7/26/2019 (GATE et al, 1999)

1/12

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-

7/26/2019 (GATE et al, 1999)

2/12

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

7/26/2019 (GATE et al, 1999)

3/12

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

7/26/2019 (GATE et al, 1999)

4/12

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-

7/26/2019 (GATE et al, 1999)

5/12

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

7/26/2019 (GATE et al, 1999)

6/12

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

7/26/2019 (GATE et al, 1999)

7/12

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

7/26/2019 (GATE et al, 1999)

8/12

176

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.

REFERENCES

Urban MB, S&reck R, Bauerle PA. NFkB contacts DNA by

a heterodimer of p50 and ~65 subunit. EMBO J 1991 ; 10 :

1817-25.

Urban MB, Bauerle PA. The 65 kDa subu nit of NFkB is a

receptor for IkB and a modulator of DNA-binding specificity.

Genes Dev 1990 ; 4 : 1975-84.

Bauerle PA, Baltimore D. Activation of DNA-binding activity

in an apparently cytoplasm ic precursor of NFkB transc ription

factor. Cell 1988 ; 53 : 211-7.

Sen R, Baltimore B. Inducibility of k immuno globulin

enhancer-binding protein NFk by a post-translational mecha-

nism. Cell 1986 ; 47 : 921-28.

Iwasaki T, Uehara Y, Graves L, Rachie N, Bomsztyk K. Her-

bymicin A blocks IL-l-induced NFkB DNA-binding activity

in lymphoid cell lines. FEBS Lett 1992 ; 298 : 240-4.

7/26/2019 (GATE et al, 1999)

9/12

Oxidative stress and pathologies

177

8

9

10

11

12

16

17

18

19

20

22

23

24

25

Schreck R, Meier B, Mannel DN, Droge W, Bauerle PA.

Dithiocarbamate as potent inhibitors of nuclear factor kB acti-

vation in intact cells. J Exp Med 1992 ; 75 : 1181-94.

Griffin GE, Leung K, Folks TM, Kunkel S, Nabel GJ. Activa-

tion of HIV gene expression during monocyte differentiation

by induction-of NFkB. Nature 1989 ; 339 : 70-3.

Kehler JP. Free radicals as mediators of tissue iniuw and dis-

.ase. Crit Rev Toxic01 1989 ; 23 : 21-7.

Moolenaar WH. Lysophosph atidic acid, a multifunctiona l

phosph olipid messenger (review). J Biol Chem 1995 ; 270 :

12949-52.

Ross R, Glomset JA. The pathogenes is of atherosclerosis (sec-

ond of two parts) (review). N Engl J Med 1979 ; 295 : 420-5.

Nataraja n V, Scribn er WM, Ha rt CM, Parthasarathy S. Oxi-

dized low density lipoprotein-mediated activation of phospho-

lipase D in smooth musc le: a possib le role in cell proliferation

and atherogenesis. J Lipid Res 1995 ; 36 : 200516.

Draper H, Hadley M. A review on recent studies on the

metabo lism of exogenous and endogenous malondialdehyde.

Xenob iotica 1990 ; 20 : 901-10.

Halliwe ll B, Gutteridge JMC. Free radicals in biology and

medicine . Oxford: Oxford Scie nces Publication s, Clarendon

Press; 1989.

Kergonou JF, Bruna E, Pennacino I, Ducousso R. Immuno-

genicity of proteins reacted with malonic dialdehyde (MDA).

Adv Bios ci 1988 ; 71 : 121-4.

Sato Y, Hotta N, Sakamoto N, Matsuko S, Oshishi N, Yagi K .

Lipid peroxide level in plasma of diabetic patients. Biochem

Med 1979 ; 21 : 104-7.

Esterbauer H, Dieber-Rhotheneder M, Waeg G, Striegl G, Jur-

gens G. Bioche mical, structural and functional properties of

oxidized low-density lipoprotein. Chem Res Toxic01 1990 ; 3 :

77-92.

Plachta H, Bartnikowska E, Obara A. Lipid peroxides in blood

from patients with atherosclerosis of coronary and peripheral

arteries. Clin Chin Acta 1992 ; 211 : 101-15.

Kawamoto M, Kagami M, Terashi A. Serum lip id peroxide

level in apoplexia. J Clin Biochem Nutr 1986 ; 1 : I-3.

Rouach H, Fatacc ioli V, Gentil M, French SW, Morimoto M,

Nordmann M. Effect of chronic ethanol feeding on lipid per-

oxidation and protein oxidation in relation to liver pathology.

Hepatology 1997 ; 2 : 351-5.

