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Biomed & Pharmacother 1999 ; 53 : 169-80
0 Elsevier, Paris
Dossier: Oxidation and antioxidizing agents
Oxidative stress induced in pathologies: the role of antioxidants
L. Gat&, J. Paul, G. Nguyen Bal, K.D. Tew*, H. Tapierol
1 Luboratoire de Phartnacologie Cellulaire et Moleculaire, UMR CNRS 8612, Universite de Paris XI - Facultk de Phartnacie,
92290 Chcftenay-Malabry, France: 2 Department of Pharmacology, Fox Chase Cancer Center, Philadelphia , PA 191 II, USA
Summary-Exposure to oxidant molecu les issue d from the environment (pollution, radiation), nutrition, or pathologies can generate reac-
tive oxygen specie s (ROS for example, H,O,, O,-, OH). These free radicals ca n alter DNA, proteins and/or membrane phosph olipids. Deple-
tion of intracellular antioxidants in acute oxidative stress or in various dis eases increases intracellular ROS accum ulation. This in turn is
responsible for several chronic pathologies including cancer, neurodegenerative or cardiovascular pathologies. Thus, to prevent against
cellular damages associated with oxidative stress it is important to balance the ratio of antioxidants to oxidants by supplementation or by
cell induction of antioxidants. 0 1999 Elsevier, Paris
aging I antioxidants I diseas es / free radicals
The generation of free radicals in vivo is a constant phe-
nomenon due either to physiological metabolism or
pathologica l alterations. Oxygen (0,) plays a double
role in the cell : it is essential for aerobic organisms, but
it can also act as a free radical since i t contains two
relatively stable unpaired electrons. When an oxygen
molecule captures an electron it becomes a superoxide
anion O,m. This molecule is normally produced by
macrophages in order to destroy bacteria during the pro-
cess of phagocytosis. However, this species can also be
generated during oxidative phosphorylation in the res-
piratory chain in mitochondria. 0, can also be gener-
ated in a dismutation reaction by the action of superox-
ide dismutase (SOD) to form hydrogen peroxide H,O,
(figure I). Furthermore, H,Oz can also be generated
from O,- by the radical-generating enzymes amino acid
oxidase and xanthine oxidase.
Hydrogen peroxide, although less reactive than 0, is
more high ly diffus ible and can cross the plasma mem-
brane. One of the physio logical functions of H,O, is the
activation of nuclear translocation of the transcription
factor NFkB, which subsequently allows the transcrip-
tion of specific genes. NFkB is a heterodimer of p65 and
~50, but it is only the ~65 subunit that has transcrip-
tional activity [ 11. In normal conditions, ~65 is associ-
ated with an inhib itory subunit IkB [2], which prevents
the translocation of NFC in to the nucleus. Although it
has been shown that ~65 can be activated by several
stimuli including
TNFa,
IL- 1, phorbol 12-myristate-
13-acetate (PMA), or H,O, [3], the action of protein
kinase C (PKC) seems to play the crucial role in the acti-
vation of ~65 [4, 51. The H,O,-induced activation of
NFkB is achieved via OH production [6]. The nuclear
translocation of NFkB after activat ion by H202 induces
the transcription of the HIV proteins and the replication
of the virus [7], thus enhancing the pathogenicity of
HIV.
By homolytic fission, a hydroxyl radical OH can be
produced from H202 (the Fenton reaction), this reac-
tion being catalyzed by transition elements such as
Fe*+. OH can also be generated from O,- or from H,O,
and trace elements (the Haber-Weiss reaction). OH is
the most highly reactive oxidant molecule, it binds and
oxidizes DNA, lipids and proteins, and it reacts with
structures from its close neighborhood [8].
