Ox Idative Stress

REVIEW ARTICLE
Sports Med 2006; 36 (4): 327-358

0112-1642/06/0004-0327/$39.95/0
2006 Adis Data Information BV. All rights reserved.
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.
3.2.1 Lipid Peroxidation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 341

3.2.2 Protein Modification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 341
3.2.3 DNA Modification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 342
3.2.4 Other Indirect Oxidative Stress Markers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 342
3.3 Antioxidant Measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 342
3.3.1 Enzymatic Antioxidant Activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 342
3.3.2 Antioxidant Vitamins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 342
3.3.3 Other Antioxidants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 342
3.3.4 Total Antioxidant Capacity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 343
3.4 Summary: is There an Ideal Method? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 343
4. Oxidative Stress and Physical Activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 343
4.1 Oxidative Stress and Exercise . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 343
4.1.1 Aerobic Exercise . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 343
4.1.2 Anaerobic Exercise . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 345
4.1.3 Mixed Exercises . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 347
4.2 Training Effects on Oxidative Stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 349
4.2.1 Aerobic Training . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 349
4.2.2 Anaerobic Training . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 350
4.2.3 Mixed Training . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 350
4.2.4 Relationship Between Training Load and Oxidative Stress . . . . . . . . . . . . . . . . . . . . . . . . . . 350
4.2.5 Oxidative Stress and Overtraining . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 352
4.3 Summary: Oxidative Stress, Training and Overtraining . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 352
5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 353
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.
tigue, many diseases and aging.[2,3] However, they

exert positive effects on the immune system and
essential metabolic functions.[4] Antioxidants are
components that suppress FR and their harmful effects. If the production of FR is larger than antioxidant activity, there is an oxidative stress state with
cell damages.[5]
Sports Med 2006; 36 (4)
Oxidative Stress and Physical Activity
Physical activity increases the FR production and

the antioxidant utilisation. Nutrition provides an important part of the antioxidant; however, insufficient
micronutrient supply is often reported in athletes.[6,7]
It has also been shown that oxidative stress can
increase during periods of intensive training. Therefore, oxidative stress may be one of the actors of the
overtraining syndrome.[8,9]
This article presents the basis of oxidative stress
and determines the relationship between oxidative
stress, exercise, training and overtraining.
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. Free Radicals (FR) and

Activated Species
FR are molecules or molecule fragments with
one or more unpaired electrons in the valence
shells.[10-12] FR are very unstable and very reactive
because they tend to catch an electron to other
molecules (oxidation).[5,13] Their lifetime is very
short (from milliseconds to nanoseconds [table I]).
FR are produced by an electron transfer that requires
a high energy input.[11] When reacting with other
radicals or molecules, a FR can form new radicals.[5]
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-
Table I. Classification and main effects of free radicals

Free Radical
Contraction
Reactive oxygen species
ROS
Half-life
Main effects
Superoxide ion
O2
105 sec
Lipid oxidation and peroxidation

Protein oxidation
DNA damage
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
Reactive nitrogen species
RNS
Nitric oxide
NO
Nitric dioxide
NO2
Peroxynitrite
ONOO
Reactive sulphur species
RSS
Thyil radical
RS
Lipid peroxidation
DNA damage
Proteins oxidation
110 sec
0.051 sec
Proteins oxidation
DNA damage
ROS production
Sports Med 2006; 36 (4)
330
Finaud et al.
trons. Dioxygen prefers to receive one electron at a

time and converts it into a superoxide ion (O2).[5]
Following this process, 25% of oxygen consump 2) is converted to O2.
tion (VO
tive and very toxic ROS and there is no specific

antioxidant against this FR. This FR causes lipid
peroxidation and protein oxidation.[16]
1.2 Programmed Formation of ROS
1.1.2 Superoxide Ion

O2 is created with
the addition of one electron

on dioxygen (equation 1) and becomes highly reactive.
O 2 + e- O 2 (Eq. 1)
Fentons reaction is an iron-salt-dependent decomposition of dihydrogen peroxide, generating the
highly reactive hydroxyl radical. It occurs in the
presence of ferrous ions (Fe2+) and O2. Iron is
mainly present in tissues in a ferric ion state (Fe3+).
The reaction (equation 2d) is called the Haber-Weiss
reaction.
a
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
1.1.3 Hydrogen Peroxide
Equation 3 summarises the first and the second

stages of Fentons reaction (equations 2a and 2b).
This reaction forms hydrogen peroxide (H2O2) in an
acid environment and is catalysed by the superoxide
dismutase (SOD) enzyme.
SOD
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
Hydroxyl radical (OH) is the end product of