Practice D, Iliuano L, Pulc inelli FM, Bonavita MS, Gaz-

zaniga P, VioIi F. Hydrogen peroxide triggers activation of

human platelets selectively exposed to non-aggregating con-

centrations of arachidonic acid and collagen. J Lab Clin Med

1992 ; 119 : 364-70.

Miller DK. Sadowski S. Sodermann DD. Kuehl FA. Endothe-

lial cell prostayclin production induced by activated neu-

trophils. J Biol Chem 1985 ; 60 : 1006-14.

Tien M, Aust SD. Comparative aspects of several model lipid

peroxidation systems. In: Yagi K, ed. Lipid peroxides in biol-

ogy and medicine. Orlando: Acade mic Press ; 1982. p. 23-9.

S&h L. Cholesterol oxidation. In: Vigo-Pelfrey C, ed. Mem-

brane lioid oxidation. Boca Raton: CRC Press; 1990. o. 129-54.

Steinberg D, Parthasarathy S, Carew TE , Khoo jC, Witz-

turn JL. Beyond ch olesterol: modifica tions of low-density

lipoprotein that increase its artherogenicity. N Engl J Med

1989 ; 320 : 915-24.

Galle J, Bengen J, Schollmeyer P, Wanner C. Impairment of

endothelium-dependant dilation in rabbit renal arteries by oxi-

dized lipoprotein(a): role of oxygen-derived radicals. Circula-

tion 1995 ; 92 : 1582-9.

26 Kasa i H, Crain PF, Kuchino Y, Nishimura S, Ootsuyama A,

Tanooka H. Formation of 8-hydroxyguanine in cellular DNA

by agents producing oxygen radicals and evidence for its

repair, Carcinogen esis 1986 ; 8 : 1849-5 1.

27

28

29

30

31

32

33

34

35

36

37

38

39

Ames BN. Dietary carcinogens and anticarcinogens. Scienc e

1983 ; 221 : 1256-64.

Floyd RA. The role of 8-hydroxyguanosine in carcinogen esis.

Carcinogene sis 1990 ; 1 I : 1447-50.

Fraga C G, Shigenaga MK, Park J, Deaaan P,Ames BN. Oxida-

tivedama ge tobNA during aging : 8-hydroxy-2-deoxyguano-

sine in rat organ DNA and urine. Proc Nat1 Acad Sci USA

1990 ; 87 : 4533-7.

Dandona P, Thusu K, Cook S, Snyder B, Nicotera T. Oxidative

DNA damage diabetes mellitus. Lancet 1996 ; 347 : 444-5.

Sipowicz MA, Chomarat P, Diwan BA, Anver MA,

Awasthy YC, Ward JM, et al. Increased oxidative DNA dam-

age and hepatocyte overexpression of spec ific cytochrome

P450 isoforms in hepatitis of mice infected with Helicobacter

hepaticus.

Am J Path01 1997 ; 4 : 933-41.

Chung MH, Kasa i H, Jones DS, Inoue H, Ishikawa H, Oht-

suka E, et al. An endonuclease activity of Escherichia coli that

specifica lly removes X-hydroxyguanine residues from DNA.

Mutat Res 1991 ; 254 : I-12.

Domigan NM, Charlton MW, Duncan CC, Winterboum CC,

Kettle AJ. Chlorination of tyrosyl residues in peptides by

myeloperoxidase and human neutrophils. Biol Chem 1995 ;

270 : 16542-8.

Lewisch SA, Levine RL. Determination of 2-oxohistidine by

amino acid analysis. Ann B iochem 1995 ; 231 : 440-6.

Wisema n H, Halliwell B. Damage to DNA by reactive oxygen

and nitrogen specie s: role in inflammatory disease and pro-

gression to cancer. Biochem J 1996 ; 313 : 17-29.

Berliner JA, Heinecke JW. The role of oxidized lipoproteins in

atherogenesis. Free Rad Biol Med 1996 ; 20 : 707.

Stadtman JA. Protein oxidation and aging. Scienc e 1992 ; 257 :

1220-4.

Moncada S, Palmer RMJ, H iggs E A. Nitric oxide: physiology,

physiopathology and pharmacology (review). Pharmacol Rev

1991 ; 43 : 109-42.

Bredt DS, Snyder SH. Isolation of nitric oxide syn thase, a

calmod ulin requiring enzyme. Proc Nat1 Acad Sci USA 1990 ;

87 : 682-5.

40 Stuehr DJ, Cho HJ. Kwon NS, Weise MF, Nathan CF.

Purification and characterization of the cytokine induced

macrophage nitric oxide synthase: an FAD and FMN contain-

ing flaboprotein. Proc Nati Acad Sci USA 1991 ; 88 : 7773-7.

