Documenti di Didattica
Documenti di Professioni
Documenti di Cultura
Oxidative Stress
Relationship with Exercise and Training
Julien Finaud, Gerard Lac and Edith Filaire
Laboratoire Biologie Interuniversitaire des Activites Physiques et Sportives, Universite Blaise
Pascal de Clermont-Ferrand, Aubi`ere, France
Contents
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 328
1. Free Radicals (FR) and Activated Species . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 329
1.1 Biochemistry of Reactive Oxygen Species (ROS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 329
1.1.1 Dioxygen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 329
1.1.2 Superoxide Ion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 330
1.1.3 Hydrogen Peroxide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 330
1.1.4 Hydroxyl Radical . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 330
1.2 Programmed Formation of ROS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 330
1.3 Unprogrammed Formation of ROS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 330
1.3.1 ROS Formation During Oxygen Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 330
1.3.2 ROS Formation During Ischaemia Reperfusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 332
1.3.3 ROS Formation During Haemoglobin and Myoglobin Oxidation . . . . . . . . . . . . . . . . . . . . . 332
1.3.4 Other Ways of ROS Production . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 333
1.4 Biological Effects of ROS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 333
1.4.1 Positive Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 333
1.4.2 Negative Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 333
2. Antioxidants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 335
2.1 Enzymatic Antioxidants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 335
2.1.1 Superoxide Dismutase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 335
2.1.2 Catalase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 335
2.1.3 Glutathione Peroxidase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 336
2.1.4 Relationship with Exercise and Training . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 336
2.2 Non-Enzymatic Antioxidants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 336
2.2.1 Vitamin E (Tocopherol) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 336
2.2.2 Vitamin C (Ascorbic Acid) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 338
2.2.3 -Carotene and Vitamin A (Retinol) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 338
2.2.4 Flavonoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 338
2.2.5 Thiols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 338
2.2.6 Coenzyme Q10 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 339
2.2.7 Uric Acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 339
2.2.8 Heat Shock Proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 339
2.2.9 Ferritin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 339
2.2.10 Albumin, Caeruloplasmin and Bilirubin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 339
2.3 Antioxidant Supplementation in Athletes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 340
2.3.1 Beneficial Effects of Antioxidant Supplementation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 340
2.3.2 Pro-Oxidant Effects of Overloaded Antioxidant Supplementation . . . . . . . . . . . . . . . . . . . 340
2.4 Summary: Exercise and the Antioxidant System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 340
3. Methods to Assess Oxidative Stress in Biological Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 340
3.1 Direct Detection of FR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 340
3.2 Measurement of Oxidative Damage to Lipids, Proteins and DNA Molecules . . . . . . . . . . . . . . . 341
328
Finaud et al.
Abstract
Free radicals are reactive compounds that are naturally produced in the human
body. They can exert positive effects (e.g. on the immune system) or negative
effects (e.g. lipids, proteins or DNA oxidation). To limit these harmful effects, an
organism requires complex protection the antioxidant system. This system
consists of antioxidant enzymes (catalase, glutathione peroxidase, superoxide
dismutase) and non-enzymatic antioxidants (e.g. vitamin E [tocopherol], vitamin
A [retinol], vitamin C [ascorbic acid], glutathione and uric acid). An imbalance
between free radical production and antioxidant defence leads to an oxidative
stress state, which may be involved in aging processes and even in some
pathology (e.g. cancer and Parkinsons disease). Physical exercise also increases
oxidative stress and causes disruptions of the homeostasis. Training can have
positive or negative effects on oxidative stress depending on training load,
training specificity and the basal level of training. Moreover, oxidative stress
seems to be involved in muscular fatigue and may lead to overtraining.
Regular physical activity, associated with a balanced diet, is known as an important factor for
health.[1] However, exhaustive and/or intense physical activity can induce diseases, injuries and chronic
fatigue, which can lead to the overtraining syndrome, partially because of the toxicity of free radicals (FR). FR, which are highly produced during
physical exercise,[1] are involved in muscular fa 2006 Adis Data Information BV. All rights reserved.
329
Among FR, reactive oxygen species (ROS) are derived from oxygen. ROS contains FR and reactive
forms of oxygen (table I). This article will focus on
ROS, which are involved in essential physiological
phenomenon such as immunity or oxidative stress.
Other FR families exist, such as reactive nitrogen
species (RNS) and reactive sulphur species (RSS)
[table I]. These species could be formed by reactions
with ROS or could increase ROS production.[14]
1.1 Biochemistry of Reactive Oxygen
Species (ROS)
1.1.1 Dioxygen
Aerobic organisms require dioxygen (O2) because this molecule acts as an electron acceptor
during the oxidation of energetic substrates. Paradoxically, dioxygen is a permanent threat.[10] Indeed, ROS are continually produced from exogenous origins (radiation exposure, air pollutants, intoxication by oxygen, smoke, alcohol) or from
endogenous origin (oxygen metabolism).[4,11] During oxygen metabolism, dioxygen receives two elec-
Contraction
ROS
Half-life
Main effects
Superoxide ion
O2
105 sec
Ozone
O3
Stable
Singlet oxygen
1O2
1 sec
Hydroxyl radical
OH
Hydrogen peroxide
H2O2
Stable
Hypochlorous acid
HOCl
Stable
109 sec
Alkoxyl radical
RO
106 sec
Peroxyl radical
ROO
7 sec
Hydroperoxyl radical
ROOH
RNS
Nitric oxide
NO
Nitric dioxide
NO2
Peroxynitrite
ONOO
RSS
Thyil radical
RS
Lipid peroxidation
DNA damage
Proteins oxidation
110 sec
0.051 sec
Proteins oxidation
DNA damage
ROS production
330
Finaud et al.
O 2- + H + O 2 H
O 2H + O 2-+ H + H 2O 2 + O 2
Fe 3+ + O 2- Fe 2+ + O 2
Fe 2+ + H 2O 2 Fe 3+ + OH + OH -
(Eq. 2)
In the immune system, neutrophils and macrophages are in charge of destroying foreign substances (antigens). Those immunity cells produce
O2 with the reduced nicotinamide-adenine
dinucleotide phosphate (NADPH)-oxidase system,
which is present in leukocytes.[17] During this process (equation 4), two O2 molecules are needed so
this reaction is called oxidative burst.
NADPH-oxidase
2 O 2 + NADPH
2 O 2- + NADP + + H +
(Eq. 4)
As shown in section 1.1.3, O2 can be converted
to H2O2 by SOD in Fentons reaction. After that,
H2O2 can be transformed into HOCL, which is very
active for antigen degradation.[18] Thus, an important quantity of ROS can be formed during the
immunity process and plays an essential biological
role for homeostasis control.[15,17]
1.3 Unprogrammed Formation of ROS
2 O 2- + 2 H + H 2O 2 + O 2
(Eq. 3)
H2O2 is not a FR because it has no unpaired
electron, but it is considered a ROS because of its
toxicity and its capacity to cause ROS formation. In
leukocytes, myeloperoxydase (MPO) transform
H2O2 in hypochlorous acid (HOCL), one of the
strongest physiological oxidants and a powerful antimicrobial agent.[15]
1.1.4 Hydroxyl Radical
It is generally considered that the oxygen metabolism, which occurs into mitochondria, is associated
with the generation of ROS.[19] Oxidative phosphorylations result in adenosine triphosphate (ATP) formation. Substrate oxidation occurs in the Krebs
cycle and in the electron transport chain with oxygen as the electron acceptor. In the respiratory chain,
9599% of oxygen consumed is reduced into water
(H2O) by a tetravalent reduction (equation 5) catalysed by coenzyme Q (CoQ).[17,20]
CoQ
O 2 + 4 e- + 4 H + 2 H 2 O
(Eq. 5)
However, 15% of O2 will form O2.[21-23] The
ROS formation is proportional to the respiratory
chain activity, but the latter is not always propor 2.[19] Two major sites of production of
tional to VO
ROS have been localised in the respiratory chain:
Sports Med 2006; 36 (4)
331
Mitochondria
NAD+
Complex I
Succinate
Fumarate
Retonone
Complex III
Complex II
Reversed
CoQH2
e- flow
CoQ
CoQ-
O2 O2-
Antimycin A
b cyt.
