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Nutrition Research Reviews (2006), 19, 174–186 DOI: 10.1017/NRR2006125
q The Author 2006
Bioactivity of vitamin E
Regina Brigelius-Flohé
Department of Biochemistry of Micronutrients, German Institute of Human Nutrition
Potsdam-Rehbrücke, Arthur-Scheunert-Allee 114-116, D-14558 Nuthetal, Germany
More than 80 years after the discovery of the essentiality of vitamin E for mammals, the molecular
basis of its action is still an enigma. From the eight different forms of vitamin E, only a-tocopherol
is retained in the body. This is in part due to the specific selection of RRR-a-tocopherol by the
a-tocopherol transfer protein and in part by its low rate of degradation and elimination compared
with the other vitamers. Since the tocopherols have comparable antioxidant properties and some
tocotrienols are even more effective in scavenging radicals, the antioxidant capacity cannot be the
explanation for its essentiality, at least not the only one. In the last decade, a high number of so-
called novel functions of almost all forms of vitamin E have been described, including regulation of
cellular signalling and gene expression. a-Tocopherol appears to be most involved in gene
regulation, whereas g-tocopherol appears to be highly effective in preventing cancer-related
processes. Tocotrienols appear to be effective in amelioration of neurodegeneration. Most of the
novel functions of individual forms of vitamin E have been demonstrated in vitro only and require
in vivo confirmation. The distinct bioactivities of the various vitamers are discussed, considering
their metabolism and the potential functions of metabolites.
Vitamin E: Bioactivity: a-Tocopherol: Vitamers: Antioxidants
Introduction The reason for the high efficacy of RRR-a-tocopherol is
obviously its preferential retention in the organism. Whereas
Vitamin E is a family of eight compounds, a-, b-, g- and
in the intestine all forms of vitamin E are absorbed without
d-tocopherol and a-, b-, g- and d-tocotrienol (Fig. 1), with
discrimination, in the liver only a-tocopherol is sorted out by
a-tocopherol being the predominant form in mammals (for the a-tocopherol transfer protein (a-TTP) for incorporation
reviews, see Burton & Traber, 1990; Brigelius-Flohé & into VLDL and subsequent distribution to peripheral tissues
Traber, 1999). The tocopherols have three chiralic centres (for a review, see Traber & Arai, 1999). a-TTP specifically
which in the natural forms are present exclusively as RRR- binds a-tocopherol. The affinity to other forms of vitamin E is
isomers. Synthetic a-tocopherol is a racaemic mixture lower, being 38 % for b-, 9 % for g-, and 2 % for d-tocopherol.
containing all possible combinations of R and S stereo- The affinity for the synthetic SRR form is 11 % and for
isomers. Vitamin E has been detected as a factor capable of a-tocotrienol 12 % compared with that for a-tocopherol
preventing the resorption of fetuses in rats and is now (Hosomi et al. 1997). The crucial role of a-TTP for
commonly used for the breeding of farm animals. The need a-tocopherol distribution is demonstrated by the infertility
for vitamin E for the successful reproduction of rats is taken of a-TTP knockout mice (Jishage et al. 2001) and the severe
as a measure for the bioactivity of individual forms of general vitamin E deficiency with characteristic neurological
vitamin E. In this fetal resorption – gestation assay, disorders and ataxia in patients with a mutation in the a-TTP
a-tocopherol has the highest activity (100 %), followed by gene (Ben Hamida et al. 1993; Ouahchi et al. 1995; Hentati
b-tocopherol (57 %), g-tocopherol (37 %) and d-tocopherol et al. 1996). Thus, one of the reasons for the preference for
(1·4 %). The activities of a-tocotrienol and b-tocotrienol are a-tocopherol is its selective recognition by a-TTP. A second
30 and 5 % of that of a-tocopherol (for a review, see Azzi & reason for the high bioactivity of a-tocopherol is its
Stocker, 2000). Also the bioactivity of natural and synthetic comparatively low metabolic degradation. Tocopherols and
a-tocopherol is different. Compared with RRR-a-toco- tocotrienols are metabolised by side-chain degradation. All
pherol, RRS has 90 %, RSS 73 %, SSS 60 %, RSR 57 %, SRS forms of vitamin E are degraded along the same pathway; their
37 %, SRR 31 % and SSR 21 % activity in the rat fetal metabolic rates, however, differ greatly. This will definitely
resorption – gestation test (Weiser & Vecchi, 1982). influence the bioactivities of individual forms of vitamin E.
Abbreviations: CEHC, carboxyethyl hydroxychroman; COX, cyclo-oxygenase; CYP, cytochrome P450; IC50, 50 % inhibitory
concentration; PKC, protein kinase C; PXR, pregnane X receptor; a-TTP, a-tocopherol transfer protein.
Corresponding author: Professor Dr Regina Brigelius-Flohé, fax þ 49 33200 88407, email flohe@dife.de
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https://doi.org/10.1017/S0954422407202938Bioactivity of vitamin E 175
R1
R1
HO
CH3 HO
H3 C H H3C H CH3 CH3 CH3
2 2
R2 O 4' 8' CH3 R2 O
CH3 CH3
CH3 CH3
Tocopherol CH3 Tocotrienol
(2R4'R8'R) (2R)
ω-Hydroxylation (phase 1 enzymes)
β-Oxidation
R1
HO
CH3
(a) CMBHC
R2 O COOH
CH3
CH3 Glucuronidation
Sulfatation
R1 (phase 2 enzymes)
HO
CEHC
R2 O COOH
CH3
CH3
Urinary or biliary excretion
via phase 3 transporters?