41 Forstermann U. Biochemistry and molecular biology of nitric

oxide synthases (review). Arzneimittel-forshung 1994 ; 44 :

402-7.

42 Sess a WC. The nitric oxide synthase family of proteins. J Vas

Res 1994 ; 31 : 131-43.

43 Halliwe ll B, Gutteridge JMC. Free radicals, antioxidants and

human disease: where are we now? J Lab Clin Med 1992 ; 119 :

598-620.

44 Ursini F, Maiorino M, Gregolin C. Phosp holipid hydroper-

oxidase elutathione oeroxidase. Int J Tis s Reac 1986 ; 8 :

99-103. -

45 Janero DR. Therapeutic potential of vitamin E in the patho-

genes is of spontaneous atherosclerosis. Free Rad Biol Med

1991 ; I : 129-44.

46 De Leve LD, Kaplowitz N. Glutathione metabolism and its role

in hepatotoxicity. Pharmacol Ther 1991 ; 52 : 287-305.

47 Deneke SM, Fanburg BL. Regulation of cellular glutathione.

Lung Cell Mol Physiol 1989 ; I : L163-73.

48 Kaplowitz N, Aw TY, Ookhtens M. The regulation of

hepatic glutathione. Annu Rev Pharmacol Toxic01 1985 ; 25 :

715-44.

49 Loguercio C, Delvecchio Blanc0 C, Coltorti M, Nardi G. Alter-

ation of erythrocyte glutathione, cysteine and glutathione syn-

thetase in alcoh olic and non-alcoho lic cirrhosis. Stand J Clin

Lab Invest 1992 ; 52 : 207-13.

7/26/2019 (GATE et al, 1999)

10/12

178 L. Gate et al.

50

51

52

53

54

55

56

51

58

59

60

61

62

63

64

65

,

Shigesawa T, Sato C, Marumo F. Significan ce of plasma

glutathione determination in patients with alcoh olic and non-

alcoho lic liver disease . J Gastroenterol Hepatol 1992 ; 7 : 7-11.

Staal FJT, Roederer M, Israelski M, Dubp J , Mole LA,

MC Shane D, et al. Intracellular glutathione levels in T-ce ll

subsets decrease in HIV-infected individuals. AIDS Res Hum

Retroviruses 1992 ; 8 : 305-l 1.

Holroyd KJ, Buhl R, Borok Z, Roum JH, Bokser AD,

Grimes GJ, et al. Correction of glutathione deficiency in the

lower respiratory tract of HIV seropositive individuals by glu-

tathione aerosol treatment. Thorax 1993 ; 48 : 985-9.

Mihm S, Ennen J, Pessara U, Kurth R, Droge W. Inhibition of

HIV-l replication and NFkappaB activity by cysteine and cys-

teine derivatives. AIDS 1991 ; 5 : 497-503.

Pachter P, Timerman AP, Lykens MG, Merola AJ. Deficiency

of alveolar fluid glutathione in patients with sepsis and

the adult respiratory distress syndrome. Chest 1991 ; 100 :

1397-403.

Grigg J, Barber A, Silverman M. Bronchoalveolar lavage fluid

glutathione in incubated premature infants. Arch Dis Child

1993 ; 69 : 49-51.

Smith LJ, Houston M, Anderson J. Increased levels of glu-

tathione in bronchalveolar lavage from patients with asthma.

Am Rev R espir Dis 1993 ; 147 : 1461.4.

Jenner P. Oxidative damage in neurodegenerative disease.

Lancet 1994 ; 344 : 796-8.

Sian J, Dexter DT, Less AJ, Daniel S, Jenner P, Marsden CD.

Glutathione-related enzymes in brain in Parkinsons disease.

Ann Neurol 1994 ; 36 : 356-61.

Hoshida S, Kuzuya T, Yamas hita N, Nishida M, Kitahara S,

Hori M, et al. Gamma-glutamylcysteine ethyl ester for myocar-

dial protection in dogs during ische mic and reperfusion. J Am

Co11 Cardiol 1994 ; 24 : 1391-7.

Forman MB, Puett DW, Cates CU, MC Croskey DE, Beck-

man JK, Greene HL, et al. Glutathione redox pathway and per-

fusion iniurv. Circulation 1988 : 78 : 202-3.

Duruibe V, bkonmah A, Blyden GT. Effect of cyclosporin on

rat liver and kidney glutathione content. Pharmacology 1989 ;

39 : 205-12.

Wang C, Salahudeen AK. Cyclosporine nephrotoxicity: atten-

uation by an antioxidant-inhibitor of lipid peroxidation in vitro

and in vivo. Transplantation 1994 ; 58 : 940-6.

