many plant seeds and in the US diet, but has drawn little attention
compared with ?-tocopherol, the predominant form of vitamin E
in tissues and the primary form in supplements. However, recent
studies indicate that ?-tocopherol may be important to human
health and that it possesses unique features that distinguish it
from ?-tocopherol. ?-Tocopherol appears to be a more effective
trap for lipophilic electrophiles than is ?-tocopherol. ?-Toco-
pherol is well absorbed and accumulates to a significant degree
in some human tissues; it is metabolized, however, largely to
which is mainly excreted in the urine. ?-CEHC, but not the cor-
responding metabolite derived from ?-tocopherol, has natriuretic
activity that may be of physiologic importance. Both ?-tocopherol
and ?-CEHC, but not ?-tocopherol, inhibit cyclooxygenase activ-
ity and, thus, possess antiinflammatory properties. Some human
and animal studies indicate that plasma concentrations of ?-toco-
pherol are inversely associated with the incidence of cardiovas-
cular disease and prostate cancer. These distinguishing features of
?-tocopherol and its metabolite suggest that ?-tocopherol may
contribute significantly to human health in ways not recognized
previously. This possibility should be further evaluated, espe-
cially considering that high doses of ?-tocopherol deplete plasma
and tissue ?-tocopherol, in contrast with supplementation with
?-tocopherol, which increases both. We review current information
on the bioavailability, metabolism, chemistry, and nonantioxidant
activities of ?-tocopherol and epidemiologic data concerning
the relation between ?-tocopherol and cardiovascular disease
Am J Clin Nutr 2001;74:714–22.
?-Tocopherol is the major form of vitamin E in
metabolism, electrophile trap, antiinflammatory activity,
cardiovascular disease, cancer, review
?-Tocopherol, ?-tocopherol, bioavailability,
Oxidative damage is a major contributor to the development of
cancer, cardiovascular disease (CVD), and neurodegenerative dis-
orders (1, 2). Antioxidant vitamins defend against oxidative
injury and are therefore believed to provide protection against
various diseases. ?-Tocopherol is quantitatively the major form of
vitamin E in humans and animals and has been extensively stud-
ied. In contrast, ?-tocopherol—although being the most abundant
form of vitamin E in the US diet—has received little attention
since the discovery of vitamin E in 1922 and is not included in
the current dietary intake recommendations (3). This is mainly
because the bioavailability and bioactivity of ?-tocopherol, as
assessed in animal studies, are lower than those of ?-tocopherol.
However, in contrast with the previous assumption that ?-toco-
pherol is not important because it is not maintained at the same
concentrations as is ?-tocopherol in the body, recent evidence
suggests that ?-tocopherol has properties that may be important
to human health and that are not shared by ?-tocopherol. The
qualities that distinguish ?-tocopherol from ?-tocopherol are
likely a result of its distinct chemical reactivity, metabolism,
and biological activity. In this review we summarize the current
knowledge of ?-tocopherol’s bioavailability, metabolism, chem-
istry, nonantioxidant activity, and role in human diseases, with an
emphasis on aspects that distinguish it from ?-tocopherol.
STRUCTURE OF TOCOPHEROLS AND THEIR MAJOR
Vitamin E occurs in nature in ≥8 structurally related forms, ie,
4 tocopherols (?, ?, ?, and ?) and 4 tocotrienols (?, ?, ?, and ?)
(Figure 1), all of which are potent membrane-soluble antioxi-
dants. Tocopherols have a saturated phytyl side chain with 3 chi-
ral centers that are in an R configuration (designated as * in Fig-
ure 1) at positions 2, 4?, and 8? in the naturally occurring forms.
Tocopherols differ in the number of methyl groups they have at
the 5- and 7-positions of the chromanol ring. For instance, ?-toco-
pherol is unsubstituted at the C-5 position, whereas ?-tocopherol is
fully substituted in the chromanol ring. It is now clear that all
Am J Clin Nutr 2001;74:714–22. Printed in USA. © 2001 American Society for Clinical Nutrition
?-Tocopherol, the major form of vitamin E in the US diet, deserves
Qing Jiang, Stephan Christen, Mark K Shigenaga, and Bruce N Ames
1From the University of California, the Department of Molecular and Cell
Biology, Berkeley; the Children’s Hospital Oakland Research Institute, Oak-
land, CA; and the Institute for Infectious Diseases, University of Berne,
2Supported by a Postdoctoral Fellowship from the American Heart Asso-
ciation–Western Affiliates (grant 98-24 to QJ); the Swiss National Science
Foundation (grant 31-52702 to SC); the Wheeler Fund for the Biological Sci-
ences at the University of California, Berkeley; the Department of Energy
(grant DE-FG03-00ER62943); and the National Institute of Environmental
Sciences Center (grant ES01896 to BNA).