(b)
R1 R2
α-Toco- CH3 CH3 - pherol/trienol
β-Toco- CH3 H - pherol/trienol
γ-Toco- H CH3 - pherol/trienol
δ-Toco- H H - pherol/trienol
Fig. 1. Structures of tocopherols, tocotrienols, and their metabolites (a). The nature of R1 and R2 at the chroman ring is explained (b).
Carboxyethyl hydroxychroman (CEHC) is the final metabolite; carboxymethylbutyl hydroxychroman (CMBHC) is the precursor of CEHC.
Over the last decade distinct novel functions have been eliminated in the urine. Precursors of CEHC, carboxy-
described for different forms of vitamin E. They may be methylbutyl hydroxychromans, can also be found in the
relevant to cancer, neurodegeneration and inflammation. urine, although to a much lesser extent (Parker & Swanson,
Underlying mechanisms – as far as elucidated – are not 2000; Schuelke et al. 2000) (Fig. 1). Considering the
related to the antioxidant capacity of tocopherols and pathway of degradation reveals that vitamin E is
tocotrienols. These functions will be summarised and metabolised like xenobiotics. First, a functional group is
discussed in the present review in respect to the metabolic introduced via the phase 1 enzyme(s) CYP3A4 or CYP4F2,
rate of individual forms of vitamin E and, accordingly, the then b-oxidation follows. The degradation product is
relevance of the novel function to human health. conjugated by phase 2 enzymes such as UDP-glucuronosyl-
transferases or sulfotransferases, and the conjugate is finally
eliminated via the bile or urine. Whether elimination
Metabolism of vitamin E
requires phase 3 transporters such as MDR-1 or MRP-2
Vitamin E is not metabolically inert. All forms of vitamin E remains to be investigated.
are degraded by the same mechanism, an initial To evaluate the metabolic fate of the different vitamers
v-hydroxylation followed by b-oxidation (for reviews, see in vivo, concentrations of metabolites have been measured
Brigelius-Flohé et al. 2002b; Pfluger et al. 2004). in human urine (Swanson et al. 1999; Schuelke et al. 2000),
v-Hydroxylation is catalysed by cytochrome P450 enzymes human plasma (Stahl et al. 1999; Radosavac et al. 2002;
(CYP), of which CYP3A4 (Parker et al. 2000; Birringer et al. Galli et al. 2003, 2004) and rat bile (Hattori et al. 2000;
2001) and CYP4F2 (Sontag & Parker, 2002) are the most Kiyose et al. 2001). Consistently 1 –3 % of the ingested
likely candidates. The final products of all forms are the a-tocopherol can be found as a-CEHC in human urine
respective carboxyethyl hydroxychromans (CEHC) (Fig. 1). (Schuelke et al. 2000). In contrast, g-tocopherol has been
CEHC are conjugated with glucuronic acid or sulfate and calculated to be metabolised to g-CEHC up to 50 %
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https://doi.org/10.1017/S0954422407202938176 R. Brigelius-Flohé
(Swanson et al. 1999). A recent study reported that this (Lehmann et al. 1998), which is described as a xenobiotic
percentage can even be higher (Galli et al. 2002). Whereas sensor for lipophilic compounds with discrete polarity
basal plasma levels of g-tocopherol in eight healthy (Watkins et al. 2001). Vitamin E meets the characteristics of
volunteers were fifteen times lower than those of such PXR ligands and, indeed, the activation of a PXR-
a-tocopherol (2·03 v. 31·6 mmol/l), the levels of plasma driven reporter gene by different forms of vitamin E could
g-CEHC were at least ten times higher than that of a-CEHC be demonstrated (Landes et al. 2003). Tocotrienols
(160 v. 12·5 nmol/l). From an oral intake of 100 mg displayed the highest in vitro activity followed by d- and
2
H-labelled g-tocopherol, 18 mg was transferred into the a-tocopherol, while a-tocopherol proved the more potent
blood, confirming limited intestinal absorption of high inducer in vivo (see later).
dosages. Interestingly, 2H-labelled g-CEHC concentration These findings imply that at least some forms of vitamin
in plasma also accounted for 18 mg g-tocopherol equiva- E may induce their own metabolism and may also affect the
lents, indicating an almost quantitative degradation (Galli metabolism of other CYP substrates. The consequences may
et al. 2002). However, only one-third of the plasma g-CEHC be both beneficial and detrimental: maintenance of an
appeared in the urine, which suggests alternative routes for optimum xenobiotic metabolising system may protect
g-CEHC excretion. The urinary amount of g-CEHC (6·5 mg against harmful food ingredients and environmental
g-tocopherol equivalents) accounts for 6·5 % of the ingested poisons, but the induction of this system may also weaken
or 36 % of the absorbed parent compound. Assuming that the therapeutic efficacy of essential drugs, as has been
the same situation holds true for g-tocotrienol, the 4 – 6 % discussed elsewhere (Brigelius-Flohé, 2003, 2005; Traber,
of the applied g-tocotrienol that was recovered as g-CEHC 2004). The findings also imply that most forms of vitamin E
in the urine (Lodge et al. 2001) would equally indicate an are eliminated like xenobiotics even at low intake, which
almost 100 % degradation of g-tocotrienol, as discussed by raises the question why nature decided to degrade the
Galli et al. (2002). Such a high degradation of g-tocopherol tocotrienols, g- and d-tocopherol but not a-tocopherol.
could not be confirmed recently. Leonard et al. (2005b)
reported that only 1 % of the dose is eliminated in the urine.