Amano J, Suzuki A, Sunamori M. Salutary effect of reduced

glutathione on renal function in coronary artery bypass opera-

tion. JAm Co11 Sure 1994 : 179 : 714.20.

Julius M, Lang CA, Gleiberman L, Harburg E, Di Franceisco W,

Schork A. Glutathione and morbidity in a community-based

sample of elderly. J Clin Epidem iol 1994 ; 47 : 102 l-6.

Lang CA, Naryshkin S, Schneider DL, Mills BJ, Linder-

man RD. Low blood glutathione in healthy aging adults. J Lab

Clin Med 1992 ; 120 : 720-5.

66 Flaaa EW, Coates RJ, Jones DP, Bvers TE, Greenberg RS, Gti-

dleyG, et al. Dietary glutathione intake and the risk of oral and

pharyngeal cancer. Am J Epidem iol 1994 ; 139 : 453-65.

67 Tew KD. Glutathione associated enzymes in anticancer drug

resistance. Perspectives in cancer research. Cancer R es 1994 ;

54 : 43 13-20.

68 Aw TY, Wierzbicka G, Jones DP. Oral glutathione increases

tissue glutathione in vivo. Chem Biol Interact 1991 ; 80 :

89-97.

69 Grattagliano I, Wieland P, Schranz C, Lauterburg BH. Dispo-

sition of glutathione monoethyl ester in the rat: glutathione

ester is a slow release of extracellular glutathione. Proc Nat1

Acad Sci USA 1995 ; 272 : 484-8.

70 Lomaestro BM, Malone M. Glutathione in health and disease:

pharmacotherapeutic issue s. Ann Pharmacother 1995 ; 29 :

1263-73.

71

72

13

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

Holmgren A. Thioredoxin. Annu Rev Biochem 1985 ; 254 :

237-7 1.

Bjomstedt M, Xue J, Huang W, Akesson B, Holmgren A. The

thioredoxin and glutaredoxin systems are efficient electron

donors to human plasma glutathione peroxidase. J Biol Chem

1994 ; 269 : 29382-4.

Bjomstedt M, Kumar S, Holmgren A. Selenoglutathione is a

highly efficient oxidant of reduced thioredoxin and a substrate

for mamm alian thioredoxin reductase. J Biol Chem 1992 ;

267 : 8030-4.

Homgren A, Elias SJ, Aslund F, Bjomsted t M, Liangwei Z,

Ljung J, et al. Redox regulation by the thioredoxin and glutare-

doxin system s. In: Montagnier L, Olivier R, Pasquier C, eds.

Oxidative stress in cancer, AIDS and neurodegenerative dis-

eas es. New York: Ma rcel Dekker; 1998. p. 229-46.

Holmgren A, Aslund F. Glutaredoxin. Methods Enzymol

1995 ; 252 : 283-92.

Weis chel A, Gaskaska JR, Powis G, Montfont WR. Crystal

structures of reduced, oxidized and mutated human thioredox-

ins: evidence for a regulatory homo-dimer. Structure 1996 ; 4 :

735-5 1.

Cabisc ol E, Levine RL. The phosphate activity of carbonic

anhydrase III is reversibly regulated by glutathionylation. Proc

Nat1 Acad Sci USA 1996 ; 93 : 4170-4.

Staal FJ, Roederer M. Herzenberg LA. Intracellular thiol reg-

mate activation of nuclear factor kappa-B and transcription of

humanimm unodeficiencv virus. Proc Nat1 Acad Sci USA

.990 ; 87 : 9946-7.

Malmezat T, Breuillo D, Pouyet C, Mirand PP, Obled C.

Metabolism of cysteine is modified during the acute phase of

seps is in rats. J Nutr 1998 ; 1 : 97-105.

Huxtable RJ. Physiolog ical actions of taurine. Physiol Rev

1992 ; 72 : 101-63.

Aruoma I, Halliwe ll B, Hoey BM, Bu tler J. The antioxidant

action of taurine, hypotaurine and their metabo lic A precur-

sors. Bioche m J 1988 : 256 : 251-5.

Tado lini B, Pintus G, Pinna GG, Bennardini F, Franconi F.

Effects of taurine and hypotaurine on lipid peroxidation.

Biochem Biophys Res Commun 1995 ; 213 : 820-6.

You JS, Chang K J. Effects of taurine supplemen tation on lipid

peroxidation, blood glucose and blood lipid metabolism in

streptozotocin-induced diabetic rats. Adv Exp Med Biol 1998 ;

I : 163-8.

Raschke P, Massoudy P, Becker BE Taurine protects the heart

from neutrophil-induced reperfusion injury. Free Rad Biol

Med 1995 ; 4 : 461-71.