3Address reprint requests to BN Ames, Children’s Hospital Oakland
Research Institute, 5700 Martin Luther King Jr Way, Oakland, CA 94609-1673.
Received April 17, 2001.
Accepted for publication June 22, 2001.
at UNIVERSITAT BERN on September 28, 2012
tocopherols, and possibly all tocotrienols (4, 5), share a similar
degradation pathway that involves oxidation of the phytyl chain to
the corresponding hydrophilic metabolites without modification of
the chromanol ring (6–8). It was estimated, in unsupplemented
humans, that 50% of ?-tocopherol is converted to the water-soluble
(?-CEHC) and is then excreted into the urine (9).
SOURCE, BIOAVAILABILITY, AND BIOACTIVITY
Because humans and animals do not synthesize their own vita-
min E, they primarily acquire tocopherols from plants, which are
the only species capable of making vitamin E. ?-Tocopherol is
often the most prevalent form of vitamin E in plant seeds and in
products derived from them (10). Vegetable oils such as corn,
soybean, and sesame, and nuts such as walnuts, pecans, and
peanuts are rich sources of ?-tocopherol (10). Because of the
widespread use of these plant products, ?-tocopherol represents
?70% of the vitamin E consumed in the typical US diet (10).
In contrast, ?-tocopherol is the predominant form of vitamin E
in most human and animal tissues, including blood plasma. In
rats, ?-tocopherol concentrations are generally much higher
than those of ?-tocopherol (11, 12) (Table 1). In humans, plasma
?-tocopherol concentrations are generally 4–10 times higher
than those of ?-tocopherol (13). Studies that report ?-tocopherol
concentrations in human tissues other than plasma are rare and
mostly limited to adipose tissue (17). However, Burton et al (14)
reported that ?-tocopherol constitutes as much as 30–50% of the
total vitamin E in human skin, muscle, vein, and adipose tissue.
Importantly, ?-tocopherol concentrations in these tissues appear
to be 20–40-fold greater than those in plasma (14) (Table 1). Fur-
thermore, ?-tocopherol concentrations are substantially higher
in human than in rodent tissues. For example, concentrations of
?-tocopherol in human skin and muscle, ie, 180 and 107 nmol/g
tissues, respectively, are 20–50-fold higher than those measured
in rodents (Table 1) (15, 16). In addition, it is well documented
that plasma and tissue ?-tocopherol are suppressed by ?-toco-
pherol supplementation (17, 18). In sharp contrast, ?-tocopherol
supplementation leads to a marked increase in both tocopherols
(11). The difference in ?-tocopherol concentrations between
humans and rodents and ?-tocopherol’s depression of ?-toco-
pherol are likely associated with ?-tocopherol’s metabolism; this
topic will be discussed in the next section of this review.
The biological activity of vitamin E has traditionally been
determined with use of the rat fetal resorption assay, in which
such activity is defined as the ability of supplemented tocopherol
or tocotrienol to prevent embryo death in mothers depleted of
vitamin E (19). In this assay, ?-tocopherol exhibits the highest
biological vitamin E activity, whereas ?-tocopherol exhibits only
?10–30% of the activity of ?-tocopherol (19). This difference in
activity, however, appears to be caused by the large difference in
retention of ?- and ?-tocopherol in rodents, which is reflected by
the lower plasma and tissue concentrations of ?-tocopherol than
of ?-tocopherol, a consequence that can also be explained by
their different metabolisms.
ABSORPTION AND METABOLISM OF ?-TOCOPHEROL
The utilization of deuterium-labeled tocopherols (mainly ?- and
?-tocopherol) has greatly facilitated our understanding of the
REVIEW OF ?-TOCOPHEROL715
FIGURE 1. Chemical structures of vitamin E and urinary degrada-
tion products. *Chiral centers that are in an R configuration in toco-
pherols and tocotrienols and in an S configuration in their metabolites.
Concentrations of ?- and ?-tocopherol in the plasma and tissues of humans and rodents
Rats and mice2
440 ± 279
155 ± 163
127 ± 74
29.5 ± 4.1
3.0 ± 2.8
79.8 ± 6.9
8.9 ± 3.0
176 ± 80
180 ± 89
1Data from references 13 and 14.
2Data from reference 15 and 16. The animals were fed diets with a ratio of ?- to ?-tocopherol of 2:1, 40–60 and 20–30 mg/kg, respectively.
3Data for rodents from reference 15.