Functions of vitamin E
These authors also suggested alternative routes for g-CEHC
excretion. Interestingly, however, women produced almost The antioxidative property of vitamin E was already
twice the amount of g-CEHC from 2H-labelled g-tocopherol recognised in the early 1930s. Since then, it has been
than men. The explanation was offered that women classified as the major lipid-soluble antioxidant which
metabolise certain CYP3A4 substrates faster, which would protects lipids and membranes from oxidative damage
make them better equipped to handle xenobiotics. This in vitro and in vivo (Tappel & Zalkin, 1960; Burton &
implies that g-tocopherol is, indeed, considered to be Ingold, 1981; Burton et al. 1982). Antioxidants in their
foreign and women might profit less from an enhanced proper definition are compounds which react with free
g-tocopherol intake. radicals and, thus, interrupt free radical chain reactions. The
Metabolism of a-tocotrienol has been investigated in cell respective functional group in the vitamin E molecule is the
culture (Pfluger et al. 2004). In HepG2 cells, a-tocotrienol hydroxylic group at position 6 in the chroman ring (Fig. 1).
yielded fourteen times the amount of a-CEHC than This group is characteristic for all forms of vitamin E and,
a-tocopherol within 72 h. Surprisingly, however, the therefore, they can all react as antioxidants, in a test-tube at
precursor, a-carboxymethylbutyl hydroxychroman, was least. When tested with organic peroxyl radicals as
about seventy-five times higher with a-tocotrienol than oxidising partners, the order of the antioxidant potential of
with a-tocopherol. If this also holds true in vivo, the low tocopherols is a- . b- $ g- . d-tocopherol (Burton &
amount of a-tocotrienol that was determined as a-CEHC in Ingold, 1981). This reflects the order of bioactivity
the urine (1 – 2 % of the applied dosage) (Lodge et al. 2001) estimated in the fetal resorption – gestation assay, but by
would not reflect the actual metabolic rate and underestimate no means in quantitative terms. Also a-tocotrienol even has
the metabolism of a-tocotrienol. Clearly, an excretion of an up to sixty times higher antioxidant activity against Fe2þ/
CEHC and precursors via the bile has to be taken into ascorbate- and Fe2þ/NADPH-induced lipid peroxidation in
account. More detailed investigations of metabolic rates and rat liver microsomal membranes than a-tocopherol
routes are required for all of the vitamers, since a satisfactory (Serbinova et al. 1991). This again does not correlate with
balance has not yet been established for any of them. It can its activity in the conventional bioassays and further
only be stated with certainty that the available studies demonstrates that the in vitro antioxidant activity does not
disclose a dramatically faster degradation of g- than of allow conclusions in respect to the in vivo effect. This
a-tocopherol, which recently has also been corroborated by discrepancy has shed considerable doubt on the prevailing
measuring, for the first time, liver CEHC concentrations in view that the antioxidant property of vitamin E is the real
rats (Leonard et al. 2005a). basis of its biological function (for reviews, see Azzi &
The metabolism of a vitamin by pathways, which are Stocker, 2000; Munteanu et al. 2004; Zingg & Azzi, 2004).
usually engaged in the detoxification of xenobiotics, was The impact of the current controversy is underscored by
intriguing and provoked the question if, under certain recent reports on clinical trials that disprove any efficacy of
circumstances, vitamin E is considered as ‘foreign’. Like vitamin E or other antioxidants in preventing CVD, cancer
many xenobiotics, vitamin E induced endogenous CYP3A or other disorders believed to result from oxidative stress
in cultured cells (Landes et al. 2003) and in mice (Kluth (Heart Protection Study Collaborative Group, 2002;
et al. 2005; Traber et al. 2005). Induction of CYP3A forms Genkinger et al. 2004; Lonn et al. 2005; Poston et al.
is mediated by the nuclear pregnane X receptor (PXR) 2006; for reviews, see Brigelius-Flohé et al. 2002a; Upston
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https://doi.org/10.1017/S0954422407202938Bioactivity of vitamin E 177
et al. 2003; Stocker & Keaney, 2004; Pham & Plakogiannis, fed a vitamin E- and Se-deficient diet. The specific effect of
2005). Even harmful effects of vitamin E have been either vitamin E or Se was assessed by analysing genes, the
suggested from meta-analyses of clinical trials expressing of which could be restored by feeding only one
(Vivekananthan et al. 2003; Miller et al. 2005). Thus, to of the two micronutrients (Fischer et al. 2001). Another
understand the real biological role of vitamin E we have to study used pregnant rats fed a-tocopherol plus a tocotrienol-
look beyond free radical biochemistry. enriched diet, and gene expression was analysed in the fetal
brains (Roy et al. 2002). Two studies investigated the effect
of vitamin E deficiency on the male reproductive tract in
a-Tocopherol rats. In the epididymis, mainly genes encoding oxidative
The key observation that initiated the search for novel stress-related proteins were described to be regulated (Jervis
functions of vitamin E was the specific inhibition of smooth & Robaire, 2004), whereas in testes vitamin E deficiency
muscle cell proliferation by a- but not b-tocopherol time-dependently up regulated enzymes involved in
(Boscoboinik et al. 1991). The underlying mechanism was testosterone synthesis and cell cycle progression (Rota
identified as an inhibitory dephosphorylation of protein et al. 2004). In liver, a-tocopherol up regulated
kinase C (PKC) that is catalysed by an a-tocopherol- g-glutamylcysteine synthetase, which correlated with an
stimulated phosphoprotein phosphatase (Tasinato et al. increase of liver glutathione, and down regulated the CD36
1995; Ricciarelli et al. 1998). a-Tocopherol was then shown scavenger receptor, coagulation factor IX and 5-a-steroid
to inhibit key events in inflammatory signalling, such as reductase type I also correlating with functional parameters
platelet aggregation, release of IL-1b from lipopolysacchar- (Barella et al. 2004). The down regulation of CD36 in aortic
ide-activated macrophages, adhesion of monocytes to smooth muscle cells deserves special interest, since it might
endothelial cells, production of monocyte chemoattractant explain the sometimes observed anti-atherosclerotic effect
protein-1 and IL-8 in human aortic endothelial cells, LDL- of a-tocopherol in experimental animals (Ricciarelli et al.