FeSR
Myxothiazol
Fig. 1. Possible locations of mitochondrial reactive oxygen species formation inside electron chain transport (reproduced from Nohl et al.,[26]
with permission. the Biochemical Society). b cyt. = b cytochrome; CoQ = coenzyme Q; CoQH2 = reduced coenzyme Q10; CoQ =
oxidised coenzyme Q10; FeSR = Rieske iron-sulphur protein; NAD+ = oxidised nicotinamide-adenine dinucleotide; NADH = reduced
nicotinamide-adenine dinucleotide; O2 = superoxide ion.
complex I and complex III (see figure 1).[20,23] Distribution and quantity of ROS production inside
these complexes fluctuate according to the needs of
2, central temperature and other parameATP, VO
ters that vary with physical exercise.[19] Inside complexes I and III, reduced coenzyme Q10 (CoQH2)
contribute to ROS formation (equation 6).[24] CoQ
may be transformed into a superoxide generator
when the ubisemiquinone anion, arising from oneelectron oxidation of ubiquinol, becomes accessible
to protons.[25]
CoQH 2 + O 2 CoQH + O 2
CoQH + O 2 CoQ + H + + O 2-
(Eq. 6)
There is a synergistic action of CoQH2 and cytochrome b566 in complex III.[24] However, this hypothesis is still controversial because CoQ, in its
reduced form, may act as an antioxidant.[19] It was
recently shown that ROS are not spontaneously released from mitochondria, but appear when the mitochondrial membrane potential reaches a maximum
(state IV).[26] This fact is confirmed by other studies.[27] The site of single-electron deviation to dioxygen seems to be ubiquinol interacting with the
Rieske iron-sulphur protein and low-potential cytochrome b of the complex III.[26] Another study re 2006 Adis Data Information BV. All rights reserved.
332
Finaud et al.
Intracellular space
Mitochondria:
Mn-SOD
GPX
Electron chain
transport
Membranes:
Vit E,
carotenoids,
flavonoids
ROS
NADPH
Nucleus
XO
Cytosol:
CAT, GPX, Cu-Zn-SOD,
Vit C, GSH
Extracellular space
Blood
Circulating antioxidants:
Vit C, lipoic acid, GSH
ROS
Membranes, circulating
cells and lipoproteins:
Vit C, carotenoids, flavonoids
Fig. 2. Potential sources of reactive oxygen species (ROS) in skeletal muscle and locations of the major intracellular and extracellular
antioxidants. CAT = catalase; GPX = glutathione peroxidase; GSH = glutathione; NADPH = reduced nicotinamide-adenine dinucleotide
phosphate; SOD = superoxide dismutase; Vit = vitamin; XO = xanthine oxidase.
[ADP] and adenosine monophosphate [AMP]). Inside hypoxic tissues, XDH can be converted into
xanthine oxidase (XO).[20,32] During reperfusion,
O2 can then be formed by a reaction catalysed by
XO between oxygen, hypoxanthine and xanthine.[1,33,34] Nevertheless, the role of XO in muscles
is discussed because there is a poor amount of XO
inside them.[19,32] Other alternative explanations
seem to be possible to explain the increased production of FR during ischaemia reperfusion. Some studies have shown that ischaemia reperfusion increased
mitochondrial FR production.[19] Other studies
pointed out that phagocyte infiltration, catecholamine, myoglobin and methmyoglobin auto-oxidation take part in FR production during ischaemia
reperfusion.[35]
1.3.3 ROS Formation During Haemoglobin and
Myoglobin Oxidation
Oxidation of haemoglobin can cause ROS formation.[4,17,36] In the human body, 3% of the total
haemoglobin (about 750g) is transformed by autooxidation. This reaction, which increases during exercise, produces methaemoglobin and O2.[1,37-40]
Sports Med 2006; 36 (4)
Other processes involved in ROS production during exercise are increased central temperature, catecholamine and lactic acid, which has the ability to
convert O2 into OH.[1,44]
1.4 Biological Effects of ROS
1.4.1 Positive Effects
333
ROS can also oxidise blood and structural proteins and inhibit the proteolytic system.[62] During
oxidation, proteins can lose amino acids or can be
fragmented. Those reactions lead to alteration of
structural proteins or alteration of enzyme functions.[60] Protein and amino acid oxidation is accompanied by overall increases in the relative level of
protein carbonyl groups[11,63-65] and of oxidised
amino acids,[16,66] which are used as general indexes
for the occurrence of oxidative damage.[16,60,67] Protein oxidation can be the consequence of inflammation, physical exercise or ischaemia reperfusion.[65,66] Oxidised proteins are catabolised in order
to reform amino acids but carbonyl by-products
cannot enter this process. Therefore, they induce a
Sports Med 2006; 36 (4)
334
Finaud et al.
Exercise
ROS-RNS
Alteration of
mitochondrial
functions
Increased
anaerobic
pathways
utilisation
Decreased
electron transfer
Decreased ATP
formation
Increased ROS
formation
Increased Pi
Acidosis
Alteration
of the action
potential
Alteration
of the
redox status
Increased Pi
Acidosis
Muscular fatigue
Decreased force
Overtraining?
Fig. 3. The different hypothesis about the effects of reactive oxygen species (ROS) on muscular fatigue. ATP = adenosine triphosphate;
redox = oxidation-reduction; RNS = reactive nitrogen species; Pi = inorganic phosphate.
ing contraction and in post-exercise muscular damage and suffering.[1,7,31,72-76] The different hypothesis
about the effects of ROS on muscular fatigue is
summarised in figure 3. Precisely, when ROS concentration is too important or too prolonged, a timeand dose-dependent muscular force decrease and a
time- and dose-dependent muscular fatigue increase
can be observed.[47,72,77] Numerous factors seem to
be implicated in FR-induced muscular fatigue (figure 3). The alteration of the mitochondrial functions
with exposure to ROS is considered a major factor
of muscular fatigue.[72,77] Indeed, mitochondria are
particularly susceptible to the ROS-induced oxidative damage on lipids, proteins and DNA, and damages to mtDNA can induce alterations to the respiratory complexes, with a consequent decrease of electron transfer and ATP formation. Thus, aerobic
pathways become less efficient. Consequently, it
seems that this phenomenon can induce an increase
of anaerobic pathways utilisation. This can have
negative effects in muscle because anaerobic pathways induce both an increased inorganic phosphate
(Pi) level and acidosis, which are two major factors
of muscular fatigue.[72]
Sports Med 2006; 36 (4)
Contractile proteins (actin and myosin) and calcium pump are muscular compounds that are sensitive
to redox status. Redox status is directly linked and
modified by ROS concentration. Thus, when ROS
production is important, redox status can be altered.