4Data for rodents from reference 16. These mice were fed a diet containing 30 mg ?-tocopherol/kg and ?9 mg ?-tocopherol/kg.
at UNIVERSITAT BERN on September 28, 2012
absorption and transport of tocopherols, as documented in an
excellent review by Kayden and Traber (20). The recently increas-
ing interest in the study of tocopherol metabolism has led to a
rapid expansion of our knowledge in this area. We summarize the
current knowledge of the absorption and metabolism of ?- and
?-tocopherol in Figure 2. Both ?- and ?-tocopherol and dietary
fat are taken up without preference by the intestine and secreted in
chylomicron particles together with triacylglycerol and choles-
terol. The nearly identical incorporation of ?- and ?-tocopherol
in chylomicrons after supplementation with equal amounts of the
2 tocopherols indicates that their absorption is not selective
(20, 21). During the subsequent lipoprotein lipase–mediated
catabolism of chylomicron particles, some of the chylomicron-
bound vitamin E appears to be transported and transferred to
peripheral tissues such as muscle, adipose, and brain (22). The
resulting chylomicron remnants are subsequently taken up by the
liver, where ?-tocopherol is preferentially reincorporated into
nascent VLDLs by ?-tocopherol transfer protein (?-TTP) (21),
which enables further distribution of ?-tocopherol throughout the
body. However, ?-tocopherol appears to be degraded largely to the
hydrophilic ?-CEHC (7) by a cytochrome P450–dependent
process (23) and is then primarily excreted into urine (9). Catabo-
lism of ?-tocopherol by this route appears to be quantitatively
much less important than that of ?-tocopherol because the corre-
sponding metabolite of ?-tocopherol, ?-CEHC, is excreted in
large amounts only when the daily intake of ?-tocopherol exceeds
150 mg (6) or plasma concentrations of ?-tocopherol are above a
threshold of 30–40 ?mol/L (24). Even then, urinary excretion of
?-CEHC is lower than that of ?-CEHC (25, 26).
?-CEHC was originally discovered by Wechter et al (7) in the
pursuit of identifying an endogenous natriuretic factor in human
urine. They showed that ?-CEHC possesses natriuretic activity
by way of inhibition of the 70 pS potassium channel in the thick
ascending limb cells of the kidney, whereas ?-CEHC does not
exhibit any appreciable activity (7, 27). In a radioisotope tracing
study, the same investigators unambiguously established that
?-CEHC is derived from naturally occurring RRR-?-tocopherol.
Using X-ray crystallographic analysis, they showed that ?-CEHC
has an S(+) stereochemistry at the C-2 position, indicating that
phytyl-chain oxidation of RRR-?-tocopherol is not accompanied
by racemization (28). Although 5?-carboxychroman was sub-
sequently identified as another metabolite in cell culture super-
natant fluid and human urine, ?-CEHC appears to be quantitatively
far more important (29). Plasma ?-CEHC concentrations are
reported to be 50–100 nmol/L in humans (26) and >300 nmol/L
in rats (30). In human urine, ?-CEHC exists predominantly as a
glucuronide conjugate with concentrations ranging from 4 to
33 ?mol/L (9), which increase to >100 ?mol/L after supple-
mentation with ?-tocopherol (29).
Recent work by Parker et al (23) strongly suggests that the
degradation of tocopherols is a cytochrome P450 3A–dependent
process because ketoconazole, a specific inhibitor of this
enzyme, markedly reduced accumulation of tocopherol metabo-
lites in the supernatant fluid of cultured hepatocytes supplemented
with tocopherols. The codetection of both 3?-(?-CEHC) and
5?-carboxylate metabolites, products thought to be derived
from ?-oxidation followed by ?-oxidation of the phytyl side
chain, is also consistent with a cytochrome P450–mediated
mechanism (6, 29). Parker et al (23) also showed that sesamin,
the sesame lignan, inhibited ?-CEHC formation in this system,
most likely as a result of the inhibition of cytochrome P450 activ-
ity. This observation provides an explanation for the previous
finding by Yamashita et al (31, 32) that rats fed a diet contain-
ing both ?-tocopherol and sesame seeds or sesame lignans have
plasma and liver concentrations of ?-tocopherol comparable
with those of ?-tocopherol. In the sesame seed– or sesame lig-
nan–treated rats, ?-tocopherol and ?-tocopherol similarly
inhibited lipid peroxidation, erythrocyte hemolysis, and liver
In summary, the biological disposition and retention of ?-toco-
pherol appear to be regulated by a metabolism that is quite differ-
ent from that of ?-tocopherol (Figure 2). Chylomicron-associated
716JIANG ET AL
FIGURE 2. Absorption, transport, and metabolism of ?-tocopherol (?-T) and ?-tocopherol (?-T) in peripheral tissues (eg, muscle and adipose). 1)
Both ?-T and ?-T are similarly absorbed by the intestine along with dietary fat and are secreted into chylomicron particles. 2) Some of the chylomicron-
bound vitamin E is transported to peripheral tissues with the aid of lipoprotein lipase. 3) The resulting chylomicron remnants are subsequently taken up
by the liver. 4) In the liver, most of the remaining ?-T but only a small fraction of ?-T is reincorporated into nascent VLDLs by ?-tocopherol transfer
protein (?-TTP). 5) Substantial amounts of ?-T are probably degraded by a cytochrome P450 3A–mediated reaction to 2,7,8-trimethyl-2-(?-car-
boxyethyl)-6-hydroxychroman (?-CEHC). 6) Plasma vitamin E is further delivered to tissues by LDL and HDL. 7) ?-CEHC is excreted into urine.