induced proliferation of smooth muscle cells, and activation 2000). Most interesting findings came from gene expression
of NADPH oxidase in human monocytes (for a review, see analyses in the brain of a-TTP-deficient mice. In the cortex
Brigelius-Flohé et al. 2002a). Most of these processes of these mice, genes involved in the myelination and
depend on the activity of PKC, mostly PKCa, and inhibition synaptogenesis were much less expressed than in wild-type
of PKC by a-tocopherol may well be the common link controls (Gohil et al. 2003). A hierarchical cluster analysis
between these various effects. The described effects of further suggested that a-TTP might be required for normal
a-tocopherol undoubtedly are anti-inflammatory and functioning of glial cells and oligodendrocytes (Gohil et al.
should, in consequence, be anti-atherosclerotic and anti- 2004). A more detailed investigation of a-tocopherol-
carcinogenic. Such effects, however, have not been regulated genes in the brain will finally provide a molecular
observed in clinical trials, which is not easily explained. basis for neurological disorders that develop in vitamin E
Most of the effects have been observed in cell cultures only deficiency (Hayton et al. 2006).
and the culture media usually do not contain a-tocopherol or Some of the a-tocopherol-regulated genes almost
any other form of vitamin E (Leist et al. 1996). Incubation consistently show up in the lists published in the quoted
with a-tocopherol, thus, just restored a normal physiologi- papers. They were grouped by Azzi et al. (2004) into five
cal vitamin E content. This would imply that at a low or clusters – genes that are involved in:
deficient vitamin E status the systems in charge of host-
(1) the uptake and degradation of vitamin E;
defence or acute-phase response, respectively, do not work
(2) lipid uptake and atherosclerosis;
adequately. In this context it is worth considering that in the
(3) the modification of extracellular proteins;
clinical trials it was primarily patients or subjects who
(4) inflammatory processes;
entered the study with a low vitamin E status that appeared
(5) cellular signalling and cell cycle control.
to gain more benefit than those with higher vitamin E
plasma levels. Many of the quoted anti-inflammatory A systematic analysis of the a-tocopherol response has
actions that are dampened by a-tocopherol involve redox not yet been seriously attempted. Only Gohil et al. (2003,
processes or even free-radical reaction and, therefore, may 2004) tried to find transcription factors that are common to
again be attributed to its antioxidant capacity. For a simple the regulated genes. They found the retinoic acid-related
antioxidant action, however, a linear dose –response is orphan receptor (ROR) a, which belongs to the family of
typical, while a plateau effect near common physiological nuclear receptors, repressed in the cortex and adrenal glands
intakes speaks in favour of a specific interaction of of a-TTP-deficient mice. RORa-knockout mice develop the
a-tocopherol with defined molecular targets. In practical ataxia and memory dysfunction typical for vitamin-E and
terms, the saturatable dose – effect relationship predicts that a-TTP deficiency, which points to RORa as a potential
an adequate a-tocopherol status but not a ‘supranutritional’ target of a-tocopherol. However, by no means all
supplementation might prove to be pivotal to the a-tocopherol-regulated genes are dependent on RORa,
maintenance of the endogenous defence systems. and a-tocopherol did not activate an ROR-a-driven reporter
Novel functions of vitamin E also comprise the regulation gene (R Brigelius-Flohé, unpublished results).
of gene activity. The regulated genes were either A nuclear receptor specifically binding vitamin E, as is
individually identified to respond to different vitamers or known for vitamin D and A (for a review, see Aranda &
by global gene expression analyses in experimental animals Pascual, 2001), has not been identified yet. However, there
fed with different forms and concentrations of vitamin are some hints that vitamin E is able to activate nuclear
E. The first microarray data were obtained from livers of rats receptors in principle. The activation of the PXR-driven
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https://doi.org/10.1017/S0954422407202938178 R. Brigelius-Flohé
reporter gene in HepG2 cells (Landes et al. 2003) and the g-Tocopherol
up regulation of peroxisome proliferator activated
g-Tocopherol is the major form of vitamin E in many plant
receptor-g mRNA and activity (De Pascale et al. 2006;
seeds. Due to the high consumption of soyabean products it
Hsieh et al. 2006; Munteanu et al. 2006) points in this is also the major form of vitamin E in the US diet (Stone &
direction. A direct binding of tocotrienols but not
Papas, 2003). However, as discussed earlier, the plasma
tocopherols to PXR has been demonstrated (Zhou et al.