Benedetti MS, Russo A, Marrari P, Dostert P. Effects of aging

on the content in sulfur-containing amino acids in rat brain.

J Neural Transm Gen S ect 1991 ; 3 : 191-203.

Sen CK, Roy S, Packer L. Therapeutic potential of the antiox-

idant and redox properties of alpha-lipoic acid. In: Montag-

nier L, Olivier R, Pasquier C, eds. Oxidative stress in cancer,

AIDS and neurodegenerative disease s. New York: Marcel

Dekker; 1998. p. 25 1-67.

Packer L, Witt-EH, Trischler HJ. Alpha-lipoic acid as a bio-

logica l antioxidant. Free Rad Biol Med 1995 : 19 : 227-50.

Matsugo S, Yan LJ, Han D, Trischler HJ, Packer L. Elucida-

tion of antioxidant activitv of dihvdroliuoic acid toward

hydroxyl radic al using a novel hydioxyl generator NP-III.

Biochem Mol Biol Int 1995 : 37 : 375-83.

Jocelyn PC. The standard redox potential of cysteine-cystine

from the thiol-disulphide exchange reaction with glutathione

and lipoic acid. Eur J Biochem 1967 ; 2 : 327-3 1.

Podda M, Trischler HJ, Ulrich H, Packer L. Alpha-Lipoic

acid supplementation prevents symptoms of vitamin E

deficiency. Biochem Biophys Res Commun 1994 ; 204 :

98-104.

7/26/2019 (GATE et al, 1999)

11/12

Oxidative stress and pathologies

179

91 Busse E, Zimmer G, Schopo hl B, Korhuber B. Influence of

alpha-lipoic acid on intracellular glutathione in vitro and in

vivo. Arz Forsh 1992 ; 42 : 829-3 1.

92 Sen CK, Packer L. Antioxidant and redox regulation of gene

transcription. FASEB J 1996 ; 10 : 709-20.

93 Baur A, Harrer T, Peukert M, Jahn G, Kalden JR, Flecken-

stein B. Alpha-lipoic acid is an effective inhibitor of human

immuno-deficiency virus (HIV-l) replication. K lin Wochen-

schr 1991 ; 69 : 722-4.

94 Frei BB, Ames BN. Relative importance of vitamin E in

antiperoxidative defences in human blood and low-density

lipoprotein (LDL). In: Packer L, Fuchs J, eds. Vitamin E

in health and disease s. New York: Marcel Dekker; 1998.

p. 131-41.

95 Packer J E, Slater TF, Willso n RL. Direct observation of a free

radical interaction between vitamin E and C. Nature 1979 ;

278 : 737-8.

96 Bode AM, Cunningham L, Rose RC. Spontaneous decay of

oxidized ascorbic acid (dehydro-L-ascorbic acid) evaluated

by high-pressure liquid chromatography. Clin Chem 1990 ;

36 : 1807-9.

97 Reaven PD, Herold DA, Barnett J, Edelman S. Effects of vita-

min E on susce ptibility of low-density lipoprotein and low-

density lipoprotein subfraction to oxidation and or protein

glycation in NIDDM. Diabetes Care 1995 ; 18 : 807-16.

98 Nyssoner K, Pokkala E, Saloner R, Korpela H, Saloner SF.

Increase in oxidation resistance of artherogenic serum

lipoprotein following antioxidant supplementation: a ran-

domized double-blind placebo-controlled clinic al trial. Eur J

Clin Nutr 1994 ; 48 : 633-42.

99 Stampfer MS, Hennekens CH, Manson JE, Colditz GA, Ros-

ner B, Willet WC. Vitam in consum ption and the risk of coro-

nary dise ase in women. N Engl J Med 1993 ; 328 : 1444-9.

100 Boogaerts, MA, Van De Broeck J, Deckmyn H, Roelant C,

Vermylen J, Verwilghen RL. Protective effect of vitamin Eon

immune triggered, granulocyte mediated endothelial injury.

Thromb Haemost 1984 ; 1 : 89-92.

101 Hennig B, Boissonn eault GA, Wang Y. Protective effects of

vitamin E in age-related endothelial cell injury. Int J Vitam

Nutr Res 1989 ; 2 : 273-9.

102 Janero DR, Burghardt B. Oxidative injury to myocardial

membrane: direct modulation by endogenous alpha-toco-

pherol. J Mol Cell Cardiol 1989 ; 11 : I 11 l-24.

103 Witting PK, Mohr D, Stocker R. Asses sment of prooxidant

activity of vitamin E in human low-density lipoprotein in

plasma. In: Packer L, ed. Methods in Enzymol (vol. 299).

New York: A cadem ic Press; 1999. p. 362-71.