Consequently, muscular contraction (contractile
proteins) and muscular contraction control (calcium
pump) may be altered.[33] ROS can induce an intracellular calcium increase and intracellular enzymes
inactivation (particularly enzymes implicated in aerobic and anaerobic pathways) into muscular cells,
which could participate to muscular fatigue.[78]
Moreover, during certain forms of exercise, such as
eccentric exercise, an important iron release (from
ferritin or haemoglobin) can be observed. Iron release can aggravate exercise and post-exercise oxidative stress and muscular fatigue and damages.[79]
Moreover, data tend to show that the action potential
for muscle contraction can be modified by ROS.[80]
Indeed, ROS causes remarkable perturbation of the
inward potassium transport system in muscle. It has
been shown that muscle soreness-induced decrease
in maximal force generation is a result of an increase
in muscular nitric oxide (NO).[81] Indeed, NO was
reported to decrease contractile force by inhibition
of Ca21-ATPase activity in the sarcoplasmic reticulum. Moreover, NO induces hyperpolarisation of
membrane potential (thereby leading to reduced
force generation) and also may directly inhibit the
force-generating proteins in skeletal muscle. In summary, it seems possible that ROS- and RNS-induced
decrease in maximal force generation can be a part
of a protective mechanism by which skeletal muscle
protects itself from further peak force-generated
damage.[81] Moreover, repetitive muscular ROS-induced fatigue associated with inadequate recovery is
supposed to induce overtraining syndrome.[73,82,83]
2. Antioxidants
An antioxidant can be defined as a substance that
helps to reduce the severity of oxidative stress either
by forming a less active radical or by quenching the
damaging FR chain reaction on substrates such as
proteins, lipids, carbohydrates or DNA.[84] A range
of antioxidants are active in the body including
2006 Adis Data Information BV. All rights reserved.
335
enzymatic (endogenous) and non-enzymatic (mainly brought by food) antioxidants.[74] All of them can
be intracellular or extracellular antioxidants (figure
2). Antioxidant enzymes include SOD, catalase
(CAT) and glutathione peroxidase (GPX). Non-enzymatic antioxidants include a variety of FR
quenchers such as vitamin A (retinol), vitamin C
(ascorbic acid), vitamin E (tocopherol), flavonoids,
thiols (including glutathione [GSH], ubidecarenone
(ubiquinone Q10), uric acid, bilirubin, ferritin) and
micronutrients (iron, copper, zinc, selenium, manganese), which act as enzymatic cofactors. The antioxidant system efficiency depends on nutritional intakes (vitamins and micronutrients) and on endogenous antioxidant enzyme production, which can be
modified by exercise, training, nutrition and aging.[84] Moreover, the antioxidant system efficiency
is important in sport physiology because exercise
increases the production of FR.
2.1 Enzymatic Antioxidants
2.1.1 Superoxide Dismutase
SOD is the major defence upon superoxide radicals and is the first defence line against oxidative
stress. SOD represents a group of enzymes that
catalyse the dismutation of O2 and the formation
of H2O2 (equation 7).
SOD
2 O 2- + 2 H + H 2O 2 + O 2
(Eq. 7)
In all cells, at rest, the major part of mitochondrial-produced O2 is reduced by mitochondrial SOD
and the other part diffuse into the cytosol.[85] In
muscular cells, 6585% of SOD activity is done in
the cytosol.[74] Different forms of SOD are present in
the body (see table II and figure 2). Manganese is a
cofactor of the Mn-SOD form, which is present in
mitochondria as well as copper and zinc, which are
cofactors of Cu-Zn-SOD, present in cytosol.
2.1.2 Catalase
336
Finaud et al.
Cofactors
Cellular localisation
Targets
Mn-SOD
Manganese
Mitochondria
Anion superoxide
Peroxynitrite
Cu-Zn-SOD
Copper
Zinc
Anion superoxide
Peroxynitrite
CAT
Iron
Hydrogen peroxide
GPX
Selenium
Hydrogen peroxide
Peroxynitrite
CAT
2 H 2O
2 H2O + O 2
(Eq. 8)
Catalase can also use H2O2 in order to detoxify
some toxic substances via a peroxidase reaction
(equation 9). This reaction needs a substrate such as
phenol, alcohol (ethanol; A) or formic acid.
CAT
H 2O 2 + H 2A (substrate) 2 H 2O + A
(Eq. 9)
2.1.3 Glutathione Peroxidase
The GPX present in cell cytosol and mitochondria has the ability to transform H2O2 into water
(equation 10). This reaction uses GSH and transforms it into oxidised glutathione (GSSG).
GPX
H 2O 2 + 2 GSH
GSSG + 2 H2O
(Eq. 10)
GPX and CAT have the same action upon H2O2,
but GPX is more efficient with high ROS concentration and CAT has an important action with lower
H2O2 concentration.[21,86]
2.1.4 Relationship with Exercise and Training
337
Localisation
Actions
Targets
Vitamin E (tocopherol)
Lipids
Cell/mitochondria membranes
ROOH 1O2
Vitamin A (retinol)
Lipids
Cell membranes
1O2
Aqueous middle
Cytosol
Extracellular liquids
Vitamin E regeneration
LDL protection
Glutathione
Aqueous middle
Direct antioxidants
Cysteine
Intracellular middle
Glutathione precursor
Lipoic acid
Aqueous middle
Thioredoxin
Aqueous middle
Mn-SOD synthesis
Vitamin C regeneration
ROOH
OH O2
1O2
OH
H2O2 ROOH
H2O2
Glutaredoxin
Aqueous middle
Flavonoids
Coenzyme Q10
Internal membrane of
mitochondria
Uric acid
Aqueous middle
O2 OH ROOH RO
ROO
ROOH OH O3 HOCL
Pro-oxidant ions (Fe2+, Fe3+,
Cu2+)
ONOOH
trapping
Erythrocytes, haemoglobin, DNA,
lipids protection
Indirect antioxidants
HSP
Aqueous middle
Iron
Aqueous middle
Catalase cofactor
Ferritin
Aqueous middle
Zinc
Aqueous middle
Copper
Aqueous middle
Selenium
Aqueous middle
GPX cofactor
Manganese
Aqueous middle
Albumin
Aqueous middle
Give electron to FR
Cu2+ trapping
Caeruloplasmin
Aqueous middle
Give electron to FR
Cu2+, Fe2+ and Fe3+ trapping
Bilirubin
Aqueous middle
Give electron to FR
Lipid peroxidation inhibition
Erythrocyte protection
1O2
= singlet oxygen; FR = free radicals; GPX = glutathione peroxidase; H2O2 = hydrogen peroxide; HOCL = hypochlorous acid; HSP =
heat shock proteins; LDL = low-density lipoprotein; O2 = superoxide ion; ONOOH = peroxynitrous acid; O3 = ozone; OH = hydroxyl
radical; RO = alkoxyl radical; ROO = alkylperoxyl radical; ROOH = hydroperoxyl radical; SOD = superoxide dismutase.
338
Finaud et al.
Vitamin C is a water-soluble vitamin and is probably the most important antioxidant in extracellular
fluids, but is also effective in cytosol.[82,96] Vitamin
C is more abundant in tissues in which ROS production is more important. This phenomenon is defined
as an adaptation against oxidative stress.[96] In
fluids, vitamin C has the ability to neutralise ROS
(OH, O2, fatty acid peroxyl radical (LOO), alkoxyl radical [RO]).[82] Inside cells, vitamin C reinforces the action of vitamin E and GSH by regenerating their active form after they have reacted with
ROS.[56,78,97] Vitamin C also has the ability to trap
copper ions, which have a powerful oxidant action.