Thus oxidants can modulate the generation of second
messengers such as diacyglycerol or phosphatidic acid
(PA). This latter is generated by phospholipase D (PLD)
and PKC activat ion. PA has mitogenic properties
increasing DNA synthesis and cell prolife ration in
smooth muscle cells [9], and this prolife ration may be
important in the formation of atherosclerotic plaques
[lo] . Moreover, oxidized low-density lipoproteins
(LDL) when acting as an activator of PLD, can induce
proliferation of smooth muscle cells [ 111, and it may in
part be responsible for arteriosclerosis. Thus, by their
deleterious effects on macromolecules, oxidants can
induce cellular alterations which can lead to the devel-
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170
L. Gatt et al.
SOD
20,+2n+
-
Hz02 + 02
HP,
(Fe2i Fe)
OH+OH- Fenton reaction
H?O> + 01
(Fe*/ Fe3+)
OH+O H- 02 Haber-Weiss reaction
Figure 1. Chemica l reactions which lead to the generation of reac-
tive oxygen specie s.
opment of various pathologies [8]. Interestingly how-
ever, there have been a number of reports which have
demonstrated the contribution of natural and synthetic
antioxidants, or the induction of cellular antioxidant
systems in the prevention or the modulat ion of the
adverse effects of oxidative stress.
CELLULAR EFFECTS OF OXIDATIVE
STRESS AND RELATED DISEASES
Lipoperoxidation
Lipid peroxidation occurs in polyunsaturated fatty
acids. The process is init iated by a hydroxyl radica l OH
when this species captures a hydrogen atom from a
methylene carbon in the polyalkyl chain of the fatty acid
(fi,pul-e 2). Under aerobic conditions a fatty acid with an
unpaired electron undergoes a molecular rearrange-
ment by reaction with O2 to generate a peroxyl radical.
This product is highly reactive and can combine with
other peroxyl radicals to alter membrane proteins. The
radicals can also capture hydrogen molecules from the
adjacent fatty acids to form a lip id hydroperoxide, sub-
sequently inducing the propagation of lipid peroxida-
tion. Thus, the peroxidation of unsaturated fatty acids
can induce the conversion of several fatty acid side-
chains in lip id hydroperoxides, which in turn leads to
the formation of a reaction chain.
During lipid peroxidation, malondialdehyde (MDA),
a highly reactive dialdehyde, can also be generated
[ 121. MDA can react with the free amino-group of pro-
teins, phospholipids or nucle ic acids, to produce inter-
and intra-molecular I-amino-3-iminopropene (AIP)
bridges and structural modifications of biolog ical
molecules [ 131. These MDA-induced structures are
subsequently recognized as non-self by the immune
system which leads to an autoimmune response [14].
In several pathologies such as diabetes [ 151, hyper-
lipem ia [ 161, atherosclerosis [ 171, apoplexy [ 181, and
liver diseases [ 191, t has been shown that lip id perox-
LH+OH . L+H,O
Propagation
L+o,
LOO+LH
. LOO
. LOOH+L
Hydqxroxide decomposition
LOOH
- LO
- Malondialdehyde
Figure 2. Mechanism of lipid peroxidation.
LH: polyunsaturated fatty acid; L: alkyl radical; LOOH: lipid
hydroperoxide; LO-: alkoxyl radic al.
idation increased significantly. The role of oxidants has
also been implicated in the inflammation process [20,
211 via cellu lar enzymes such as lipooxygenases and
cyclooxygenases. These enzymes produce the physio-
logical specific fatty acyl peroxides eicosanoids. More-
over, the cholesterol or fatty acid moieties of the plas-
matic low-density lipoproteins (LDL) can also be
oxidized during oxidative stress [22, 231. Oxidized
LDL is considered to be the key event in the develop-
ment of atherosclerosis [24, 251.
DNA oxidation
The oxidation of guanine by the hydroxyl radical (OH*)
to 8-hydroxy-2-deoxyguanosine (8-OHdG), alters
DNA [26] and leads to mutagenesis [27] and carcino-
genesis [28]. DNA altera tion has been suggested to be
responsible in part in the processes of aging [29], d ia-
betes mellitus [30], inflammatory diseases [27], and
liver disease [31]. The altered DNA can be specifically
repaired by DNA glycosylase [32]. However, if the
degree of oxidative stress is too great, DNA repair by
glycosylases is circumvented to induce mutagenesis
and/or carcinogenesis.