at UNIVERSITAT BERN on September 28, 2012
tissue uptake of vitamin E, which occurs before liver metabolism,
is possibly important for the accumulation of ?-tocopherol in skin,
adipose, and muscle tissue. This could explain the strong correla-
tion in humans between dietary ?-tocopherol uptake and ?-toco-
pherol concentrations in these tissues (14). However, hepatic
catabolism of ?-tocopherol appears to be responsible for the rela-
tively low preservation of ?-tocopherol in plasma and tissues,
whereas ?-TTP-mediated ?-tocopherol transfer plays a key role in
the preferential enrichment of ?-tocopherol in most tissues. It is
possible that ?-TTP maintains the ?-tocopherol concentration not
only by facilitating its reincorporation into nascent VLDLs but
also by preventing it from being catabolized (21, 33, 34). This is
in contrast with ?-tocopherol, which appears to be largely
degraded by cytochrome P450 once it enters the liver. Evidence
supporting this possibility includes the findings that both ?- and
?-tocopherol are similarly degraded by cytochrome P450–mediated
catabolism in cultured hepatocytes (23) and that patients with an
?-TTP defect have substantially lower plasma concentrations of
?-tocopherol than do individuals with no such defect.
Schuelke et al (24) recently reported that patients with an ?-TTP
defect have enhanced urinary excretion of ?-CEHC despite their
having much lower plasma ?-tocopherol concentrations than do
healthy control subjects. In some of these patients, the reincorpo-
ration of RRR-?-tocopherol into VLDLs is not preferred to other
stereoisomers, such as SRR-?-tocopherol (35), in contrast with
healthy individuals who preferentially enrich RRR-?-tocopherol,
presumably by hepatic ?-TTP (21). The observation that supple-
mentation of ?-tocopherol depletes plasma and tissue ?-tocopherol
is likely also rooted in ?-TTP’s preferential affinity for ?-toco-
pherol. This is likely because an increase in ?-tocopherol may fur-
ther reduce ?-tocopherol’s incorporation into VLDLs, which con-
sequently leaves more ?-tocopherol to be degraded by cytochrome
P450. On the other hand, ?-tocopherol supplementation may spare
?-tocopherol from being degraded, which would explain why
?-tocopherol supplementation results in an increase in ?-toco-
pherol concentrations (11). In addition, cytochrome P450 activity
appears to be important in determining plasma and tissue concen-
trations of ?-tocopherol. The observation that rodents and humans
often have substantially different P450 activities (36) may partially
explain the finding that rats have lower ?-tocopherol concentra-
tions (12) but higher ?-CEHC concentrations in plasma (30) than
do humans (26). This possibility requires further investigation.
Finally, in addition to the urinary excretion of ?-tocopherol as
?-CEHC, biliary excretion may be an alternative route for eliminat-
ing excess ?-tocopherol, as proposed earlier (37). This notion is also
supported by the fact that the ratio of ?- to ?-tocopherol in bile is
severalfold higher than that in plasma (31, 37, 38). Excess ?-toco-
pherol secreted into feces during supplementation may play a role
in eliminating fecal mutagens and thus reduce colon cancer (38, 39).
CHEMISTRY OF ?-TOCOPHEROL
The antioxidant activity of tocopherols is rooted in their abil-
ity to donate phenolic hydrogens (electrons) to lipid radicals.
Because of its lack of one of the electron-donating methyl
groups on the chromanol ring, ?-tocopherol is somewhat less
potent in donating electrons than is ?-tocopherol and is, thus, a
slightly less powerful antioxidant (40). Thus, ?-tocopherol is
generally considered to be more potent than is ?-tocopherol as a
chain-breaking antioxidant for inhibiting lipid peroxidation (40).
However, the unsubstituted C-5 position of ?-tocopherol appears
to make it better able to trap lipophilic electrophiles such as
reactive nitrogen oxide species (RNOS). Excess generation of
RNOS is associated with chronic inflammation-related diseases
such as cancer, CVD, and neurodegenerative disorders (1, 2).