Fentons reaction (equation 2). OH is a very reac 2006 Adis Data Information BV. All rights reserved.
1.3.1 ROS Formation During Oxygen Metabolism
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
Electron chain transport

NADH
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.
vealed that about 50% of O2 production arises

from reduced nicotinamide-adenine dinucleotide
(NADH)-dehydrogenase inside complex I, between
a mercurial-sensitive and a retonone-sensitive component, most likely a nonhaeme iron-sulphur function. This hypothesis is still controversial.[26] The
possible locations of ROS formation inside the mitochondrial respiratory chain are represented in figure
1.
The assumption that mitochondria are the major
intracellular source of ROS was essentially based on
in vitro experiments with isolated mitochondria.[19,20,26] Artifacts due to the preparation procedure or inadequate measurement of ROS may lead
to methodological mistakes.[26] In vivo study provides direct evidence that mitochondria (in heart
muscle) produce ROS during exercise.[16] So, both
in vitro and in vivo studies tended to affirm that the
mitochondrial respiratory chain can not only be a
major source of ROS at rest and during exercise in
the working muscle, but also in tissues such as liver,
kidneys and non-working muscles that undergo partial ischaemia during physical exercise.[19] At the
same time, mitochondria are particularly susceptible
to the ROS-induced oxidative damage on lipids,
proteins and DNA. In particular, damage to mitoSports Med 2006; 36 (4)
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.
chondrial DNA (mtDNA) induces alterations to the

polypeptides in the respiratory complexes, with consequent decrease of electron transfer, leading to
further production of ROS. Thus, a vicious circle of
oxidative stress and energetic decline is established.[28,29] However, training does not seem to
modify ROS release from mitochondria.[27] Nevertheless, there is a lack of knowledge about the exact
mechanisms of ROS production inside the mitochondria, and further studies are needed.
1.3.2 ROS Formation During Ischaemia Reperfusion
The second major source of ROS is ischaemia

reperfusion phenomenon, which occurs after surgical interventions, after shocks or during physical
exercise (figure 2).[17,30-32] During exhaustive or anaerobic exercise, blood flow is brought to active
territories such as skeletal muscles while other tissues can be in an hypoxic situation.[1,19] After exercise, these tissues receive a great quantity of oxygen.
This phenomenon is described as ischaemia
reperfusion. Xanthine dehydrogenase (XDH) has
an important role in the formation of uric acid from
purins degradation (ATP, adenosine diphosphate
[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)
Myoglobin can also be oxidised by auto-oxidation

or by FR during ischaemia reperfusion with the
production of H2O2.[35,38,40] Myoglobin can then interact with H2O2 and produce other radicals such as
ferryl radicals or peroxyl radicals.[41-43]
1.3.4 Other Ways of ROS Production
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
ROS are involved in the immunity phenomenon,

in particular by acting against antigens during phagocytosis.[10,12,17] This role increases during inflammation. Inflammation can be caused by physical
exercise, particularly by intense and traumatising
exercises such as eccentric exercises.[45] Although
most studies have concentrated on the harmful effects of FR, ROS play an important role in cellular
signals or in biogenesis of cells because they can
serve as cell messengers or modify oxidation-reduction (redox) status.[5,12,46-48] ROS are also known to
be involved in enzyme activation, in drug detoxification or in facilitating glycogen repletion.[10] ROS
also play an essential role in muscular contraction.[47-50] This role has been pointed out because
inhibition of ROS production leads to a loss of
muscular fibres contractile force. Conversely, increasing ROS leads to an increased strength contraction.[47,49,50] However, an important amount of ROS
in muscular tissue is implicated in muscular fatigue
and can represent one of the negative effects of
ROS.
1.4.2 Negative Effects
Despite some helpful effects, ROS have possible

harmful effects because they can alter the size and
shape of the compounds they interact with.[1,10,51,52]
Consequently, ROS can induce apoptosis into
healthy cells and can provoke inflammation or altered cellular functions. All those deteriorations take
part in some degenerative pathology such as cat 2006 Adis Data Information BV. All rights reserved.
333
aract, cancers, Alzheimers or Parkinsons diseases