Protein oxidation
Proteins are also targets for free radicals. Oxidat ive
molecules such as hypochlorous acid can induce the
production of 3-chlorotyrosine from tyrosine [33], and
histidine can be oxidized to 2-oxohistidine in metal-cat-
alyzed oxida tive reactions which can occur in the metal
binding site of proteins [34]. Alterations of signal trans-
duction mechanisms, transport systems, or enzyme
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Oxidative stress and pathologies
171
activities have been shown [35]. Protein oxidat ion may
be at least in part responsible for atherosclerosis,
ischemia-reperfusion injury, and may also be associated
with aging [36, 371.
Dysregulation of nitric oxide (NO) synthesis
NO is synthesized from L-arginine by nitric oxide syn-
thase (NOS). NOS is a dimeric protein , each of the two
subunits having an average molecular mass of 150 kDa.
NOS plays a role in the transformation of L-argin ine
to L-hydroxyarginine, and in the transformation of
L-hydroxyarginine to L-cit rulline and NO. NO is an
intracellular messenger which itself plays an important
role in the nervous system, the immune system, and in
the cardiovascular system [38].
There are three isoenzymes of NO which have spe-
cific locations. Isoenzyme I is localized in neural cells
and is responsible for the central regulation of blood
pressure and smooth-muscle relaxation, but it is also
associated with cel l death in cerebrovascular stroke
[39]. Isoenzyme II is found in macrophages [40] and is
implicated in the pathology of autoimmune responses
and in septic shock [41]. Isoform III is found in endothe-
lia l cells and is involved in the dilatation of blood ves-
sels and also prevents the adhesion of platelets and
white cells to blood vessel [42].
EFFECTS OF ANTIOXIDANTS
AND THE DELETERIOUS EFFECTS
OF OXIDATIVE STRESS
Antioxidant enzymes
Cells have developed enzymatic systems which convert
oxidants into non-toxic molecules, thus protecting the
organism from the deleterious effects o f oxidative stress
(fisure ).
Superoxide dismutase
Superoxide dismutase (SOD) converts the superoxide
anion 02- into a less toxic product, namely H,O, and 0,.
Two forms of SOD exist, a manganese conta ining SOD
(MnSOD, present in mitochondria), and a copper-zinc
dependant SOD (CuZnSOD) present in the cytosol
[43]. These enzymes are the first li ne in cell defense
against oxidative stress.
Catalase
Catalase (CAT) is the second enzyme which acts in cel-
lular detoxification. CAT converts H,O, into H,O and
02.
Superoxide Dismutase
20;+2H -
HA + 01
Catalase
2
HA
b 2n,o+02
Glutathione peroxidase
2 GSH + H,Oz -
GSSG + 2 H,O
Glutathione reductase
GSSG + NADPH, H - 2GSH + NADP+
Figure 3. Reactions catalyzed by antioxidant enzymes.
Glutathione peroxidase
In H,02 detoxification, the selenium dependant glu-
tathione peroxidase (GSHPX) converts H,O, into water
via the oxidation of reduced glutathione (GSH) in oxi-
dized glutathione (GSSG). GSHPX exists also in an
insoluble form associated with the membrane (phos-
pholipid hydroperoxide glutathione peroxidase), and
which acts on lip id hydroperoxide [44]. There also
exists a second membrane-associated enzyme involved
in the metabolism of glutathione, glutathione reductase
(GSSGRed). GSSGRed is a flavoprotein which permits
the conversion of GSSG to GSH via the oxidation of
NADPH to NADP+. This reaction is essential for the
availab ility of GSH in vivo. Deprivation of trace ele-
ments such as Cu, Mn, Zn, Se, or vitamins such as
riboflavin, leads to the inactivation of the antioxidant
enzymes and oxidat ive stress associated disease [31].
Induction of antioxidant enzymes leads to the amelio-
ration of the patient [45].