RNOS formed during inflammation include peroxynitrite (41),
nitrogen dioxide, and nitrogen dioxide–like species generated
from myeloperoxidase or superoxide dismutase (SOD)-H2O2-NO2
(42–44). In pioneering studies, Cooney et al (45, 46) found that
?-tocopherol is superior to ?-tocopherol in detoxifying nitrogen
dioxide. They showed that reaction of ?-tocopherol with nitro-
gen dioxide leads to the formation of a nitrosating intermediate
that, in turn, generates nitroso products. In contrast, they also
showed that ?-tocopherol reduces nitrogen dioxide to the less
harmful nitric oxide or traps nitrogen dioxide to form 5-nitro-
?-tocopherol (5-N?-T), analogous to the nitration of tyro-
REVIEW OF ?-TOCOPHEROL717
FIGURE 3. Main reactions of ?-tocopherol (?-T) and ?-tocopherol (?-T) with oxygen radicals and nitrogen oxide species. 5-N?-T, 5-nitro-?-tocopherol.
at UNIVERSITAT BERN on September 28, 2012
sine (Figure 3) (45, 46). Subsequently, we (47) and Hoglen et al
(48) showed that ?-tocopherol was also nitrated by peroxynitrite
and 3-morpholinosydnonimine. Because the chromanol ring of
?-tocopherol is fully substituted, this form of vitamin E cannot
form a stable nitro adduct (45, 47).
The most important reactions of ?- and ?-tocopherol with
electron-abstracting oxidants, eg, lipid peroxyl radicals and
RNOS, are summarized in Figure 3. In vitro mechanistic studies
established that under physiologically relevant conditions, per-
oxyl radicals or peroxynitrite mainly oxidizes ?-tocopherol
to 8a-hydroxy-?-tocopherone, which is then hydrolyzed to
?-tocopherol quinone (?-TQ) (47, 49). Depending on the nature
of the oxidant, oxidation of ?-tocopherol, however, leads to the
production of both ?-TQ, the analogue of ?-TQ, and of 5-substi-
tuted products including tocored and 5-N?-T (47, 48). Reaction
of ?-tocopherol with the strong electrophile peroxynitrite or
SIN-1 primarily generates 5-N?-T and tocored (47, 48), whereas
?-TQ is predominant in the reaction with NO2
nitrating agent but also a potent 2-electron oxidant.
We observed that the yield of 5-N?-T generated during liposo-
mal peroxidation initiated by peroxynitrite or 3-morpholinosyd-
nonimine was independent of the presence of ?-tocopherol, sug-
gesting that ?-tocopherol may complement ?-tocopherol in
scavenging membrane-soluble RNOS (47). However, this conclu-
sion was later questioned by Goss et al (50), who found that
5-N?-T could only be detected after ?-tocopherol had been
almost completely consumed. Although the reasons for these
apparently discrepant findings are not entirely clear, it is likely that
they reflect differences in experimental conditions, such as the use
of saturated liposomes in some studies (50) and unsaturated lipo-
somes in others (47). Nevertheless, nitration of ?-tocopherol is
more extensive than that of tyrosine when LDL is treated with per-
oxynitrite (47) or when nitration is initiated by SOD-H2O2-NO2
(42). This is most likely a consequence of a higher reactivity of
?-tocopherol toward electrophilic RNOS (47) and the increased
solubility of RNOS in lipid membranes. 5-N?-T was therefore
proposed as another marker, in addition to 3-nitrotyrosine, for
detecting the formation of RNOS (51, 52). Whether nitration of
?-tocopherol is a physiologically relevant process and occurs even
in the presence of ?-tocopherol can only be determined by in vivo
experiments in which adequate analytic methods are used.
Hensley et al (51) recently reported an HPLC method for meas-
uring 5-N?-T in which coulometric array detection is used. Using
this method, they reported an increase in 5-N?-T (both unadjusted
and adjusted for ?-tocopherol) in rat astrocytes stimulated with bac-
terial lipopolysaccharide. We recently developed a highly sensitive
HPLC assay with electrochemical detection in which tissue 5-N?-T
can be measured simultaneously with ?-tocopherol, ?-toco-
pherol, and unesterified cholesterol (S Christen, Q Jiang, MK Shi-
genaga, BN Ames, unpublished observations, 1998). Using this
method, we detected a significant 2-fold increase in ?-toco-
pherol–adjusted plasma 5-N?-T in a rat model of zymosan-induced
peritonitis, even in the presence of high plasma ?-tocopherol con-
centrations (53). Surprisingly, the level of ?-tocopherol nitration,
even under basal conditions, was in the low percentage range. In
contrast, nitration of protein-bound tyrosine generally ranges within
parts per million. This may be an indication of the preferred loca-
tion of RNOS, such as nitrogen dioxide, in lipid environments.
Clearly, further studies that consider the metabolism of both ?-toco-
pherol and nitrated ?-tocopherol (eg, urinary excretion) are needed
to clarify the role of ?-tocopherol as an RNOS scavenger in vivo.