or in cell aging.[3]
Lipid Oxidation
Lipoprotein oxidation is an important factor in

the pathogenesis of atherosclerosis.[53,54] In fact,
ROS initiate lipoprotein oxidation, in particular lowdensity lipoprotein (LDL) oxidation.[55] This oxidation is dependent on blood antioxidant capacity[56,57]
and can increase with oxidative stress linked to
physical exercise.[58,59] However, those effects are
partially or totally compensated in athletes because
exercise decreases cardiovascular accident risk.[59]
ROS also have the ability to oxide polyunsaturated
free-fatty acids (PUFFA), which take part in cell
membrane constitution.[11,21,51] This reaction initiates lipid peroxidation, a chain reaction that produces other FR such as ROO or ROOH and substances such as conjugated dienes or malondialdehyde (MDA).[54] Lipid peroxidation changes the
fluidity of cell membranes, reduces the capacity to
maintain an equilibrated gradient of concentration,
and also increases membrane permeability and inflammation.[60] Consequently, it is possible to detect
a loss of intracellular liquids, a diminution of calcium transport in the endoplasmic reticulum, alterations of mitochondrial functions and cell alterations,
together with loss of cryptozoic proteins and enzymes.[10,31] Every type of cell can be damaged by
ROS, including muscular cells and erythrocytes.[61]
Protein Oxidation
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.
proteolysis blocking and an accumulation of oxidised proteins.[64,65] Consequently, protein turnover,

genetic transcription and cell integrity are reduced
under ROS actions. ROS also have the ability to
alter the lysosomal system and the proteasomes, two
major pathways by which proteins are degraded.[62]
DNA Oxidation
ROS are also known to cause DNA strand breaks

and base repair damage.[10,51,63,68] Every part of
DNA is susceptible to attack by ROS.[69] The DNA
repair system is continual, but its capacity can be
overreached or the repair processes can be altered.[68,70] As a consequence, DNA oxidation can
provoke mutagenesis and is a major contributor to
human cancer and cell aging.[17,60,68,70,71] Different
major sources of DNA damages have been found as
a result of: smoking, chronic inflammation and leakage from mitochondria, which increased with physical exercise.[51,70,71]
Implication of FR in Muscular Fatigue
A minimal amount of ROS is necessary for muscular contraction.[47,49,50] Nevertheless, oxidative

stress, which results in muscle-increased ROS concentration, is associated with muscular fatigue dur 2006 Adis Data Information BV. All rights reserved.
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
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
CAT is present in every cell and in particular in

peroxysomes, cell structures that use oxygen in order to detoxify toxic substances and produce
Sports Med 2006; 36 (4)
336
Finaud et al.
Table II. Localisation and actions of antioxidant enzymes

Antioxidants
Cofactors
Cellular localisation
Targets
Mn-SOD
Manganese
Mitochondria
Anion superoxide
Peroxynitrite
Cu-Zn-SOD
Copper
Zinc
Cytosol mitochondria (membrane)
Anion superoxide
Peroxynitrite
CAT
Iron
Peroxysome, cytosol and mitochondria
Hydrogen peroxide
GPX
Selenium
Cytosol and mitochondria
Hydrogen peroxide
Peroxynitrite
CAT = catalase; GPX = glutathione peroxide; SOD = superoxide dismutase.
H2O2.[86] Catalase converts H2O2 into water and

oxygen (equation 8).
2.2 Non-Enzymatic Antioxidants
CAT
2 H 2O
2 H2O + O 2
2.2.1 Vitamin E (Tocopherol)
(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
Antioxidant enzymes are endogenous (table II).

However, their production can be modulated by
certain factors. Exercise and training are well known
to be potential factors of SOD, CAT and GPX
increase as shown by numerous studies (see section
3 for more details).[16,22,74,87]
Vitamin E is a fat-soluble vitamin made up of