Thiol molecules
Glutathione
Glutathione (GSH) is a tripeptide g-L-glutamyl-L-
cysteinyl-L-glycine which represents the major non-
protein thiol in the body. This molecule is found in large
quantities in organs exposed to toxins such as the kid-
ney, the liver, the lungs, and the intestines (millimo lar
concentrations). In contrast, very litt le is found in body
fluids (micromolar concentrations) 1461. In the cell
GSH plays a role in protein synthesis, amino acid trans-
port, DNA synthesis, and more generally, in cellu lar
detoxification. GSH is involved in the conversion of
H,O, to water, and in the reduction of lipid hydroper-
oxides. It can be conjugated to xenobiotics via glu-
tathione S-transferase, a reaction which increases the
hydrophilic properties of the xenobiotic favoring the
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172
L. GatC et al.
L-cysteine + L-glutamate
1
-glutamylcysteine synthetase
y-glutamylcysteine
+
L-cysteine
Glutathione synthetase
Glutathione
1
-glutamyl transpeptidase
Glutamate
+
Cysteinylglycine
I
Dipeptidases
Cysteine + Glycine
Taurine
N&-c 400 +
2
NH~H-COOH
CY
H CY
c 00
w
&-c~+C~-C~-N~COOH
&OH
h
+
AH
&N-CH-COOH
k
NH2
LH-CI+C~-CO-NH-CH-CO-~~~CH-C~~H
boon b
k
.bH
ml
coon + NH,-
CH-CO-NH-CH-COOH
%-CH--cooH + t-JN--CH -COOH
A
0
NHI- CHI-CM2 -$t+-OH
b
Figure 4. Metabolism of glutathione.
elimination of the xenobiotic. Since GSH enterspoorly
into the cells except in epithelial cells), intracellular
GSH is derived mainly from synthesis [47], and the
main source of plasma GSH is from the liver [48].
GSH is synthesized rom L-glutamine, L-cysteine, and
L-glycine via two enzymes: y-glutamylcysteine syn-
thaseand glutathione synthase figure 4).
An alteration in the metabolismof GSH is associated
with several pathologies. Plasmatic and hepatic con-
centrations of GSH decreasedramatically in patients
with viral hepatitis, and chronic liver injury causedby
chronic hepatitis or liver cirrhosis [49, SO]. GSH also
plays an important role in the activation of T-lympho-
cytes [51]. In HIV infection, a systemicGSH and cys-
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Oxidative stress and pathologies
173
Figure 5. Woredoxin system. TR: thioredoxin reductase; Trx: thioredoxin.
teine deficiency is linked to an increase of virus repli-
cation. Antiox idant production is also responsible for
inflammation and consequently the dysregulation of
immune system [52] . The administration of N-acetyl-
cysteine (NAC) to HIV positive patients increase the
leve l of GSH in CD4+ lymphocytes, inhibi ts the activ-
ity of NFkB, and arrests vi ral replica tion [53].
Due to cystine oxidation, cysteine is toxic. Therefore,
NAC has been used as an exogenous source of cysteine
to replenish the intracellular glutathione in GSH-defi-
cient patients. GSH depletion is also observed in lung
diseases such as acute respiratory disease (ARDS) [54],
and in neonatal lung damage [55]. Although asthma is
associated with free radical production, the over-
expression of GSH has been shown in alveolar [56].
cer cells may be associated to the development of resis-
tance to chemotherapy [67]. S ince GSH has poor
bioava ilability, its clinical use has been restricted [68]
and hydrophobic forms such as monoethylester of
glutathione have been synthesized. Such synthetic
molecules are cleaved in GSH by cellu lar esterases and
after an oral administration to GSH-deprived rats, it has
been shown an increase in plasmatic and hepat ic con-
centration of GSH [69]. After hydrolysis, NAC can be
a source of cysteine, the major amino acid in synthesis
of GSH [70].
The thioredoxin and glutaredoxin systems
In Parkinsons disease [57], the leve l of glutathione
in the substantia n igra in parkinsonian patients is lower
than in control patients. This decrease is related to the
increased degradation of y-glutamyltranspeptidase
[58]. During myocardial ischemia and reperfusion, a
reduction of GSH is observed in the ischemic tissue,
and myocardial injury is inversely proportional to the
myocardial concentration of GSH [59]. The adminis-
tration o f GSH synthesis activators (y-glutamylcysteine
or NAC) significantly reduces the infarct size and
myocyte death [59, 601.