? (48), a
The precise location of ?- and ?-tocopherol in the lipid envi-
ronment may be partially responsible for their different reactivi-
ties. The lack of a methyl group makes ?-tocopherol relatively
less hydrophobic, which may affect its location and interaction
with lipids and aqueous-phase components. Although evidence
supporting this hypothesis is sparse, the contradictory finding
that the protective effect of ?- and ?-tocopherol on lipid peroxi-
dation was different in liposomes and LDLs is somewhat
supportive. Thus, ?-tocopherol inhibited peroxynitrite- and SIN-
1–induced lipid peroxidation in liposomes to a greater degree
than did ?-tocopherol, whereas ?-tocopherol offered better pro-
tection in LDL (47). A superior effect of ?-tocopherol was also
observed when lipid peroxidation was initiated by peroxynitrite
in brain homogenates (54). ?-Tocopherol is predominantly
located in the biomembrane of brain homogenates, which have a
lipid arrangement similar to that of the liposome model. Differ-
ences in the liposomal and LDL particle lipid environments and
the arrangement of tocopherol species within these particles
could play an important role in the protective effects observed,
the understanding of which requires further investigation.
The effect of lipid microenvironment on the chemical reactiv-
ity and biological consequence of tocopherols is also evident in
tocopherol-mediated lipid peroxidation, a phenomenon that
was discovered and studied by Upston et al (55). In this respect,
?-tocopherol has less potent prooxidant (tocopherol-mediated
lipid peroxidation) activity than does ?-tocopherol because it
contains a less active phenolic hydrogen molecule and a rela-
tively more stable phenolic radical (56).
Besides its well-known chain-breaking antioxidant activity,
?-tocopherol at concentrations of 50–100 ?mol/L were shown
by Tasinato et al (57) to inhibit smooth muscle cell proliferation
by inhibiting protein kinase C activity. Although both ?-toco-
pherol and ?-tocopherol exhibit a similar antiproliferative
effect, ?-tocopherol does not share this activity (58), indicating
that this effect is independent of antioxidant activity. Because
smooth muscle cell proliferation plays an important role in the
development of atherosclerosis, the potential benefit of vitamin E
in preventing CVD may partially stem from its ability to inhibit
smooth muscle cell proliferation.
Recently, we found that both ?-tocopherol and ?-CEHC possess
antiinflammatory activity (59): ?-tocopherol and ?-CEHC inhibit
prostaglandin E2synthesis in lipopolysaccharide-stimulated
macrophages and in interleukin 1? (IL-1?)–activated epithelial
cells at an IC50(ie, the concentration that causes a 50% reduction)
of 4–10 ?mol ?-tocopherol/L and ?30 ?mol ?-CEHC/L, respec-
tively. In contrast, ?-tocopherol has no effect at these concentra-
tions. We further showed that ?-tocopherol and ?-CEHC directly
inhibit cyclooxygenase-2 (COX-2) activity in intact cells but do
not affect expression of COX-2 protein. Similarly to the antipro-
liferative effect of ?-tocopherol, this antiinflammatory property
of ?-tocopherol is yet another effect of vitamin E that is inde-
pendent of antioxidant activity. Because chronic inflammation
contributes to the development of degenerative diseases, the anti-
inflammatory activity of ?-tocopherol and its major water-soluble
metabolite may be important in human disease prevention.
Human colon cancer, for example, is associated with an elevated
expression of COX-2 and formation of prostaglandin E2(60). In
addition, frequent use of nonsteroidal antiinflammatory drugs
718JIANG ET AL
at UNIVERSITAT BERN on September 28, 2012
reduces the incidence of colon cancers (61–63). Interestingly,
Cooney et al (45) found that ?-tocopherol is superior to ?-toco-
pherol in inhibiting neoplastic transformation of C3H/10T1/2 cells.
The antiinflammatory activity of ?-tocopherol could partially
explain this difference in potency.
A recent study by Sjoholm et al (64) found that ?-tocopherol
(10 ?mol/L), but not ?-tocopherol, partially protected insuli-
noma ? cells (RINm5F cells) against IL-1?–induced decreases
in cell viability, insulin production, and stimulation of insulin
release in response to certain stimuli. These effects were attrib-
uted to the superiority of ?-tocopherol in detoxifying RNOS
(64). However, it was reported that IL-1? treatment leads to an
induction of COX-2 expression and enhancement of PGE2
release in RINm5F cells (65) and that COX-2 inhibitors protect
against the autoimmune destruction of ? cells (66). In light of
our recent finding that ?-tocopherol inhibits COX-2 activity (59),
the abovementioned protective effects of ?-tocopherol may also
be partially due to its antiinflammatory activity. In any event,
these results suggest that ?-tocopherol may play a role in pre-
venting type 1 diabetes, a devastating complication that affects
millions of Americans.
?-TOCOPHEROL AND CARDIOVASCULAR DISEASE
Potentially beneficial effects of vitamin E on CVD were inten-
sively explored in many intervention and epidemiologic studies
(67,68),which were recently reviewed in the latest Dietary Reference
Intakes for Vitamin C, Vitamin E, Selenium and Carotenoids (3).