104 Beno I, Volkovov K, Staruchov M, Koszeghyov L. The activ-

ity of Cu/Zn-superoxide dismutase and catalase of gastric

mucosa in chronic gastritis, and the effect of alpha-tocopherol.

Bratisl Lek Listy 1994 ; 1 : 9-14.

105 Janero DR, Burghardt B. Myocardial vitamin E (alpha-toco-

pherol) contents of spontaneously hypertensive and Wistar

Kyoto normotensive rats. Int J Vitam Nutr Res 1988 ; 3 :

292-4.

106 Gey KF. Inverse correlation of vitamin E and ische mic heart

disease. Int J Vitam Nutr Res 1989 ; 21 : 224-3 1.

107 Mezes M, Per P, Nemeth P, Jevor T. Studies of the blood lipid

peroxide status and vitamin E levels in patients with chronic

active hepatitis and alcoho lic liver disease. Int J Clin Phar-

macol Res 1986 ; 14 : 333-8.

108 Martensson J, Han J, Griffith OW, Meister A. Glutathione

ester delays the onset of scurvy in ascorbate-deficient guinea

pigs. Proc Nat1 Acad Sci USA 1993 ; 90 : 317-31.

109 Nowak D, Ruta U, Piasecka G. Ascorb ic acid inhibits poly-

morphonuclear leukocytes influx to the place of inflamma-

tion-possible protection of lung from phagocyte-mediated

injury. Arch Immu nol Ther Exp (Warsz) 1989 : 3 Suppl ;

213-8.

110 Frei B, England L, Ames BN. Ascorbate is an outstanding

antioxidant in human blood plasma . Proc Nat1 Acad S ci USA

1989 ; 86 : 6377-8 1.

I1 1 Wefers H, Sies H. The protection by ascorbate and glutathione

against microsom al lipid peroxidation is dependent on vita-

min E. Eur J Biochem 1988 ; 2 : 353-7.

112 Smit MJ, Anderson R. Inhibition of mitogen-activated prolif-

eration of human lymphocytes by hypochlorous acid in vitro:

protection and reversal by ascorbate and cysteine. Agents

Actions 1990 ; 3 : 33843.

113 Hornig B, Arakawa N, Kohler C, Drexler H. Vitamin C

improves endothelial function of conduit arteries in patients

with chronic heart failure. Circulation 1998 ; 4 : 363-8.

114 Anderson R, Theron AJ, Ras GJ. Ascorb ic acid neutralizes

reactive oxidants released by hyperactive phagocytes from

cigarette smokers. Lung 1988 ; 1 : 149-59.

115 Jain SK, William s DM. Reduced levels of plasma ascorbic

acid (vitamin C) in sickle c ell disease patients: its possib le role

in the oxidant damage to sickle cells in viva. C lin C him A cta

1985 ; 2-3 : 257-61.

116 Riemersma RA, Wood DA, Macintyre CC, Elton R, Gey KF,

Oliver ME Low plasm a vitamins E and C. Increased risk of

angina in Scottish men. Ann NY Acad Sci 1989 ; 29 :

291-5.

117 Tribble DL, Giuliano LJ, Fortmann SP. Reduced plasma

ascorbic acid concentrations in nonsmokers regularly exposed

to environmental tobacco smoke. Am J Clin Nutr 1993 ; 6 :

886-90.

I I8 Parinandi NL, Weis BK, Natarajan V, Schm id HH. Peroxida-

tive modification of phosph olipids in myocardial membranes.

Arch Biochem Biophys 1990 ; 1 : 45-52.

119 Sadrzadeh SM, Eaton JW. Hemoglobin-mediated oxidant

damage to the central nervous system requires endogenous

ascorbate. J Clin Invest 1988 ; 5 : 1510-5.

120 Blumberg JB. Considerations of the scien tific substantiation

for antioxidant vitamins and beta-carotene in disease preven-

tion. A m J Clin Nutr 1993 ; 6 Suppl : 1521-6.

121 Krinsky NI. Antioxidant functions of carotenoids. Free Rad

Biol Med 1989 ; 6 : 617-35.

122 Ciaccio M, Valanza M, Tesoriere L, Bonjiomo A, Albiero R,

Livrea MA. Vitamin A inhibits doxorubicin-induced mem-

brane peroxidation in rat tissues in viva. Arch Biochem Bio-

phys 1993 ; 1 : 103-8.

123 Livrea MA, Tesoriere L, Bonjiorno A, Pintaudi AM,

Ciaccio M, Riccio AM. Contribution of vitamin A to the oxi-

dation resistance of human low density lipoproteins. Free

Radic Biol Med 1995 ; 3 : 401-9.