concentration in human subjects and experimental animals
2004). However, PXR is not very likely to mediate the
irrespective of the dosages ingested hardly exceeds 10 % of
biological signals typical for vitamin E. PXR reacts with a
that of a-tocopherol. Due to the lack of one methyl group
large number of structurally highly diverse compounds
at the chroman ring, g-tocopherol is a slightly less
which are recognised as foreign and, thus, are prone to be
powerful antioxidant than a-tocopherol (Kamal-Eldin &
eliminated (Watkins et al. 2001). The capability of
Appelqvist, 1996). The presence or absence of the methyl
a-tocopherol and tocotrienols to induce PXR-driven gene
group at position 5 in the chroman structure determines the
expression rather indicates that high concentrations (in the
mode of action of tocopherols with reactive nitrogen oxide
case of a-tocopherol) and the substances as such (in the species. The reaction of g-tocopherol with reactive
case of tocotrienols) are destined to be eliminated instead
nitrogen oxide species, such as peroxynitrite (ONOO2),
of mediating cellular signals. There remains the possibility
nitrogen dioxide (†NO2) or nitrogen dioxide-like species,
that the gene regulation by a-tocopherol is also mediated results in the formation of 5-nitro-g-tocopherol (Christen
by PKC inhibition, which could prevent a pivotal
et al. 1997; Hoglen et al. 1997) (Fig. 2). In contrast, the
phosphorylation of transcription factors, co-activators,
reaction of a-tocopherol with nitrogen dioxide fundamen-
or repressors. The increased retinoic acid-induced
tally differs. a-Tocopherol, due to the methyl group in
phosphorylation of RXR and subsequent activation of
position 5, is oxidised to a-tocopheryl quinone, and it
CRABP-II gene expression upon a-tocopherol treatment
cannot be nitrated.
of fibroblasts is a first hint supporting this hypothesis
Reactive nitrogen oxide species are generated in
(Gimeno et al. 2004).
inflammatory processes. They have also been associated
with inflammation-related diseases such as cancer, CVD and
neurodegenerative disorders. Consequently, the capacity of
b-Tocopherol g-tocopherol to inhibit inflammatory processes has been
Our diet contains only low amounts of b-tocopherol. tested. g-Tocopherol decreased prostaglandin E2 production
Reasonable concentrations can only be found in wheat by inhibiting cyclo-oxygenase (COX) 2 activity in cultured
germ, soyabean or sunflower-seed oil (Stone & Papas, cells (Jiang et al. 2000) and in rats (Jiang & Ames, 2003).
2003). This may be the reason why studies exploring an Anti-inflammatory effects of g-tocopherol and the puta-
isolated biological effect of b-tocopherol are scarce. In most tively underlying mechanism of trapping reactive nitrogen
cases b-tocopherol has only been used to demonstrate that oxide species have been extensively reviewed recently
a-tocopherol effects were unique and antioxidant-indepen- (Jiang et al. 2001; Wagner et al. 2004).
dent. Although b-tocopherol has similar antioxidant g-Tocopherol has gained huge interest because of its
properties as a-tocopherol, none of the a-tocopherol- putative capacity to prevent cancer. Indeed cancer-related
induced effects could be mimicked by b-tocopherol. The processes responded much better to g-tocopherol than to
effects were either absent or substantially lower with a-tocopherol. The types of cancers which best respond to
b-tocopherol. For example, activation of PKC, resulting in vitamin E are prostate and colon cancer. a-Tocopherol
an inhibition of PKC-dependent activation of NADPH supplementation reduced prostate cancer incidence by 32 %
oxidase by phorbol myristate acetate in monocytes (Cachia in the ‘Alpha-Tocopherol Beta Carotene Cancer Prevention’
et al. 1998), was inhibited by a- but not by b-tocopherol study (Heinonen et al. 1998). The association of
(Boscoboinik et al. 1991). Similarly, up regulation of a-tocopherol, g-tocopherol and Se with the incidence of
a-tropomyosin (Aratri et al. 1999) and down regulation of prostate cancer was investigated in a nested case –control
CD36 (Ricciarelli et al. 2000) was only triggered by a- and study (Helzlsouer et al. 2000). Men in the highest quintile of
not by b-tocopherol. Also, b-tocopherol did not plasma g-tocopherol levels had a 5-fold lower risk of
inhibit the proliferation of smooth muscle cells, whereas prostate cancer compared with those in the lowest quintile.
g-, d- and a-tocopherol were equally inhibitory (Chatelain Significant protective effects of high levels of a-tocopherol
et al. 1993). The lack of b-tocopherol efficacy in these and Se were only observed when g-tocopherol concen-
systems does not comply with its biological activity in the trations were high. In the recently published CLUE studies,
rat gestation – resorption assay, which is 57 % that of a reduced risk of prostate cancer in subjects of the highest
a-tocopherol (see earlier), i.e. relatively high. Also, at least quintile of serum g-tocopherol was reported (Huang et al.
in cultured cells, its metabolic rate is almost comparable 2003). Also a nested control study within the ‘Alpha-
with that of a-tocopherol (Birringer et al. 2001), i.e. equally Tocopherol Beta Carotene Cancer Prevention’ study cohort
low. Thus, the low activity of b-tocopherol, when tested for revealed that men with higher circulating levels of
the novel functions, underscores the specificity displayed by a-tocopherol and g-tocopherol had a lower prostate cancer
a-tocopherol. However, the efficacy of both tocopherols in risk (Weinstein et al. 2005). In summary, the studies, which
the resorption – gestation assay also reveals that the latter have been reviewed elsewhere (Campbell et al. 2003a;
depends on a common metabolic pathway that remains to be Hensley et al. 2004), reveal stronger evidence for an anti-
elucidated. carcinogenic action of g- than of a-tocopherol.
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https://doi.org/10.1017/S0954422407202938Bioactivity of vitamin E 179
α-Tocopherol γ-Tocopherol
CH3
H
HO
HO
C16H33 C16H33
H3 C O H3C O
CH3 CH3
CH3
CH3
+ NO2•
+ 2NO2•
CH3 OH NO2
O HO
C16H33
CH3
C16H33
H3 C O H3 C O
CH3
CH3
CH3
+ NO –
+ NO2–
α-Tocopherylquinone 5-Nitro-γ-tocopherol
Fig. 2. Reactions of a- and g-tocopherol with nitrogen dioxide.