Most of these studies focused exclusively on ?-tocopherol but
made no firm conclusions about the protective effects of
?-tocopherol supplementation on CVD (67, 68). Although much
less is known about ?-tocopherol than about ?-tocopherol, much
evidence suggests that ?-tocopherol may be important in the
defense against CVD. First, several investigations found that
plasma ?-tocopherol concentrations are inversely associated with
increased morbidity and mortality due to CVD. Ohrvall et al
(69) and Kontush et al (70) reported that serum concentrations
of ?-tocopherol, but not of ?-tocopherol, were lower in CVD
patients than in healthy control subjects. In a concomitant cross-
sectional study of Swedish and Lithuanian middle-aged men,
Kristenson et al (71) found that plasma ?-tocopherol concentra-
tions were twice as high in the Swedish men, but that the Swedish
men had a 25% lower incidence of CVD-related mortality. In
contrast, this inverse correlation was not observed with ?-toco-
pherol. Second, in a 7-y follow-up study of 34486 postmenopausal
women, Kushi et al (72) concluded that the intake of dietary vita-
min E (mainly ?-tocopherol), but not of supplemental vitamin E
(mainly ?-tocopherol), was significantly inversely associated
with increased risk of death by CVD. Recently, these investiga-
tors further showed that dietary vitamin E was associated with a
reduced incidence of death from stroke in postmenopausal
women (73). In contrast, Stampfer et al (74) reported a signifi-
cantly reduced risk of CVD associated with a high ?-tocopherol
intake from supplements but not from dietary vitamin E.
Although the reasons for this discrepancy are not clear, the over-
all dietary vitamin E (presumably mainly ?-tocopherol) intake
in both studies was much lower than the total intake among
supplement users. Finally, it was reported that the regular con-
sumption of nuts, which are an excellent source of ?-tocopherol,
lowers the risk of myocardial infarction and death from ischemic
heart disease (75).
In addition to the above-cited human studies, several animal
studies also provide some evidence that ?-tocopherol might be
beneficial against CVD. Saldeen et al (76) investigated the
effects of ?- and ?-tocopherol supplementation on platelet aggre-
gation and thrombosis in Sprague Dawley rats. They found that
?-tocopherol supplementation led to a more potent decrease in
platelet aggregation and delay of arterial thrombogenesis than
did ?-tocopherol supplementation (76). ?-Tocopherol supple-
mentation also resulted in stronger ex vivo inhibition of super-
oxide generation, lipid peroxidation, and LDL oxidation. In a
follow-up study, this same group reported that ?-tocopherol was
significantly more potent than was ?-tocopherol in enhancing
SOD activity in plasma and arterial tissue and in increasing the
arterial protein expression of both manganese SOD and Cu/Zn
SOD (77). Furthermore, although both tocopherols increased
nitric oxide generation and endothelial nitric oxide synthase
activity, only ?-tocopherol supplementation resulted in increased
protein expression of this enzyme (77). Because endothelium-
derived nitric oxide is a key regulator of vascular homeostasis,
up-regulation of endothelial nitric oxide synthase and nitric
oxide formation by ?-tocopherol could be important in prevent-
ing vascular endothelial dysfunction (78). Together, the above-
mentioned human and animal studies seem to warrant further
investigations into the role of ?-tocopherol in CVD.
?-TOCOPHEROL, CANCER, AND SMOKING
Recent epidemiologic studies also showed both positive and
negative correlations between plasma concentrations of ?-toco-
pherol and the risk of cancer. Nomura et al (79) showed that serum
concentrations of ?-carotene, ?-carotene, total carotenoids, and
?-tocopherol, but not of ?-tocopherol, were significantly lower in
patients with upper aerodigestive tract cancers than in control
subjects. These investigators observed a statistically nonsignifi-
cantly lowered risk of prostate cancer in Japanese American men
with relatively high serum ?-tocopherol concentrations in another
study (80). Giuliano et al (81) reported that serum concentrations
of ?- and ?-tocopherol were 24% lower in women with persis-
tently positive papillomavirus infection, which is a high-risk
index of cervical cancer. Recently, Helzlsouer et al (82) con-
ducted a nested case-control study to examine the association of
?-tocopherol, ?-tocopherol, and selenium with the incidence of
prostate cancer. The most striking finding was that men in the
highest quintile of plasma ?-tocopherol concentrations had a
5-fold reduction in the risk of prostate cancer compared with
those in the lowest quintile. Interestingly, they also found that
significant protective effects of high concentrations of selenium
and ?-tocopherol were only observed when ?-tocopherol concen-
trations were high. In contrast, higher serum ?-tocopherol con-
centrations were observed in patients with invasive cervical
cancer than in control subjects (83). Zheng et al (84) reported a
positive correlation of serum ?-tocopherol and selenium concen-
trations with the risk of oral and pharyngeal cancer.