Thus, vitamin C supplementation has often been
studied. In athletes, its preventive effects against
oxidative stress are discussed.[32,95,98,99] A deficiency
in vitamin C has negative effects on performance
and vitamin C supplementation (especially in combination with other antioxidants such as vitamin E)
helps to maintain an adequate vitamin C level in
tissues.[7]
2.2.3 -Carotene and Vitamin A (Retinol)
Coenzyme Q10 (CoQ10) is an endogenous molecule that is essential for ATP synthesis and is especially present in mitochondrial membrane.[48,119]
CoQ10 is known to act as an antioxidant with a direct
action upon peroxyl radicals or with an indirect
action by regenerating vitamins C and E.[120,121]
CoQ10 also has beneficial effects, such as protection
against cardiovascular diseases, cancer and cell aging or apoptosis.[48,119,122,123] However, CoQ10 acts
as a mediator for gene expression and protein synthesis in muscle.[48] In this case, CoQ10 acts as a prooxidant by giving rise to O2, which is converted to
H2O2 by SOD. H2O2 then acts as a second messenger for genetic expression. CoQ10 supplementation
has been tested in sporting groups with limited results on oxidative stress reduction and physical performance.[124,125]
2.2.7 Uric Acid
Heat shock proteins (HSP) are a variety of proteins known to have protective effects against various stresses. HSP increase with exercise, particular 2006 Adis Data Information BV. All rights reserved.
339
340
Finaud et al.
Every antioxidant is a redox agent that can protect against FR in some circumstances and promote
FR production in others.[157] Therefore, some precautions must be taken because antioxidants can
have pro-oxidant effects, especially when megadoses are used.[44,79] Such findings were demonstrated for vitamin C,[79] -carotene[6,7] and CoQ10.[158] It
was also shown that quercetin can have pro-oxidant
2006 Adis Data Information BV. All rights reserved.
The production of ROS can be revealed according to direct methods. The electron spin resonance
technique is a direct spectroscopic method that alSports Med 2006; 36 (4)
341
342
Finaud et al.
ROS induce several types of DNA damage including strand breaks, DNA-protein cross-links and
base modifications. Nowadays, numerous methods
are used for DNA modification quantification.[69]
The most used marker is the nucleotide 8-hydroxy-2-deoxyguanosine (8-OHdG), which is produced by FR-induced guanine oxidation. The oxidised DNA is continually repaired, and oxidised
nucleotides such as 8-OHdG are excreted via blood
and urine. Thus, invasive or non-invasive methods
are possible.[12] However, there have been doubts
about the precision of this method because of the
possible artefactural production of 8-OHdG by autooxidation during and after sample extraction.[69,165]
3.2.4 Other Indirect Oxidative Stress Markers
A further technique for the measurement of antioxidant capacity of the body and oxidative stress is
the measurement of thiol proteins. Like other antioxidants, a loss of thiol proteins can appear during a
long period of oxidative stress. However, the quantification of GSH, the most important thiol in the
human body, and GSSG (the oxidised form of GSH)
is a popular technique to assess oxidative stress. The
GSH/GSSG ratio is an interesting marker of oxidative stress because FR oxidise GSH into
GSSG.[112,113]
Uric acid is an important plasmatic and muscular
antioxidant.[131,137] However, uric acid concentration
can vary because of oxidative stress, purins cycle
and renal excretions. Uric acid alone, therefore, can
not represent a reliable marker of antioxidant capacity and oxidative stress; however, allantoin, a uric
acid oxidation product, may be a valuable endogenous marker of oxidative stress. Thus, it could be
considered as a good parameter to quantify oxidative stress because allantoin is theoretically absent
from human body fluids under normal circumstances. Nevertheless, some results suggest that alSports Med 2006; 36 (4)
343
out with methods including aerobic exercise (running, cycling and swimming [see table
IV]).[51,53,58,90,96,162,173-175] Aerobic exercise is accom 2, which may increase FR
panied by an increased VO
2, which, in
activity. Aerobic exercise increases VO
turn, may increase FR production. Therefore, many
studies suggested that such physical activity enhanced FR production both in animals and in
humans.[51,53,58,90,96,173-176]
However, this phenomenon cannot occur with
low exercise intensity (<50% maximum oxygen
2max]). In such a case, antioxidant
consumption [VO
capacity is not overreached and FR-induced damage
does not appear.[174] Moreover, the more intense the
exercise intensity is, the more important the FR
production and the oxidative stress are.[96,174] This is
confirmed by some studies that show a correlation
2 and oxidative stress.[162] However,
between VO
other studies show that oxidative stress does not
increase after intense aerobic exercise.[53,76,179] Such
contradictory results can be explained by antioxidant nutritional status (which is not always controlled in studies), exercise intensity or training level. Effectively, these studies are done with trained
endurance athletes who are adapted to exercise effects such as FR production.[53,76,179] However,
trained subjects can exhibit oxidative stress as well
as sedentary subjects.[59,153] Moreover, some differences can be explained by the methods used for the
measurement of oxidative stress as shown in the
paragraph above.
Effects on Antioxidants
Endurance exercise also causes some modifications in the non-enzymatic antioxidant concentrations or enzymatic antioxidant activity. Numerous
studies, both in animals and in humans, have shown
that antioxidant enzyme activity increases (SOD,
GPX, CAT) in blood or in tissues after aerobic
exercise.[16,22,178,180] This adaptation may occur very
quickly (about 5 minutes) after FR production and
seems to be specific to oxidative muscular fibres,
which is the main FR production location during
exercise.[74,87,180] However, the increase of antioxidant enzyme activity is not proportional to exercise
intensity.[181]
Sports Med 2006; 36 (4)
344
Finaud et al.
Table IV. Human studies on the effects of aerobic exercise on markers of oxidative stress
Study (year)
Subjects
2max 6 UT
Cycling at 40%, 70% and 100% VO
Markers
Effect
Activity
2max)
MDA (at 40% VO
2max)
MDA (at 70% VO
2max)
MDA (at 100% VO
TBARS GSSG
MDA
CD
SOD GPX
CAT
18 VT
Running (half-marathon)
6T
Running (marathon)
22 VT
Tocopherol TRAP
CD
Retinol CoQ10
12 T
TAC
FR (ESR) MDA LH
Running (half-marathon)
17 T
MDA
CK
TEAC UA
Running (marathon)
11 VT
10 UT
Oxidised LDL
TRAP UA
Thiols
Tocopherol vit C vit A
Allantoin
UA (muscle)
GSH cysteine UA (plasma)
Swimming (800m)
10 T
CAT GPX
GSH
Running (50km)
11 T
Isoprostane
UA tocopherol vit C
TBARS neutrophil FR
production
Protein carbonyls
SOD GPX CAT
19 T
TBARS CD
TAC GSH CAT
GPX SOD
Running (21km)
15 T
MDA
CK myoglobin
Walking (50km)
Walking (80km)
29 T
16 T
CK
Protein carbonyls
UA
Ultra-marathon (80km)
28 T
LH F2-isoprostane
Vit C
8T
9 UT
GSSG
UA tocopherol
GPX
CAT = catalase; CD = conjugated dienes; CK = creatine kinase; CoQ10 = coenzyme Q10; ESR = electron spin resonance; FR = free radical;
GPX = glutathione peroxidase; GSH = glutathione; GSSG = oxidised glutathione; LDL = low-density lipoprotein; LH = lipid hydroperoxide;
MDA = malondialdehyde; SOD = superoxide dismutase; T = trained; TAC = total antioxidant capacity; TBARS = thiobarbituric reactive
substances; TEAC = trolox equivalent antioxidant capacity; TRAP = total radical antioxidant potential; UA = uric acid; UT = untrained; vit =
2max = maximum oxygen consumption; indicates decrease; indicates increase; indicates no change
vitamin; VT = very trained; VO
(stable).