Also, experimental evidence speaks in favour of a cells not able to metabolise g-tocopherol would be killed,
chemopreventive role of g- rather than of a-tocopherol. leaving healthy cells unaffected.
g-Tocopherol was much more effective in inhibiting
proliferation of colon (CaCo2), prostate (LNCaP, DU-
d-Tocopherol
145), and osteosarcoma cell lines than a-tocopherol
(Gysin et al. 2002). Similarly, proliferation of PC-3 Although d-tocopherol is present in high amounts, for
prostate cancer cells was inhibited by g-tocopherol (Galli example, in soyabean, safflower-seed and wheat-germ oil
et al. 2004) and finally g-tocopherol was a more potent and, thus, at least in the American diet (Stone & Papas, 2003),
inhibitor of neoplastic transformation in 3-methylcholan- it has not received much attention and individual functions
trene-treated C3H/10T1/2 murine fibroblasts than have not yet been investigated in detail. This might be a
a-tocopherol (Cooney et al. 1993). The underlying consequence of its low biological activity and its low level in
mechanisms might be: induction of apoptosis, as has plasma and tissues that only reach about 1 % of that of a-
been shown for the LNCaP prostate cancer cells (Jiang tocopherol (Traber & Kayden, 1989). The discrepancy
et al. 2004); down regulation of cyclins D1 and E1 between the dietary intake and the accumulation in plasma
(Gysin et al. 2002; Galli et al. 2004); suppression of ras- and tissues suggests a high metabolic rate. In fact, the CEHC
p21 expression, which is often up regulated in colon which was detected in vivo first was d-CEHC (Chiku et al.
cancer tissue and is, therefore, taken as an early 1984). In cell culture, d-tocopherol is degraded to a
biomarker for colon cancer (Stone et al. 2002); or up substantial amount (Birringer et al. 2001); its in vivo route
regulation of peroxisome proliferator activated receptor-g of elimination, however, has not been monitored in detail. In
(Campbell et al. 2003b). cultured cells, d-tocopherol is the most toxic tocopherol; only
However, g-tocopherol is not only toxic for cancer cells. 10 mM reduced cell viability of macrophages by more than
It inhibited cell viability in mouse macrophages at 90 % (McCormick & Parker, 2004). Toxicity was associated
concentrations above 20 mM , i.e. concentrations similar to with the induction of apoptosis. As discussed earlier for g-
those needed for damaging cancer cells. In contrast, human tocopherol, hepatocytes were not sensitive for d-tocopherol,
hepatocytes and bovine endothelial cells were not affected which again might be explained by their capacity to
(McCormick & Parker, 2004). Hepatocytes but not metabolise and eliminate d-tocopherol. Interestingly, long-
macrophages metabolised g-tocopherol, indicating that term exposure to d-tocopherol led to development of
metabolism might prevent the toxicity of g-tocopherol. It resistance to cytotoxicity. This shows that d-tocopherol
remains to be investigated whether g-tocopherol can also might be able to influence gene expression. The in vivo
specifically kill cancer cells and, if so, whether only cancer relevance of these observations has to be evaluated. The
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https://doi.org/10.1017/S0954422407202938180 R. Brigelius-Flohé
studies, however, suggest that tocopherols that are not a-tocopherol supplementation in patients with mild
a- are eliminated, possibly to prevent cytotoxicity cognitive impairment (Petersen et al. 2005). Thus, a
(McCormick & Parker, 2004). protective effect of even huge amounts of a-tocopherol in
addition to the dietary intake did not ameliorate the disease
development. Supplementation with such high amounts of
Tocotrienols a-tocopherol so far only ameliorated ataxia in patients with
Tocotrienols are less abundant in the human diet than a defect in the gene for a-TTP. This, however, only
tocopherols. Only palm oil, rice bran, oat, and barley underscores that a functional a-TTP is required for an
contain reasonable amounts (Stone & Papas, 2003). Their adequate a-tocopherol supply to the brain.
high antioxidant, anti-cancerogenic and cholesterol-low- In contrast, a-tocotrienol has been shown to prevent the
ering properties in vitro and in experimental animals (for glutamate-induced death of T4 hippocampal neuronal cells
a review, see Sen et al. 2006) have recently brought at nanomolar concentrations, whereas at these low
them into focus. concentrations a-tocopherol did not show any effect
Cell-culture work shows that tocotrienols can inhibit the (Sen et al. 2000). High extracellular levels of glutamate,
growth of normal primary mouse mammary epithelial cells as observed in neurological disorders, inhibit the amino acid
(McIntyre et al. 2000b), of pre-neoplastic and even more of transport system, xC2, which specifically takes up cystine in
neoplastic mouse mammary epithelial cells (McIntyre et al. exchange for glutamate. Cystine is intracellularly reduced to
2000a). The higher inhibitory potency of tocotrienols, as cysteine, the precursor of glutathione. Thus, inhibition of
compared with tocopherols, was attributed to a preferential xC2 by glutamate is considered to cause intracellular
uptake of tocotrienols by these cells. Also, the proliferation oxidative stress due to low GSH levels and, in consequence,
of human breast cancer cell lines was suppressed by to induce apoptosis. The molecular basis of the protective
tocotrienols (Nesaretnam et al. 1998). In all cases g- and effect of tocotrienols was discussed as an induction of
d-tocotrienol exerted the highest inhibitory effects. As extracellular signal-regulated kinase by activation of c-Src
underlying mechanisms, inhibition of epidermal growth or the prevention of 12-LOX activation by intracellular
factor receptor signalling (Sylvester et al. 2002), induction glutathione; thus, interference with the eicosanoid pathway
of apoptosis (Takahashi & Loo, 2004) and inhibition of (Sen et al. 2004). Even if the concentrations of tocotrienol
HMG-CoA reductase activity (Mo & Elson, 2004) or needed for the efficacy are very low, it remains to be
increasing HMG-CoA-reductase degradation (Theriault investigated whether they can be reached in the brain by
et al. 2002) have been discussed. In experimental animals feeding tocotrienols. Tissue levels of tocotrienols usually
a dietary intake of palm oil rich in tocotrienols suppressed are very low (Podda et al. 1996) and also plasma levels
carcinogen-induced mammary tumorigenesis (Sylvester cannot substantially be increased by tocotrienol supplemen-
et al. 1986; Nesaretnam et al. 1992). The main effect of tation (Lodge et al. 2001). a-Tocotrienol in plasma reached
tocotrienols on CVD parameters is the inhibition of the maximum 1 mmol/l in human subjects irrespective of the
surface expression of vascular cell adhesion molecule 1 and amount of supplementation (Mustad et al. 2002), levels of
E-selectin in human umbilical vein endothelial cells and g- and d-tocotrienol being even lower. Furthermore, half-
subsequent monocyte adhesion (Theriault et al. 2002). lives of all tocotrienols investigated in human subjects (a, g,
Whereas the lowering of cholesterol, which has been d) were 4·5 – 8·7 times shorter than those of a-tocopherol
observed in vitro, was also observed in some experimental (Yap et al. 2001; Schaffer et al. 2005).