Plasma ?-tocopherol concentrations are also affected by
smoking, which is associated with the production of RNOS. We
recently observed significantly higher plasma ?-tocopherol con-
centrations in smokers than in nonsmokers matched for dietary
antioxidant intake, whereas no difference was found in ?-toco-
pherol concentrations (85). In contrast, a study by Brown (86)
showed that plasma ?-tocopherol concentrations were lower in
smokers than in nonsmokers, albeit in a small cohort. Interest-
REVIEW OF ?-TOCOPHEROL719
at UNIVERSITAT BERN on September 28, 2012
ingly, ?-tocopherol concentrations rapidly increased when long-
term smokers ceased to smoke; however, as in the aforementioned
study, no significant changes were observed in plasma ?-toco-
Many confounding factors could be responsible for some of
these apparent discrepancies. For example, because dietary
?-tocopherol is always associated with high fat intake, which in
turn is believed to be connected to many diseases, the high lipid
content in foods could impede the beneficial effect of ?-toco-
pherol. Hence, a match of dietary intake between case and con-
trol subjects is mandatory in future studies. In addition, because
?-tocopherol metabolism may be altered under oxidative stress,
plasma ?-tocopherol concentrations may not directly reflect its
dietary intake. For instance, it was reported that cytochrome P450
activity is inhibited by interleukins and other proinflammatory
cytokines (87, 88), which would thus lead to decreased degra-
dation of ?-tocopherol and increased plasma ?-tocopherol con-
centrations. Other variables such as the type of cancer and the
kinetics (or timeline) of the development of specific diseases
may also affect the metabolism of ?-tocopherol. It is therefore
conceivable that a true association between ?-tocopherol intake
and cancer risk may be established only when these factors are
further understood and fully considered.
?-TOCOPHEROL AND AGING
Only a few studies have been conducted to evaluate the rela-
tion between ?-tocopherol and aging. Vatassery et al (89) reported
that age is associated with a significant decline in the plasma
concentration of ?-tocopherol but not of ?-tocopherol. However,
platelet concentrations of both tocopherols decrease with age.
Studies by Lyle et al (90) showed that the sum of serum ?- and
?-tocopherol, but neither tocopherol alone, was inversely associ-
ated with the incidence of age-related nuclear cataracts. The rea-
sons for these observations and the biological significance of
these findings are not known.
SUMMARY AND OUTLOOK
It has been ?80 y since vitamin E was discovered as an essen-
tial element for maintaining reproduction in vertebrates, and yet
we are just beginning to understand its physiologic functions and
potential benefits in human health. Despite the fact that various
forms of vitamin E have been identified, ?-tocopherol is the only
form that has been extensively studied and is present in most
supplements. ?-Tocopherol, being the major form of vitamin E
in many plant seeds, is unique in many aspects. Compared with
?-tocopherol, ?-tocopherol is a slightly less potent antioxidant
with regard to electron-donating propensity but is superior in
detoxifying electrophiles such as RNOS, partially because of its
ability to form a stable nitro adduct, 5-N?-T. ?-Tocopherol is
well absorbed and accumulates to a significant degree in some
human tissues, but it is also rapidly metabolized to the water-sol-
uble metabolite ?-CEHC. ?-CEHC, but not ?-CEHC, exhibits
natriuretic activity, which may be physiologically important. In
addition, ?-tocopherol and ?-CEHC, in contrast with ?-toco-
pherol, possess antiinflammatory activity. Results from recent
epidemiologic studies suggest a potential protective effect of
?-tocopherol against CVD and prostate cancer. These unique
properties of ?-tocopherol and its major metabolite raise signifi-
cant questions about the traditional definition of vitamin E activity,
which has been almost exclusively based on the results obtained
from the rat fetal resorption assay and which has been used as
the primary argument that ?-tocopherol is the only important
form of vitamin E. We propose that although ?-tocopherol is cer-
tainly a very important, if not the most important, component of
vitamin E, ?-tocopherol may contribute significantly to human
health in ways that have not yet been recognized. Because large
doses of ?-tocopherol are known to deplete plasma and tissue
?-tocopherol, it is our opinion that this possibility should be con-
sidered and carefully evaluated.
Controlled intervention studies in humans are required to clearly
establish the benefits of ?-tocopherol supplementation (91). Cel-
lular research combined with animal supplementation studies
should be valuable in helping to understand the mechanisms
behind the biological effects of ?-tocopherol. Potential synergis-
tic effects between ?-tocopherol and other antioxidants should
also be explored. These efforts should help to clarify the role of
?-tocopherol in human health.
We thank MG Traber, DC Liebler, AM Papas, and RV Cooney for critical
comments on the manuscript.
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