Aguilo et al.[175] (2005)
Cycling (171km)
Aerobic exercise effects are not limited to antioxidant enzymes. Non-enzymatic antioxidant concen-
8T
some studies suggest that GSH or GSH/GSSG decreases during exercise because of its utilisation
against FR.[58,74,112,178] In turn, vitamins E and C and
uric acid tend to increase after endurance
strain.[58,90,96] Vitamins E and C seem to be mobilised from their respective reserve in order to
preserve the body against FR harmful effects. Uric
acid increases can not be considered as a specific
adaptation against oxidative stress because it is an
end product of the purins cycle.[90,95] Together, all
these modifications provoke an increase in the total
antioxidant capacity as can be observed in several
studies.[58,172]
4.1.2 Anaerobic Exercise
Effects on FR Production
345
production.[33,34] Xanthine oxidase has been demonstrated to generate FR during ischaemia reperfusion,
but direct evidence for xanthine oxidase as a radical
generator in muscle during exercise is lacking. In
ischaemic tissues, it has been proposed that the
xanthine dehydrogenase undergoes proteolytic conversion to the oxidase form, which uses O2 as its
electron acceptor.[33,34] It is known that xanthine
oxidase in the presence of the substrates hypoxanthine or xanthine reduces molecular oxygen to O2
and H2O2. Recently, it has been demonstrated that
the enzyme can further reduce H2O2 to OH.[34]
Thus, it has been hypothesised that xanthine oxidase
and its requisite substrates would be present in high
concentrations in reperfused tissue and consequently would result in oxygen FR generation upon
reperfusion. The OH and O2 radicals generated
by the enzyme could in turn react with cellular
proteins and membranes causing cellular injury.[34]
Another source of FR production during anaerobic exercise arises from inflammation and cellular
damage, which often happen after traumatising exercise such as impact sports and clinometric or eccentric exercises.[79,94,166,186,187] An iron liberation,
from haemoglobin or ferritin, may amplify the inflammatory answer and the oxidative stress.[79] Furthermore, a positive link between the increase of
lactic acid and the rise of oxidative stress markers
has been evidenced.[22,183] This would lead to a decline in the concentration of NADH and NADPH
and then to the reduction of the antioxidant action
and the increase of the FR production.[22]
Effects on Antioxidants
346
Table V. Human studies on the effects of anaerobic exercise on markers of oxidative stress
Study (year)
Activity
6 150m sprints
100m swim
Subjects
Effect
TBARS CD MDA
Protein carbonyls
6T
MDA CD
SOD GPX
CAT
8 JT
8 UT
MDA
12 T
MDA
14 UT
LH isoprostane
CK LDH myoglobin
SOD
GPX
9T
CAT GPX
GSH
7T
UA vit C
Tocopherol vit A
8T
ESR signals
TBARS
SOD GSH
GPX
7T
10 UT
MDA
CD (trained group)
CD (untrained group)
Vit A tocopherol
18 UT
14 NRT
CAT = catalase; CD = conjugated dienes; CK = creatine kinase; ESR = electron spin resonance; GPX = glutathione peroxidase; GSH = glutathione; GSSG = oxidised glutathione;
JT = jump trained; LDH = lactate dehydrogenase; LH = lipid hydroperoxide; max = maximum; MDA = malondialdehyde; NRT = non-resistance trained; reps = repetitions; RM =
repetition maximum; SOD = superoxide dismutase; T = trained; TBARS = thiobarbituric reactive substances; UA = uric acid; UT = untrained; vit = vitamin; indicates decrease;
indicates increase; indicates no change (stable).
Finaud et al.
Markers
MDA
GSH (blood)
GSH (muscle)
GSSG (blood and muscle)
7 UT
347
Table VI. Human studies on the effects of mixed exercise on markers of oxidative stress
Study (year)
Activity
Subjects
7T
15 VT vs 6 T and 10 UT
Markers
Effect
UA (blood)
UA (muscle)
TBARS
CD
GPX SOD
GSH
UA
min (intermittent)
UA
CD = conjugated dienes; GPX = glutathione peroxidase; GSH = glutathione; MDA = malondialdehyde; SOD = superoxide dismutase; T =
trained; TBARS = thiobarbituric reactive substances; UA = uric acid; UT = untrained; VT = very trained; indicates decrease; indicates
increase; indicates no change (stable).
In summary, aerobic, anaerobic or mixed exercise causes an enhanced FR production. In the same
way, humans have an adaptive reaction with an
increased mobilisation of a variety of enzymatic and
non-enzymatic antioxidants in cells or in plasma.
However, in a large majority of cases, antioxidant
capacities are overreached, which lead to an oxidative stress situation, all the more important because
exercise intensity and duration are high and because
subjects have low training levels and inadequate
nutritional status. Some differences can be noted
between aerobic exercise and mixed or anaerobic
exercise. Indeed, contrary to endurance exercise, the
mitochondrial respiratory chain is not the main FR
production location in anaerobic and in mixed exerSports Med 2006; 36 (4)
348
Table VII. Human studies on effects of aerobic training on markers of oxidative stress
Study (year)
Activity
2max 3 wk 10wk
Running <80% VO
Running (half-marathon)
Blood samples at rest
2max 4 week
Running 60 min at 7080% VO
3mo
Running (marathon)
Post-exercise blood samples
Running
2max
60 min at 80% VO
5 wk 12wk
Running
50 min 5 wk 16wk
Blood samples after 30 min aerobic exercise
Subjects
Markers
Effect
12 T
24 T
GSH GSSG
GPX
6 T vs 6 UT
MDA CD
SOD GPX CAT
9T
TRAP vit C
UA thiols tocopherol vit A
LDL oxidation
TRAP
UA vit E vit C vit A
TBARS
Protein carbonyls
SOD GPX
CAT
LDL oxidation
LP
SOD GSH
7 UT
11 VT vs 10 UT
9 UT
17 UT
9 VT
At rest
GSH SOD
CK myoglobin TBARS
GPX
TAC
Post-exercise
CAT = catalase; CD = conjugated dienes; CK = creatine kinase; GPX = glutathione peroxidase; GR = glutathione reductase; GSH = glutathione; GSSG = oxidised glutathione; LDL
= low-density lipoprotein; LP = lag phase; MDA = malondialdehyde; SOD = superoxide dismutase; T = trained; TAC = total antioxidant capacity; TBARS = thiobarbituric reactive
2max = maximum oxygen consumption; indicates
substances; TRAP = total radical antioxidant potential; UA = uric acid; UT = untrained; vit = vitamin; VT = very trained; VO
decrease; indicates increase; indicates no change (stable).
Finaud et al.
CK myoglobin TBARS
TAC
349
cise. Ischaemia reperfusion, acidosis and catecholamine oxidation are other phenomenon that are
implicated in oxidative stress during supramaximal
exercise. However, there is a lack of knowledge and
further studies are needed to understand oxidative
stress during this kind of exercise, which is probably
more difficult to investigate.
4.2 Training Effects on Oxidative Stress
Effects on Antioxidants
Table VIII. Human studies on effects of anaerobic training on markers of oxidative stress
Study (year)
Activity
Markers
Effect
Subjects
GPX CAT
SOD
CK (after exercise)
MDA (after exercise)
SOD GPX (at rest)
CAT (at rest)
6 T vs 6 UT
MDA
CD
SOD GPX
CAT
8 UT elderly, 8 T and 8 UT
with rheumatoid arthritis
3 wk 6mo
Thiols
8-OHdG = 8-hydroxy-2-deoxyguanosine; CAT = catalase; CK = creatine kinase; GPX = glutathione peroxidase; LH = lipid hydroperoxide;
MDA = malondialdehyde; RM = repetition maximum; SOD = superoxide dismutase; T = trained; TBARS = thiobarbituric reactive
substances; UT = untrained; indicates decrease; indicates increase; indicates no change (stable).