animals (for a review, see Schaffer et al. 2005), human A recent animal study supports the concern about the
studies yielded contradictory results (O’Byrne et al. 2000; in vivo efficacy of tocotrienols. It had been shown in cell-
Kerckhoffs et al. 2002; Qureshi et al. 2002). Only a limited culture studies that almost all forms of vitamin E can
number of clinical trials performed with tocotrienols are activate a PXR-driven reporter gene and the expression of
available. In a double-blind, randomised, parallel-design endogenous CYP3A4 (Landes et al. 2003) (see earlier).
study with sixty-seven healthy hypercholesterolaemic By far the highest efficacy was observed with a- and
subjects who consumed commercially available tocotrienols g-tocotrienol. Also in vitro binding of tocotrienols to PXR
or placebo for 28 d, no beneficial effects on key CVD risk was high, whereas tocopherols were only marginally active
factors, such as 8-iso-prostaglandin F 2a excretion, level of in the competitive ligand-binding assay (Zhou et al. 2004).
LDL-cholesterol or glucose, have been observed In an attempt to demonstrate the in vivo relevance of the
(Mustad et al. 2002). in vitro findings, mice were fed high dosages (250 mg/d) of
Tocotrienols are also gaining interest in neuroprotection. g-tocotrienol for 7 d on top of a diet either deficient,
Vitamin E deficiency is associated with a progressive adequate or supranutritional with respect to a-tocopherol.
neurological syndrome in man, and with increased levels of Neither plasma nor liver a-tocotrienol levels could
oxidative damage markers in the brain (for a review, see significantly be elevated. Also CYP3a11 mRNA, the murine
Berman & Brodaty, 2004). The potential neuroprotective homologue to the human CYP3A4, was not changed by
effects of vitamin E have, therefore, been attributed to its g-tocotrienol, but was induced by a-tocopherol. The failure
antioxidant property. The Alzheimer’s Disease Cooperative of g-tocotrienol to up regulate CYP3a11 could easily be
Study, an earlier interventional trial with 341 patients, explained by an enormous excretion of g-tocotrienol
has shown that 2000 IU (900mg) all rac-a-tocopherol slow metabolites in the urine (Kluth et al. 2005). Thus,
down functional deterioration in patients with moderate degradation prevented an accumulation of g-tocotrienol to
Alzheimer’s disease (Sano et al. 1997). A recent trial with the extent required for gene activation. This shows that
769 patients, however, did not detect any benefit of novel functions of tocotrienols observed in vitro must not
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https://doi.org/10.1017/S0954422407202938Bioactivity of vitamin E 181
uncritically be extrapolated to the in vivo situation. a biological effect of dietary g-tocopherol or g-tocotrienol
Thorough analyses of the dosages leading to the required derived g-CEHC remains to be established.
plasma or tissue levels have to be performed before animal
or even human studies can be started.
Is inhibition of metabolism a solution?
Assuming that vitamin E metabolite concentrations required
Functions of vitamin E metabolites
to exert beneficial effects in vitro can never be reached
g-CEHC has been detected as Loma Linda University factor in vivo, prevention of degradation of parent vitamers might
a (LLU-a), an endogenous natriuretic factor (Wechter et al. be the method of choice to save their biological effects.
1996). It was isolated from the urine of uraemic patients and Whereas this strategy is not needed for a-tocopherol, it
chemically characterised as the final metabolite of might help to increase the plasma and tissue concentration
g-tocopherol. g-CEHC, at nanomolar concentrations, but of g-tocopherol and the tocotrienols.
not a-CEHC, promotes Na excretion by blocking a Kþ Evidence for a CYP-catalysed degradation of vitamin E
channel in the thick ascending limb of the kidney’s Henle initiated the search for inhibitors of vitamin E metabolism.
loop which prevents Kþ recycling. The resulting inhibition Among the known CYP-inhibitors tested, ketoconazole
of the Naþ/2Cl2/Kþ co-transporter will lead to natriuresis exhibited the highest inhibitory effect on g-tocopherol
(Murray et al. 1997). g-Tocotrienol could, thus, be degradation (Parker et al. 2000). Since ketoconazole is a
considered to be a vitamin functioning as a hormone potent inhibitor of the CYP3A family of P450-isoenzymes,
precursor. However, although g-CEHC is the final these findings led the authors to conclude that CYP3A4
metabolite from both g-tocopherol and g-tocotrienol, might be the enzyme responsible for the initial step in
neither of the vitamers have ever been observed to cause vitamin E degradation. The view was revised in a later
natriuresis and diuresis. Rats fed the huge dose of 10 mg publication in which preference was given to CYP4F2,
g-tocotrienol/d for 3 d after depletion of vitamin E stores for which, nevertheless, also was inhibited by ketoconazole
4 weeks excreted large amounts of g-CEHC but had an (Sontag & Parker, 2002). Whatever form of CYP will finally
increased urine volume and an accelerated Na excretion be identified as the vitamin E-v-hydroxylase, or whether
only if fed a high-salt diet simultaneously (Saito et al. 2003). there are different forms for a- and g-vitamers, it is
The results were later confirmed for g-tocopherol (Uto et al. generally accepted that CYP are involved.