The thioredoxin system comprises of NADPH, thiore-
doxin reductase (TR), and thioredoxin (Trx). I t is a
stress-inducible system which reduces the disulf ide
bond of several proteins and also oxidized GSH in
thiol groups (figure 5). The active site of Trx possesses
the conserved amino acid sequence Cys-Gly-Pro-Cys.
The oxidation of protein disulfide bonds leads gener-
ally to the loss of its activity, and in this manner the
thioredoxin system regulates the activity of differen t
proteins such as the transcription factors NFkB, AP-1
or MYB [71].
Kidneys are exposed to various cytotoxic agents
before the eliminat ion of these agents in urine. Thus,
the GSH concentration in kidney cells is important. In
different diseases such as renal ischemia [61], or intox-
ication by cyclosporin which induces the microsomal
lipoperoxidation [62], GSH levels decrease dramati-
cally. The direct administration of glutathione induces
an increase in plasmatic and renal glutathione concen-
trations [63]. Studies on the relationship between GSH
level and aging are still contradictory [64,65], and epi-
demiologica l investigations on a larger scale are neces-
sary before drawing any conclusions.
However thioredoxin can reduce other compounds,
such as lip id hydroperoxides. Trx and TR contribute
to maintain the redox status in the plasma by acting
as electron donors for the blood plasma peroxidase
in replacement of GSH [72]. TR reduces selenite in
selenide which is a precursor of the selenocysteine [73].
This amino ac id enters in to the composition of Trx,
located in the C-terminal sequence of the protein [74].
The mechanism of action of the glutaredoxin system is
similar to the thioredoxin system, however the glutare-
doxine system composed by glutaredoxin (Grx),
glutaredoxin reductase (GR), and NADPH also needs
the presence of glutath ione
(figure 6) [75].
It has also been suggested that GSH plays a role in
The active site of Grx possesses the conserved amino
cancer prevention. Recently it was shown that GSH
acid sequence Cys-Pro-Tyr-Cys. The role of the glutare-
enriched nutr ition decreases the rate of pharyngeal can-
doxin system is not entirely clear, but it may act in the
cers [66]. However, the increased leve l of GSH in can-
intracellula r balance between GSH/GSSG [76], and in
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174
Figure 6. Glutaredoxin system . GR: glutaredo xin reduc tase; Grx: glutaredo xin.
the glutathionylation of proteins such as carbonic anhy-
drase III and in the modification of its activity [77].
Recently it has been shown that the thioredoxin and
glutaredoxin systems may play a role in HIV replica-
tion by the activa tion of NFkB [78].
Taurine and hypotaurine
Taur ine and its precursor hypotaurine are p-amino acids
that are derived from cysteine metabolism [79]. These
molecules are implicated in the cellular mechanisms of
defense against oxidative stress [80]. However, data
shows that taurine does not really have an antioxidant
activity [8 l] and hypotaurine has the capacity to scav-
enge hydroxyl radical OH and to inhib it lipid peroxi-
dation [82]. However, in vivo results show that taurine
supplementation decreases lipid peroxydaion in dia-
betic rats [83], and that this amino acid protects the heart
during reperfusion postischemic [84]. Moreover, con-
centrations of taurine in specific cerebral areas such as
the striatum, the cortex, the nucleus accumbens and, the
cerebellum diminish during aging [85].
a-lipoic acid
a-lipoic acid exists in cells as lipoamide which is cova-
lently linked to different cytoplasmic protein com-
plexes by dihydrolipoamide dehydrogenase [86]. This
enzyme can reduce (using NADH) exogenous l ipoa te
to dihydrolipoate (DHLA), a potent reductant. Lipoate
can be also be reduced by glutathione reductase or
thioredoxin reductase [87]. DHLA can scavenge
hydroxyl radicals [88], and the lipoate-DHLA complex
can reduce GSSG in GSH [89] or oxidized forms of
vitamins C and E [87], thus increasing the cellu lar
defense from lipid peroxidation. Recently it has been
shown that lipoate prevents pathologies associated
with vitamin C or E deficiencies [90] and that it
increases the GSH concentration in lung and kidney
cells [91]. Lipoate can also block the activation of
NFkB induced by hydrogen peroxide and TNFa [92],
thus inhibi ting HIV replication [93].