350
Finaud et al.
Little research has been carried out on the influence of mixed training effects on oxidative stress.
Nevertheless, recent studies suggest that trained
2006 Adis Data Information BV. All rights reserved.
Activity
Subjects
Markers
Effect
26 T vs 27 UT
TBARS CD
Tocopherol CAT
Vit C GSH GPX
SOD
30 T vs 12 UT
Alpine ski
Blood samples before and after a
10d training camp
12 VT
TEAC
MDA LH protein carbonyls
15 T
GSH
UA
15 VT vs 6 T and 10 S
TBARS CD
SOD GPX
15 T vs 15 UT
8 VT
LH
LP
Tocopherol vit A
Vit C
20 VT vs 20 UT
25 VT vs 25 UT
Zinc
Copper
SOD
MDA
CAT = catalase; CD = conjugated dienes; GPX = glutathione peroxidase; GSH = glutathione; LDL = low-density lipoprotein; LH = lipid hydroperoxide; LP = lag phase; MDA =
malondialdehyde; S = sedentary; SOD = superoxide dismutase; T = trained; TBARS = thiobarbituric reactive substances; TEAC = trolox equivalent antioxidant capacity; TRAP =
total radical antioxidant potential; UA = uric acid; UT = untrained; vit = vitamin; VT = very trained; indicates decrease; indicates increase; indicates no change (stable).
351
Study (year)
Table IX. Human studies on effects of mixed training on markers of oxidative stress
352
Finaud et al.
The training programme aims to optimise individual and collective performance. However, it is
difficult to know whether the programme applied to
the athletes is well adapted or leads to persistent
fatigue known as overtraining.[209] This overtraining
syndrome is characterised by excessive fatigue,
drops in performance, physical changes, moodiness
and biological modifications that can be detected by
a biological check-ups.[209,210] Prolonged periods of
intense exercise training and/or intense competition
are associated with a large variety of hormonal,
immunological, haematological and biochemical
changes.[210,211] However, the different studies on
this subject are often contradictory.[210] Therefore,
no single reliable diagnostic element of the overtraining syndrome is currently available except the
decrease of the performance with the same load of
training.[9,83,209,210] It is therefore necessary to implement a longitudinal follow-up that includes selected
2006 Adis Data Information BV. All rights reserved.
load with an inappropriate diet. These studies suggest a limit beyond which oxidative stress can increase in excess and cause overtraining. Indeed, the
FR produced during exercise play an important role
in the induction of muscular lesions but also in the
induction and propagation of post-exercise inflammation, which can increase cellular lesions. Although this hypothesis is discussed, the set of these
phenomena can disrupt muscular functions and lead
to the overtraining syndrome.
5. Conclusions
FR and especially ROS are formed during normal
physiological processes by nonenzymatic and enzymatic sources and continuously cause damage to
lipids, proteins and nucleic acids. Antioxidant
defences (both enzymatic and non-enzymatic) can
temper the negative influence of FR and associated
reactions.
Physical exercise provokes intracellular homeostasis disruptions with an unbalance between prooxidants and antioxidants. The mitochondrial respiratory chain, the ischaemia reperfusion phenomenon
and the inflammatory reaction have been identified
as the main sources of FR during and after exercise.[21] Oxidative stress is especially important after
intensive or traumatic exercise and in athletes with a
low training level and low nutritional antioxidant
intakes.[2,78]
Although a training-induced oxidative stress reduction caused by an adaptation of the antioxidant
system has been observed in several studies, data
suggest that an accumulation of intense exercise
(intense period of training and/or competition) can
provoke an increase in oxidative stress.[153] This can
be the origin of muscular fatigue and injuries.[73] If
the individual recovery capacity is overreached,
these changes can contribute to the appearance of
overtraining, which in turn may aggravate the oxidative stress.[8]
Acknowledgements
No sources of funding were used to assist in the preparation of this review. The authors have no conflicts of interest
that are directly relevant to the content of this review. This
353
work is dedicated to the late Prof. Robert (2004) and the late
Prof. Bedo (2006).
References
1. Cooper CE, Vollaard NBJ, Choueiri T, et al. Exercise, free
radicals and oxidative stress. Biochem Soc Trans 2002; 30 (2):
280-5
2. Lachance PA, Nakat Z, Jeong WS. Antioxidants: an integrative
approach. Nutrition 2001; 17: 835-8
3. Golden TR, Hinerfeld DA, Melov S. Oxidative stress and aging:
beyond correlation. Aging Cell 2002; 1: 117-23
4. Thomas MJ. The role of free radicals and antioxidants. Nutrition
2000; 16 (7-8): 716-8
5. Sen CK. Antioxidant and redox regulation of cellular signaling:
introduction. Med Sci Sports Exerc 2001; 33 (3): 368-70
6. Guilland JC, Penaranda T, Gallet C, et al. Vitamin status of
young athletes including the effects of supplementation. Med
Sci Sports Exerc 1989; 21 (4): 441-9
7. Laursen PB. Free radicals and antioxidant vitamins: optimizing
the health of the athlete. Strength Cond J 2001; 23 (2): 17-25
8. McKenzie DC. Markers of excessive exercise. Can J Appl
Physiol 1999; 24 (1): 66-73
9. Petibois C, Cazorla G, Poortmans JR, et al. Biochemical aspects
of overtraining in endurance sports. Sports Med 2002; 32 (13):
867-78
10. Jenkins RR. Free radical chemistry: relationship to exercise.
Sports Med 1988; 5: 156-70
11. Cheeseman KH, Slater TF. An introduction to free radical
biochemistry. Br Med Bull 1993; 49 (3): 481-93
12. Rimbach G, Hohler D, Fischer A, et al. Methods to assess free
radicals and oxidative stress in biological systems. Arch Tierernahr 1999; 52 (3): 203-22
13. Prior RL, Cao G. In vivo total antioxidant capacity: comparison
of different analytical methods. Free Radic Biol Med 1999; 27
(11-12): 1173-81
14. Giles GI, Jacob C. Reactive sulfur species: an emerging concept
in oxidative stress. Biol Chem 2002; 383: 375-88
15. Hampton MB, Kettle AJ, Winterbourn CC. Inside the neutrophil
phagosome: oxidants, myeloperoxidase, and bacterial killing.
Blood 1998; 92: 3007-17
16. Leewenburgh C, Hansen PA, Holloszy JO, et al. Hydroxyl
radical generation during exercise increases mitochondrial
protein oxidation and levels of urinary dityrosine. Free Radic
Biol Med 1999; 27 (1-2): 186-92
17. Fehrenbach E, Northoff H. Free radicals, exercise, apoptosis,
and heat shock proteins. Exerc Immunol Rev 2001; 7: 66-89
18. Aruoma OI. Free radicals, antioxidants and international nutrition. Asia Pac J Clin Nutr 1999; 8 (1): 53-63
19. Di Meo S, Venditti P. Mitochondria in exercise-induced oxidative stress. Biol Signals Recept 2001; 10: 125-40
20. Sjodin B, Hellsten Westing Y, et al. Biochemical mechanism for
oxygen free radical formation during exercise. Sports Med
1990; 10: 236-54
21. Jenkins RR, Goldfarb A. Introduction: oxidant stress, aging and
exercise. Med Sci Sport Exerc 1993; 25 (2): 210-2
22. Clarkson PM. Antioxidants and physical performance. Crit Rev
Food Sci Nutr 1995; 35: 131-41
23. Lenaz G. Role of mitochondria in oxidative stress and ageing.
Biochim Biophys Acta 1998; 1366 (1-2): 53-67
24. Nohl H, Jordan W. The mitochondrial site of superoxide formation. Biochem Biophys Res Commun 1986; 138 (2): 533-9
354
Finaud et al.