124 Helen A, Vijayammal PL. Effect of vitamin A supplementa-

tion on cigarette smoke - induced lipid peroxidation. Vet Hum

Toxic01 1997 ; 1 : 18-21.

125 Tesoriere L, Bonjiomo A, Pintaudi AM, D anna R, Darpa D,

Livrea MA. Synergistic interactions between vitamin A and

vitamin E against lipid peroxidation in phosphatidylcho line

liposome s. Arch Biochem Biophys 1996 ; 1 : 57-63.

126 Goode HF, Webster NR, Howdle PD, Leek JP, Lodge JP,

Sadek SA, et al. Reperfusion injury, antioxidants and hemo-

dynamics d uring orthotopic liver transplantation. Hepatology

1994 ; 2 : 354-9.

127 Honkanen VE, Pelkonen P, Konttinen YT, Mussalo-

Rauhamaa H, Lehto J, Westermarck T. Serum cholesterol and

vitamins A and E in juvenile chronic arthritis. Clin Exp

Rheumatol 1990 ; 2 : 187-91.

128 Handelman GJ, Packer L, Cross CE. Destruction of toco-

pherols, carotenoids, and retinol in human plasma by cigarette

smoke. Am J Clin Nutr 1996 ; 4 : 559-65.

7/26/2019 (GATE et al, 1999)

12/12

180 L. Gate et al.

129 Kim SY, Lee Kim YC, Kim MK, Suh JY, Chung EJ, Cho SY,

et al. Serum levels of antioxidant vitamins in relation to coro-

nary artery disease: a case control study of Koreans. Biomed

Environ Sci 1996 ; 2-3 : 229-35.

130 Pamuk ER, Byers T, Coates RJ, Vann J W, Sowe ll AL,

Gunter EW, et al. Effect of smoking on serum nutrient con-

centrations in African-American women. Am J Clin Nutr

1994 ; 4 : 891-5.

gigas extract (JCOE) on glutathione levels and glutathione

S-transferase activity in rat tissues . In vivo 1998 ; 12 : 299-4.

147 Edeas MA, Claise C. Messaoudi C. Chalas J. Abellal A.

131 Pool Zobel BL, Bub A, Muller H, Wollowski I, Rechkem-

mer G. Consump tion of vegetables reduces gen etic damage

in humans: first results of a human intervention trial

with carotenoid-rich foods. Carcinogenesis 1997 ; 9 :

1847-50.

Tapiero H, et al. Protective effect of Crassostrea gigas extract

against oxidative stress in human e ndothelial and red blood

cells. Cell P harmacol 1996 ; 3 : 337-41.

148 Lamp idis TJ, Kolonias D, Tapiero H. Effects of Crassostrea

gigas extract (JCOE) on cardiac cell function in vitro: anti-

akhythmic activity. Cell Pharmacol 1996 ; 3 : 241-6.

149 Tauiero H, Gate L, Dhalluin S. Nauven Ba G. Souora-

mamen V, Kouyate J, et al. The antioxidant effects of Cras-

sostrea gigas extract (JCOE) in human volunteers. In vivo

1998 ; 12 : 305-10.

132 Pung A, Rundhaug JE, Yoshizawa CN, Bertram JS. Beta-

carotene and canthaxanthin inhibit chemically- and physi-

cally-induced neoplas tic transformation in lOT1/2 cells. Car-

cinogen esis 1988 ; 9 : 1533-9.

133 Palozza P. Prooxidant actions of carotenoids in biologic sys-

tems. Nutr Rev 1998 ; 9 : 257-65.

134 Waterhouse AL. W ine and heart disease. Chem Ind 1995 ; 3 :

338-41.

135 Imai K, Nakashi K. Cross se ctional study of effects of drink-

ing green tea on cardiovascular and liver disease s. Br Med J

1995 ; 310 : 693-6.

136 Homma M, Oka K, Yamada T, Niitsuma T, Ihto H, Taka-

hashi N. A strategy for discovering biologically active com-

pounds with high probability in Chinese herb remedies: an

application of Saiboku-to in bronchial asthma. Ann Biochem

1992 ; 202 : 179-87.

150 Archer S. The chemotherapy of schisto som iasis. Annu Rev

Pharmacol Toxic01 1985 ; 25 : 485-508.

15 1 Ansher SS, Dolan P, Bueding E. Bioche mical effects of dithi-

olthiones. Food Chem Toxic01 1986 ; 24 : 405-15.

152 Roebuck BD, Yi Liang L, Rogers AE , Groopman JD,

Kensler TW. Protection against Aflatoxin Bl-induced hepa-

toca rcino gene sis in F344 rats by 5-(2.pyrazinyl)-4-methyl-

1,2-dithio le-3-thio ne (Oltipraz): predic tive role for short-term

molecular dosimetry. Cancer Res 1991 ; 51 ; 5501-6.