NATURAL ANTIOXIDANTS IN NUTRITION
Vitamins
Vitamin E
Vitamin E (a-tocopherol) is the major lipophil ic antiox-
idant which can reduce free radicals such as lipoperox-
ides or oxygen radicals [94]. I t is found main ly in but-
ter, soybean, eggs, and cereals seeds. The oxidized
vitam in E can be reduced by glutathione [95] or ascor-
bate (vitamin C) [96].
Diet supplementation with vitamin E is associated
with an inhib ition of the oxidation of low density
lipoprotein (LDL) [97], a reduction in the risk of
atherosclerosis [98], and a reduction in coronary heart
disease [99]. It protects against endothelium injury
[ 100, 1011, and also against myocardial membrane
injury [102]. However, it has been reported that high
doses of vitam in E are responsible for the propagation
of lip id peroxidation [ 1031 and they may decrease the
activities of superoxide dismutase and catalase in the
gastric mucosa from patients with gastritis [ 1041. Vita-
min E deficiencies are observed in myocardial cells
from hypertensive rats [105] and in the plasma from
patients with ischemic heart disease [ 1061 or with hep-
atitis [107].
Vitamin C
Vitamin C (ascorbate) is found principa lly in fresh
vegetables and fruits, and its deficiency is responsible
for scurvy. However, vitamin C deficiencies can be
part ially corrected by glutathione ester administra-
tion [108]. Ascorbate inhibi ts the chemotaxis of
macrophages in the lung and reduces lung injury [ 1091.
It protects against lipid peroxidation in the plasma
[I lo] and against the microsomes by a vitamin E
dependant pathway [ 1111. Furthermore, vitam in C
inhibits the antiproliferative effect of hypochlorous
acid in lymphocytes in vitro [ 1121. Ascorbic acid also
prevents endothel ial dysfunction in chronic heart dis-
ease by inhibit ing NO degradation [ 1131 and it neu-
tralizes oxidant molecules which are produced during
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Oxidative stress and pathologies 175
S-S
eoo,
R - a) LipoicAcid
s~cooH
R - a) Dihydrolipoic cid
L-AscorbicAcid VitaminC)
OH
a-TocopherolVitaminE)
p-carotene
Retinol VitaminA)
5- 2-pyrazinyl)-4-methyl-1,2-dithiol-3-thioneoltipraz)
Figure . Chemicaltructuresf theprincipal ntioxidant olecules
macrophageactivation by tobacco smoke [ 1141.Low
plasma evels of ascorbateare associatedwith sickle
cell disease 1151, he risk of angina [ 1161, and are
observed in non-smokersexposed to tobacco smoke
[117]. Nonetheless,ascorbate n associationwith Fez+
provides a potent oxidant system [118] and increases
the lipid peroxidation induced by hemoglobin and fer-
ric ion in the central nervous system during hemor-
rhage [I 191.
Vitamin A
Vitamin A retinol) hasan antioxidant activity that may
have a role in the prevention of severaldiseases uchas
cancer [120, 1211.Vitamin A is a lipophilic molecule
found mainly in vegetablesand milk. It protects bio-
logical membranes 122] and LDL [123, 1241against
oxidative stress. n biological systems, itamin A inter-
acts with vitamin E in order to fight eff icient ly against
oxidation [125]. Low vitamin A concentrations n the
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L. Gate et al.
plasma are observed during reperfusion injury after
hepatic transplantation [ 1261. In contrast to vitamin E,
which is decreased in the plasma of juvenile arthritis
patients, no change has been observed in the concen-
tration of vitamin A [ 1271. Since p-carotene (a precur-
sor of retinol) and the other vitamins are destroyed by
tobacco smoke [128], the plasma levels of p-carotene
are very low in coronary artery disease [129] and in
smokers [ 1301. Administ ration of carotenoids protects
against DNA alterations [ 13 I], and protect cells in vitro
against neoplastic transformation [ 1321. Nonetheless,
carotenoids can also exhibit a prooxidant activity in
particular conditions [ 1331.