2004). At best, therefore, g-tocopherol- and g-tocotrienol- The involvement of CYP can now explain a number of
derived g-CEHC might prevent hypertension and CVD previous observations: the elevation of plasma and tissue
caused by high salt intake only (Saito et al. 2003; Tanabe levels of a-tocopherol and especially of g-tocopherol in rats
et al. 2004). fed a diet containing sesame seeds or sesame oil (Yamashita
Also, other functions of tocopherol metabolites have been et al. 1992, 1995; Kamal-Eldin et al. 2000). Elevation of
described. As expected, a- and g-CEHC had antioxidant a-tocopherol in rat brain by feeding sesame seed was even
activity comparable with Trolox at micromolar concen- more effective than supplementation with a ten-fold higher
trations (Betancor-Fernandez et al. 2002). g-CEHC, like dosage of pure a-tocopherol (Abe et al. 2005). Also in human
g-tocopherol, but not a-CEHC, possesses anti-inflammatory subjects sesame oil increased serum g-tocopherol concen-
properties. It inhibited prostaglandin E2 production by trations but – in contrast to rats – not those of a-tocopherol
COX2 in lipopolysaccharide-stimulated macrophages or IL- (Cooney et al. 2001; Lemcke-Norojärvi et al. 2001). Sesame
1-treated epithelial cells with a 50 % inhibitory concen- seed is rich in g-tocopherol; however, elevation of the plasma
tration (IC50) of 30 mM , whereas the IC50 of g-tocopherol g-tocopherol level has been much higher than expected from
was about 5 –10 mM depending on the cell type investigated its g-tocopherol content. Sesame seeds and oil contain
(Jiang et al. 2000). a-CEHC was able to inhibit nitrite and furfuran lignans such as sesamin or sesaminol, which can
prostaglandin E2 release from TNFa-stimulated EOC-20 inhibit CYP activity. Its action via an inhibition of vitamin E
murine microglia, indicating inhibition of inducible nitric metabolism has been demonstrated in rats in which g-CEHC
oxide synthase and COX2 activity and induction respect- excretion completely disappeared accompanied by an
ively (Hensley et al. 2004). The IC50 here also was high elevation of g-tocopherol in liver, kidney, brain, and serum
(58 mM ) and comparable with the IC50 of non-steroidal anti- after 28 d sesame seed feeding (Ikeda et al. 2002). By the
inflammatory drugs. These huge concentrations of metab- same mechanism it may also enhance a- and g-tocotrienol
olites would never be reached in vivo. Basal plasma levels in skin and adipose tissue in rats after intake of a
concentrations of a-CEHC are about 13 nM (Galli et al. tocotrienol-rich diet (Ikeda et al. 2003).
2002) or 11 nM (Stahl et al. 1999), respectively. Those of Interestingly, other dietary phenolic compounds also
g-CEHC are 161 (Galli et al. 2002) or 66 nM (Stahl et al. affect concentrations of tocopherols. Curcumin raised the
1999). a-CEHC levels could be enhanced to about level of a-tocopherol in the lung but not in other tissues or
200 nmol/l after 7 weeks supplementation with 335 mg plasma (Kamal-Eldin et al. 2000). Rats fed anthocyanins
RRR-a-tocopherol (Stahl et al. 1999) and g-CEHC (Frank et al. 2002), or caffeic acid (Frank et al. 2003a) had
transiently increased up to 30-fold after an application of higher g-tocopherol contents in some tissues, and feeding of
100 mg 2H-labelled g-tocopheryl acetate (Galli et al. 2002). catechin enhanced a-tocopherol in rats but did not
Also a supplementation with g-tocopherol or g-tocotrienol inhibit d-tocopherol hydroxylation in HepG2 cells (Frank
at dosages effective for natriuresis in rats (10 mg per rat et al. 2003b). Whether catechin indeed acts via an
would mean about 3 –4 g per individual which is beyond the v-hydroxylase-independent mechanism as suggested, or
tolerable upper intake level) cannot be recommended. Thus, whether a- and d-tocopherol are degraded by different
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https://doi.org/10.1017/S0954422407202938182 R. Brigelius-Flohé
enzymes and, therefore, respond differently to catechins, handled under healthy and diseased conditions by the
remains to be elucidated. organism, before embarking on new clinical mega-trials that
Thus, it might be possible to elevate the levels of at present cannot be based on a solid scientific concept.
individual forms of vitamin E in plasma or in certain tissues
by a specific inhibition of the enzymes which are
responsible for their elimination. It might indeed be the
better strategy to enhance the levels of vitamin E by a Acknowledgements
dietary regimen, for example, by increasing the intake of The work was supported by the Deutsche Forschungsge-
vegetable oils containing lignans such as sesamin instead of meinschaft (DFG).
taking high dosages of supplements with unknown side
effects. Whether this is sufficient to give, for example,
g-tocopherol the chance to exert its novel functions that References
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