355
89.
90.
91.
92.
93.
94.
95.
96.
97.
98.
99.
100.
101.
102.
103.
104.
105.
106.
107.
108.
356
109. Sen CK, Packer L. Thiol homeostasis and supplements in physical exercise. Am J Clin Nutr 2000; 72: 653S-69S
110. May JM, Qu Z, Whitesell RR, et al. Ascorbate recycling in
human erythrocytes: role of GSH in reducing dehydroascorbate. Free Radic Biol Med 1996; 20 (4): 543-51
111. Groussard C, Rannou-Bekono F, Machefer G, et al. Changes in
blood lipid peroxidation markers and antioxidants after a single sprint anaerobic exercise. Eur J Appl Physiol 2003; 89:
14-20
112. Tessier F, Margaritis I, Richard MJ, et al. Selenium and training
effects on the glutathione system and aerobic performance.
Med Sci Sports Exerc 1995; 27 (3): 390-6
113. Svensson M, Ekblom B, Cotgreave I, et al. Adaptative stress
response of glutathione and acid uric metabolism in man
following controlled exercise and diet. Acta Physiol Scand
2002; 176: 43-56
114. Schulz JB, Lindenau J, Seyfried J, et al. Glutathione, oxidative
stress and neurodegeneration. Eur J Biochem 2000; 267:
4904-11
115. Shang F, Lu M, Dudek E, et al. Vitamin C and vitamin E restore
the resistance of GSH-depleted lens cells to H2O2. Free Radic
Biol Med 2003; 34 (5): 521-30
116. Serbinova E, Reznick SKAZ, Packer L. Thioctic acid protects
against ischemia-reperfusion injury in the isolated langendorff
heart. Free Radic Res Commun 1992; 17: 49-58
117. Scott BC, Aruoma OI, Evans PJ, et al. Lipoic and dihydrolipoic
acids as antioxidants: a critical evaluation. Free Radic Res
1994; 20: 119-30
118. Khanna S, Atalay M, Laaksonen DE, et al. -lipoic acid supplementation: tissue glutathione homeostasis at rest and after
exercise. J Appl Physiol 1999; 86 (4): 1191-6
119. Maulik N, Yoshida T, Engelman RM, et al. Dietary coenzyme
Q10 supplement renders swine hearts resistant to ischemiareperfusion injury. Am J Physiol 2000; 278: H1084-90
120. Witt EH, Reznick AZ, Viguie CA, et al. Exercise, oxidative
damage and effects of antioxidant manipulation. J Nutr 1992;
122 (3 Suppl.): 766-73
121. Crane FL. Biochemical functions of coenzyme Q10. J Am Coll
Nutr 2001; 20 (6): 591-8
122. Crestanello JA, Doliba NM, Babsky AM, et al. Effects of
coenzyme Q10 supplementation on mitochondrial function
after myocardial ischemia reperfusion. J Surg Res 2002; 102
(2): 221-8
123. Rosenfelt FL, Pepe S, Linnane A, et al. Coenzyme Q10 protects
the aging heart against stress: studies in rats, human tissues,
and patients. Ann N Y Acad Sci 2002; 959: 355-9
124. Braun B, Clarkson PM, Freedson PS, et al. Effects of coenzyme
Q10 supplementation on exercise performance, VO2 max, and
lipid peroxidation in trained cyclists. Int J Sport Nutr 1991; 1
(4): 353-65
125. Svensson M, Malm C, Tonkonogi M, et al. Effect of Q10
supplementation on tissue Q10 levels and adenine nucleotide
catabolism during high-intensity exercise. Int J Sport Nutr
1999; 9 (2): 166-80
126. Grootveld M, Halliwell B. Measurement of allantoin and uric
acid in human body fluids: a potential index of free-radical
reactions in vivo. Biochem J 1987; 243: 803-8
127. Hellsten Y, Tullson PC, Richter EA, et al. Oxidation of urate in
human skeletal muscle during exercise. Free Radic Biol Med
1997; 22 (1-2): 169-74
128. Green HJ, Fraser IG. Differential effects of exercise intensity on
serum uric acid concentration. Med Sci Sports Exerc 1988; 20
(2): 55-9
Finaud et al.
147. Erario MA, Gonzales S, Noriega GO, et al. Bilirubin and ferritin
as protectors against hemin-induced oxidative stress in liver.
Cell Mol Biol 2002; 48 (8): 877-84
148. Nikolaidis MG, Michailidis Y, Mougios V. Variation of soluble
transferring receptor and ferritin concentrations in human serum during recovery and exercise. Eur J Appl Physiol 2003;
89: 500-2
149. Atanasiu RL, Stea D, Mateescu MA, et al. Direct evidence of
caeruloplasmin antioxidant properties. Moll Cell Biochem
1998; 189: 127-35
150. Yesikaya A, Yegin A, Ozdem S, et al. The effect of bilirubin on
lipid peroxidation and antioxidant enzymes in cumene
hydroperoxide-treated erythrocytes. Int J Clin Lab Res 1998;
28 (4): 230-4
151. Kaur H, Hugues MN, Green CJ, et al. Interaction of bilirubin
and biliverdin with reactive nitrogen species. FEBS Lett 2003;
543 (1-3): 113-9
152. Margaritis I, Palazzetti S, Rousseau AS, et al. Antioxidant
supplementation and tapering exercise improve exercise-induced antioxidant response. J Am Coll Nutr 2003; 22 (2):
147-56
153. Palazzetti S, Richard MJ, Favier A, et al. Overload training
increases exercise-induced oxidative stress and damage. Can J
Appl Physiol 2003; 28 (4): 588-604
154. Palazzetti S, Rousseau AS, Richard MJ, et al. Antioxidant
supplementation preserves antioxidant response in physical
training and low antioxidant intake. Br J Nutr 2004; 91: 91-100
155. Finaud J, Scislowski V, Lac G, et al. Antioxidant status and
oxidative stress in professional rugby players: evolution
throughout a season. Int J Sports Med 2006; 27: 87-93
156. Schroder H, Navarro E, Tramullas A, et al. Nutrition antioxidant
status and oxidative stress in professional basketball players:
effects of a three compound antioxidative supplement. Int J
Sports Med 2000; 21 (2): 146-50
157. Herbert V. Symposium: prooxidant effects of antioxidant vitamins. J Nutr 1996; 126: 1197-200
158. Choi EJ, Chee KM, Lee BH. Anti- and prooxidant effects of
chronic quercitin administration in rats. Eur J Pharmacol 2003;
482: 281-5
159. James AM, Smith RAJ, Murphy MP. Antioxidant and prooxidant properties of mitochondrial coenzyme Q. Arch Biochem
Biophys 2004; 423: 47-56
160. Duthie GG. Determination of activity of antioxidants in human
subjects. Proc Nutr Soc 1999; 58 (4): 1015-24
161. Jenkins RR. Exercise and oxidative stress methodology: a critique. Am J Clin Nutr 2000; 72 (2- Suppl.): 670-4
162. Ashton T, Rowlands CC, Jones E, et al. Electron spin resonance
spectroscopic detection of oxygen-centred radicals in human
serum following exhaustive exercise. Eur J Appl Physiol 1998;
77 (6): 498-502
163. Frank J, Pompella A, Biesalski HK. Histochemical visualization
of oxidant stress. Free Radic Biol Med 2000; 29 (11):
1096-105
164. Chen SS, Chang LS, Wei YH. Oxidative damage to proteins and
decrease of antioxidant capacity in patients with varicocele.