Flavonoids
Flavonoids are polyphenolic compounds which occur
naturally in plants and which represent a large family
of molecules separated in twelve subgroups, including
the flavones, flavonols, flavavones, anthocyanidins, and
catechins. These compounds are not produced in ani-
mals and are poorly stocked in these organisms. These
molecules are associated with the benefic ial effects of
wine (the French paradox) [134], green tea [ 1351, and
medicinal plants [ 1361. Flavonoids which share a basic
structure with vitamin E are potent scavengers of free
radicals such as hydroxyl and superoxide radicals, and
also act as chelators of transient elements [137, 1381. It
has been reported that a flavonoid-enriched diet helps
prevent various pathologies including cancer [ 1391,
coronary heart disease [ 1401, and strokes [ 1411. These
polyphenolic compounds also have biolog ical effects
against inflammatory and allergic disorders by inhibit-
ing the release o f histamine [ 1421. It has been reported
that flavonoids possess the potentia l to inhibi t pro-
teinase activity and to scavenge oxidants [ 1431.As such,
they have shown to have an anti-HIV activity [ 1441.
Crassostrea gigas
The pept ide composition of Crassostrea gigas extract
(CGE) shows a high concentration of taurine (up to 25
of the amino acid residues). In HL60 cells exposed in
vitro to CGE, an increase in the intracellular GSH level
has been obtained [ 1451. An increase in intracellular
GSH was also found in the large and small intestine,
liver, and spleen of rats fed for four weeks with CGE
[146]. Crassostrea gigas extracts protect human
endothe lial cells against oxidative stress [ 1471, and pro-
tects cardiac myocytes from anti-arrhythmic activity
when exposed to doxorubicin [ 1481. It also increases
the GSH level in the plasma of humans [ 1491. Although
the real mechanism of action of this extract is unknown,
it cannot be excluded that taurine may be responsible
for its antioxidant activity [ 1451.
Oltipraz
Oltipraz, or 5-(2-Pyrazinyl)-4-methyl- 1,2-dithiole-
3-thione, is a member of the 1,2-dithiole-3-thione fam-
ily primary used as a schistosomicidal drug [ 1501. How-
ever, the administration of oltipraz to mice induced an
increase in the level of glutathione in the liver, the lung,
the kidney, the stomach, and the jejunum [ 15 I]. Oltipraz
is currently undergoing clin ical trials for cancer pre-
vention. It has been shown that it inhib its aflatoxin-
induced hepatocarcinogenesis [ 1521 and colon carcino-
genesis induced by azoxymethane [153]. However, it
has no effect on pulmonary adenoma induced by benzo-
[a]-pyrene [ 1541. These observations are probably due
to an induction of glutathione S-transferases [ 155, 1561
or cytochrome P-450 inh ibit ion which is responsible for
carcinogen metabolism [ 1571. Oltipraz can also stimu-
late antioxidant enzymes such as manganese superox-
ide dismutase [ 1581 or glutathione peroxidase [ 1591,
and it can decrease lipoperoxidation in the liver o f
mice [ 1601. Finally, oltipraz inhibits the replication of
HIV- 1 in H9 cutaneous T ce ll lymphomas [ 16 11.
CONCLUSION
Antiox idant systems are being shown to play an increas-
ing role in the protection against exogenous oxidative
stress. In the very near future, it will be necessary for our
well being and in the prevention against different
pathologies, to improve the efficiency of antioxidants, to
develop molecules with intrinsic antioxidant activity, or
to find molecules that will increase directly or indirectly
the leve l of endogenous antioxidant systems.
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