rat A7r5 smooth muscle cell proliferation, whereas
ß-tocopherol is ineffective. When -tocopherol and ß-tocopherol
are added together, no inhibition of cell growth is seen. Both
compounds are transported equally in cells and they do not compete with
each other for the uptake (51)
. The prevention of cell
growth inhibition by -tocopherol by ß-tocopherol suggests a
site-directed event to be at the basis of -tocopherol inhibition
rather than a general radical-scavenging reaction. The oxidized
product of -tocopherol, -tocopherylquinone, is not effective,
indicating that the effects of -tocopherol are not related to its
antioxidant properties (51)
. -Tocopherol is responsible
not only for the proliferation control of smooth muscle cells, but it
exhibits similar functions in a number of different cell lines.
-Tocopherol, -tocopherol and -tocopherol are (within
experimental error) equally inhibitory (24)
. On the other
hand, it appears that the inhibition by ß-tocopherol is 10% of that exhibited by the others compounds. Tocotrienols, although
possessing a greater antioxidant activity than tocopherols
(52)
, inhibit cell proliferation to the same extent
(24)
.
Janero’s (53)
series of 6-hydroxy-chroman-2-carbonitrile
tocopherol derivatives have relative potencies in inhibiting cell
proliferation that are not correlated significantly with their
antioxidant properties (24)
. Probucol, a potent
hydrophobic antioxidant, similar in its general properties to
-tocopherol, has been shown not to inhibit smooth muscle cell
proliferation, but to prevent the inhibition by -tocopherol, as is
the case for ß-tocopherol.
Inhibition of platelet adhesion and aggregation.
It has been shown that -tocopherol inhibits aggregation of human
platelets by a protein kinase C–dependent mechanism both in vitro and
in vivo (30
,54
55
56)
. Another study has indicated that both
- and -tocopherol decrease platelet aggregation and delay
intra-arterial thrombus formation. The fact that -tocopherol was
significantly more potent than -tocopherol suggests that a simple
antioxidant mechanism is not applicable to these effects. In fact,
-tocopherol is much less potent than -tocopherol as an
antioxidant (55)
.
Inhibition of monocyte-endothelial adhesion.
-Tocopherol enrichment of monocytes decreases agonist-induced,
LDL-induced adhesion to human endothelial cells both in vivo and in
vitro (57
,58)
. Monocyte adhesion is paralleled by cell
production of chemokines (59)
. Monocyte as well as
neutrophil diminution of adhesion induced by -tocopherol is
dependent on the inhibition of expression of adhesion molecules
(60)
. These events are relevant to the onset of
inflammation as well as in the early stages of atherogenesis.
Inhibition of production of reactive oxygen species in monocytes and neutrophils.
Inhibition of phorbol ester–induced generation of superoxide by
-tocopherol (31
,61)
has been attributed to protein
kinase C inhibition. On the contrary, vitamin E inhibition of
O2•- production in the promonocyte cell line THP-1
is due essentially to -tocopherol (62)
. -Tocopherol
also inhibits the respiratory burst in human monocytes via a mechanism
involving protein kinase C inhibition (27)
, followed by
attenuation of p47(phox) phosphorylation and membrane translocation
(36
,63)
. These studies provide strong evidence for an
intracellular, antiatherogenic effect of -tocopherol in monocytes.
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Possible Links between In Vitro Cellular Events and
-Tocopherol–Related Disease.
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TOPABSTRACTINTRODUCTIONAntioxidant Capacity Can Coexist...Molecular Mechanisms of {alpha}...Regulation of Integrated...Possible Links between In...Final Considerations.REFERENCES |
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Ataxia with vitamin E deficiency.
This autosomal recessive neurodegenerative disease, whose clinical
presentation is remarkably similar to that of Friedreich ataxia, is
caused by mutations in the gene for -TTP (7
,64
,65)
.
Does protein kinase C activation, due to the very low -tocopherol
level, play a role in the onset of the disorders?
Atherosclerosis.
Low levels of -tocopherol have been associated with increased risk
for coronary artery disease, and increased intake has been shown to be
protective (66)
. This suggests a pathogenetic role for
oxidized LDL and protection by -tocopherol (67)
. The
antiatherogenic effects of -tocopherol may also be related to its
action on crucial cells such as the inhibition of smooth muscle cell
proliferation, preservation of endothelial function, inhibition of
monocyte-endothelial adhesion, inhibition of monocyte reactive
oxygen species and cytokine release, and inhibition of platelet
adhesion and aggregation (29)
.
Cancer.
Prostate and colorectal cancers seem to be affected by -tocopherol
(68
,69)
. This may be related to the antiproliferative
effects observed in vitro.
Diabetes.
In vivo as well as in vitro evidence that vitamin E treatment can
reverse protein kinase C activation, responsible for the
glucose-induced vascular dysfunctions in diabetes, has been
provided (70
71
72)
.
Inflammation.
-Tocopherol inhibits O2•- generation and cell
adhesion (73)
in monocytes and polymorphonuclear cells
(31
,36
,61)
via protein kinase C inhibition
(27)
. These events are central to the inflammatory
process.
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Final Considerations. |
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TOPABSTRACTINTRODUCTIONAntioxidant Capacity Can Coexist...Molecular Mechanisms of {alpha}...Regulation of Integrated...Possible Links between In...Final Considerations.REFERENCES |
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-tocopherol may be
reconciled in large part by the existence of a common denominator,
namely, the described protein kinase C regulation. Some alternative,
but not contrasting interpretations exist concerning the molecular
nature of -tocopherol regulation of protein kinase C. Some other
post-transcriptional effects, such as those related to the
arachidonic acid cascade, are not yet understood in molecular terms.
The possibility of a regulation of several genes by -tocopherol is
the most challenging experimental opportunity for future studies. Here,
the existence of a common denominator (e.g., a receptor protein for
-tocopherol, an -tocopherol sensitive transcription factor or an
-tocopherol sensitive promoter element) has been postulated.
Recently, a new ubiquitous cytosolic -tocopherol binding protein
(TAP) has been discovered (9)
. Structurally, it belongs to
a family of hydrophobic ligand-binding proteins including -TTP,
retinal binding protein, cis-retinal binding protein,
SEC14, PTN 9 and rat secretory protein 45 (74)
. Future
research will be directed to understanding whether this protein has,
alone or in combination with others, -tocopherol–specific receptor
functions.
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FOOTNOTES |
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2 Manuscript received 22 February 2000.
4 Abbreviations used: -TTP, -tocopherol transfer protein; CD36, platelet glycoprotein IV/thrombospondin
receptor/class B scavenger receptor; PP2A, protein phosphatase 2A; ROS, reactive oxygen species; SEC, secretory protein gene products; TAP, -tocopherol associated protein.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONAntioxidant Capacity Can Coexist...Molecular Mechanisms of {alpha}...Regulation of Integrated...Possible Links between In...Final Considerations.REFERENCES |
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