153 Rao CV, Nayini J, Reddy BS. Effect of oltipraz (5-(2-

pyrazinyl)-4-methyl- 1,2-dithio l-3-thione ) on azoxvmethane-

induced bioche mical changes related to early colon carcino-

genes is in male F344 rats. Proc Sot Exu Biol Med 1991 : 1 :

77-84.

137 Robak J , Gryglewski RJ. Flavonoids are scavengers of super-

oxide anion s. Biochem Pharmacol 1988 ; 37 : 837-41.

138 Husain SR, Cillard J, Cillard P Hydroxyl radical scavenging

activity of flavonoids. Phytochemistry 1987 ; 26 : 126-33.

139 Middleton E, Kandaswam i C. The impact of plant flavonoids

on mamm alian biology: implicatio ns for immunity, inflam-

mation and cancer. In: Harborne JB, ed. The flavonoids:

advances in research since. New York: Acade mic Press;

1993.

154 Morse MA, Zu H, Kresty LA, S toner GD. Failure of dietary

oltipraz to inhibit benzoapyrene-induced lung tumorigenesis

in strain a mice. Cancer Lett 1995 ; 1 : 133-8.

155 Nare B, Smith JM, Prichard KR. Induction of glutathione

S-transfe rase isoenzy mes in mous e liver by 5.(2lpyrazynl)-

4-methyl-1,2-dithiole-3-thione (oltipraz). Biochem Pharma-

co1 1992 ; 4 : 873-9.

140 Hertog MGL, Feskens EJM, Hollman PCH, Katan MB,

Kromhout D. Dietary antioxidant flavonoids and risk of coro-

nary heart disease: the Zutphen elderly study. Lancet 1993 ;

342 : 1007-11.

156 Langoust S, Morel F, Meyer DJ, Fardel 0, Corcos L, Ket-

terer B, et al. A comparison of the effect of inducers on the

expression of glutathione-S-transferases in the liver of the

intact rat and in hepatocytes in primary culture. Hepatology

1996 ; 4 : 881-7.

141 Keli SO, Hertog MGL, Feskens EJM Kromhout D. Dietary

flavonoids, antioxidant vitamins and incidenc e of stroke.Arch

Intern Med 1996 ; I56 : 637-42.

142 Middleton E. Biolog ical properties of plant flavonoids: an

overview. Int J Pharmacognosy 1996 ; 34 : 127-41.

143 Muller E Reactive oxygen intermediates and human immun-

odeficiency virus (HIV) infection. Free Rad Biol Med 1992 ;

13 : 651-7.

157 Langoust S, Mahoo K, Berthou F, Morel F, Lagadic Goss-

man D, Glaise D, et al. Effects of administration of the chemo-

protective agent oltipraz on CYPIA and CYP2B in rat liver and

rat hepatocytes in culture. Carcinogene sis 1997 ; 7 : 1343-9.

158 Antras Ferry J, Mahoo K, Chevanne M, Dubo s MP, Morel F,

Guillouzo A, et al. Oltipraz stimulates the transcription of the

manganese superoxide dismutase gene in rat hepatocytes.

Carcinogen esis 1997 ; 11 : 2113-7.

144 Brinkworth RI, Stoermer MJ, Fairlie DP. Flavones are

inhibitors of HIV-l proteinase. Biochem Biophys Res Com-

mun 1992 ; 188 : 631-7.

159 Van Lieshout EM, Ekkel MP, Bedaf MM, Nijhoff WF,

Peters WH. Effects of dietary anticarcinogens on rat aas-

trointestinal glutathione peroxldase activity. &co1 Rep 1998 ;

4 : 959-63.

145 Tapiero H, Tew KD. Increased glutathione expression in cells

induced by Crassostrea gigas extract (JCOE). Biomed Phar-

macother 1996 ; 50 : 149-53.

160 Ali BH, Abdel Gayoum A, El Gawarsha K, Fakhri M. Lipid

peroxidation, glutathione and ascorbic acid concentrations in

tissues of mice treated with oltipraz: influence of cysteine and

olive oil pre-treatment. Gen Pharmacol 1991 ; 5 : 985-90.

161 Proschaska HJ, Yeh Y, Baron P, Polsky B. Oltipraz, an

146 Gate L, Schultz M, Walsh S, Dhalluin S, Nguyen Ba G,

Tapiero H, et al. Impact of dietary supplement of Crassostrea

inhibitor of human immuno deficiency virus type 1 replication.

Proc Nat1 Acad Sci USA 1993 ; 9 : 3953-7.