Free Radic Biol Med 2001; 30 (11): 1328-34
165. Hofer T, Moller L. Optimization of the workup procedure for
the analysis of 8-oxo-7,8-dihydro-2-deoxyguanosine with
electrochemical detection. Chem Res Toxicol 2002; 15:
426-32
166. Ortenblad N, Madsen K, Djurhuus MS. Antioxidant status and
lipid peroxidation after short-term maximal exercise in trained
and untrained humans. Am J Physiol 1997; 272 (4): R1258-63
357
167. Varlet-Marie E, Maso F, Lac G, et al. Hemorheological disturbances in the overtraining syndrome. Clin Hemorheol
Microcirc 2004; 30: 211-8
168. Marzatico F, Pansarasa O, Bertorelli L, et al. Blood free radical
antioxidant enzymes and lipid peroxides following long-distance and lactacidemic performances in highly trained aerobic
and sprint athletes. J Sports Med Phys Fitness 1997; 37: 235-9
169. Miyazaki H, Oh-ishi S, Ookawara T, et al. Strenuous endurance
training in humans reduces oxidative stress following exhaustive exercise. Eur J Appl Physiol 2001; 84: 1-6
170. Cao G, Prior RL. Postprandrial increases in serum antioxidant
capacity in older women. J Appl Physiol 2000; 89: 877-83
171. Kohen R, Vellaichamy E, Hrbac J, et al. Quantification of the
overall reactive oxygen species scavenging capacity of biological fluids and tissues. Free Radic Biol Med 2000; 28 (6):
871-9
172. Davies KJ, Quintanilha AT, Brooks GA, et al. Free radicals and
tissue damage produced by exercise. Biochem Biophys Res
Commun 1982; 107: 1198-205
173. Child RB, Wilkinson DM, Fallowfield JL, et al. Elevated serum
antioxidant capacity and plasma malondialdehyde concentration in response to a simulated half-marathon run. Med Sci
Sports Exerc 1998; 30 (11): 1603-7
174. Lovlin R, Cottle W, Pyke I, et al. Are indices of radical damage
related to exercise intensity? Eur J Appl Physiol 1987; 56:
313-6
175. Aguilo A, Tauler P, Fuentespina E, et al. Antioxidant response
to oxidative stress induced by exhaustive exercise. Physiol
Behav 2005; 84 (1): 1-7
176. Vider J, Lehtmaa J, Kullisaar T, et al. Acute immune response in
respect to exercise-induced oxidative stress. Pathophysiology
2001; 7: 263-70
177. Margaritis I, Tessier F, Richard MJ, et al. No evidence of
oxidative stress after a triathlon race in highly trained competitors. Int J Sports Med 1997; 18 (3): 186-90
178. Inal M, Akyuz F, Turgut A, et al. Effect of aerobic and anaerobic metabolism on free radical generation swimmers. Med Sci
Sports Exerc 2001; 33 (4): 564-7
179. Chevion S, Moran DS, Heled Y, et al. Plasma antioxidant status
and cell injury after severe physical exercise. Proc Natl Acad
Sci U S A 2003; 100 (9): 5119-23
180. Ji LL, Fu R. Antioxidant enzyme response to exercise and aging.
Med Sci Sport Exerc 1993; 25 (2): 225-31
181. Criswell D, Powers S, Dodd S, et al. High intensity traininginduced changes in skeletal muscle anti-oxidant enzyme activity. Med Sci Sports Exerc 1993; 25 (10): 1135-40
182. Radak Z, Nakamura A, Nakamoto H, et al. A period of anaerobic exercise increases the accumulation of reactive carbonyl
derivatives in the lungs of rats. Plugers Arch 1998; 435:
439-41
183. Kayatekin BM, Gonenc S, Acikgoz O, et al. Effects of sprint
exercise on oxidative stress in skeletal muscle and liver. Eur J
Appl Physiol 2002; 87: 141-4
184. Goldfarb AH, Bloomer RJ, McKenzie MJ. Combined antioxidant treatment effects on blood oxidative stress after eccentric
exercise. Med Sci Sports Exerc 2005; 37 (2): 234-9
185. Ramel A, Wagner KH, Elmadfa I. Plasma antioxidants and lipid
oxidation after submaximal resistance exercise in men. Eur J
Nutr 2004; 43: 2-6
186. Sahlin K, Cizinsky S, Warholm M, et al. Repetitive static
muscle contractions in humans: a trigger of metabolic and
oxidative stress? Eur J Appl Physiol 1992; 64: 228-36
358
187. Saxton JM, Donnelly AE, Roper HP. Indices of free-radicalmediated damage following maximum voluntary eccentric and
concentric muscular work. Eur J Appl Physiol 1994; 68:
189-93
188. Groussard C, Machefer G, Rannou F, et al. Physical fitness and
plasma non-enzymatic antioxidant status at rest and after a
Wingate test. Can J Appl Physiol 2003; 28 (1): 79-92
189. Chang CK, Tseng HF, Hsuuw YD, et al. Higher LDL oxidation
at rest and after a rugby game in weekend warriors. Ann Nutr
Metab 2002; 46: 103-7
190. Elosua R, Molina L, Fito M, et al. Response of oxidative stress
biomarkers to a 16-week aerobic physical activity program,
and to acute physical activity, in healthy young men and
women. Atherosclerosis 2003; 167: 327-34
191. Ohno H, Yahata T, Sato Y, et al. Physical training and fasting
erythrocyte activities of free radical scavenging enzyme systems in sedentary men. Eur J Appl Physiol 1988; 57 (2): 173-6
192. Accominotti M, Dutey P, Lahet C, et al. Evolution des taux de
selenium et de glutathion peroxydase sanguins de sportifs de
haut niveau. Sci Sports 1991; 6: 165-72
193. Bergholm R, Makimattila S, Valkonen M, et al. Intense physical
training decreases circulating antioxidants and endotheliumdependant vasodilatation in-vivo. Atherosclerosis 1999; 145
(2): 341-9
194. Venditti P, Di Meo S. Effect of training on antioxidant capacity,
tissue damage, and endurance of adult male rats. Int J Sports
Med 1997; 18: 497-502
195. Hollander J, Fiebig R, Gore M, et al. Superoxide dismutase gene
expression in skeletal muscle: fiber-specific adaptation to endurance training. Am J Physiol 1999; 277 (46): R856-62
196. Selamoglu S, Turgay F, Kayatekin BM, et al. Aerobic and
anaerobic training effects on the antioxidant enzymes in the
blood. Acta Physiol Hung 2000; 87 (3): 267-73
197. Powers SK, Ji LL, Leewenburgh C. Exercise training-induced
alterations in skeletal muscle antioxidant capacity: a brief
review. Med Sci Sports Exerc 1999; 31 (7): 987-97
198. Child RB, Wilkinson DM, Fallowfield JL. Resting serum antioxidant status is positively correlated with peak oxygen uptake
in endurance trained runners. J Sports Med Phys Fitness 1999;
39 (4): 282-4
199. Rall LC, Roubenoff R, Meydani SN, et al. Urinary 8-hydroxy-2-deoxyguanosine (8-OHdG) as a marker of oxidative
stress in rheumatoid arthritis and aging: effect of progressive
resistance training. J Nutr Biochem 2000; 11: 581-4
200. Vincent KR, Vincent HK, Braith RW, et al. Resistance exercise
training attenuates exercise-induced lipid peroxidation in the
elderly. Eur J Appl Physiol 2002; 87: 416-23
Finaud et al.