several isoforms known as tocopherols. -Tocopherol is the more active and abundant form.[88] Vitamin E has been called the most important chainbreaking antioxidant because of its abundance in
cells and mitochondrial membranes and its ability to
act directly on ROS.[78] Vitamin E interacts with
numerous antioxidants such as vitamin C, GSH, carotene or lipoic acid. Those antioxidants have the
capacity to regenerate vitamin E from its oxidised
form.[50] Vitamin E plays an important role in cell
membranes because it stops lipid peroxidation (table
III). The molecular structure of vitamin E enables
ROS inactivation in a lipid environment, particularly for peroxyl radicals, which come from LDL oxidation into membranes or into blood.[53,89,90] A vitamin E deficiency is frequent in healthy occidental
populations.[90,91] Such deficiency could increase
oxidative stress and fatigue associated with decreased oxidative capacity and endurance.[77,78,92,93]
Athletes often use vitamin E supplementation in
order to prevent exercise-induced ROS muscular
damages and fatigue.[7,33,78,87,94,95] However, the results are often contradictory probably because of
methodological differences such as vitamin status of
subjects before studies, vitamin E supplementation
quantity, frequency and duration, or training level.[6,76] Indeed, trained subjects present a higher vitamin E status, whereas overreaching seems to decrease it.[33,76]
Sports Med 2006; 36 (4)
337
Table III. Localisation and actions of the main non-enzymatic antioxidants

Antioxidant
Localisation
Actions
Targets
Vitamin E (tocopherol)
Lipids
Cell/mitochondria membranes
Lipid peroxidation inhibition

Membrane stabilisation
ROOH 1O2
Vitamin A (retinol)
Lipids
Cell membranes
Lipid peroxidation reduction
1O2
Vitamin C (ascorbic acid)
Aqueous middle
Cytosol
Extracellular liquids
Vitamin E regeneration
LDL protection
Glutathione
Aqueous middle
Substrate for GPX

Vitamins E and C regeneration
Direct antioxidants
Cysteine
Intracellular middle
Glutathione precursor
Lipoic acid
Aqueous middle

Vitamins C and E and cysteine
regeneration
Thioredoxin
Aqueous middle
Mn-SOD synthesis
Vitamin C regeneration
ROOH
OH O2
1O2
OH
H2O2 ROOH
H2O2
Glutaredoxin
Aqueous middle
Flavonoids
Linked with glucids
Pro-oxidant enzymes inhibition

Pro-oxidant ions (Fe2+, Fe3+,
Cu2+)
trapping
LDL protection
Coenzyme Q10
Internal membrane of
mitochondria
Vitamin C and E regeneration

LDL protection
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
Protection of proteins (cells)
Iron
Aqueous middle
Catalase cofactor
Ferritin
Aqueous middle
Free iron trapping
Zinc
Aqueous middle
SOD cofactor (Cu-Zn-SOD)

LDL and thiols protection
FR production inhibition
Copper
Aqueous middle
SOD cofactor (Cu-Zn-SOD)
Selenium
Aqueous middle
GPX cofactor
Manganese
Aqueous middle
SOD cofactor (Mn-SOD)
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
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.
Sports Med 2006; 36 (4)
338
Finaud et al.
2.2.2 Vitamin C (Ascorbic Acid)
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)
Vitamin A is a fat-soluble vitamin present in

many lipid substances. -carotene, present in cell
membranes, is converted into vitamin A when the
body needs it. Although the mechanism of its in vivo
action is unclear, -carotene is suggested to deactivate ROS (in particular singlet oxygen and lipid
radicals) and to reduce lipid peroxidation.[74,100] Although less important than vitamin E inside the
antioxidant system, -carotene and vitamin A act in
tandem with vitamin C and vitamin E in order to
protect cells against ROS.[101] -carotene supplementation seems to have beneficial effects against
exercise-induced oxidative stress without enhancing
physical performance.[102,103]
2.2.4 Flavonoids
Flavonoids (Fl-OH) are phenolic substances

formed in plants from amino acids phenylalanine,
tyrosine and malonate.[93,104] In vitro studies pointed
out the antioxidant effects of flavonoids that have
the ability to inhibit pro-oxidant enzymes or to form
complexes with pro-oxidant ions such as Fe2+, Fe3+
or Cu2+. Flavonoids also have direct trapping action
upon some ROS by direct hydrogen atom donation.

Despite increasing evidence for the in vitro antioxidant effects of flavonoids, there is a lack of knowledge on their in vivo actions.[52,104,105] However,
some studies tend to confirm the in vivo antioxidant
properties of flavonoids.[106] Moreover, flavonoids
seem to have a sparing effect on vitamin E and carotene.[52,106] The in vivo effects of flavonoids are
discussed because some of them can have pro-oxidant effects and because flavonoids are present in
the body as metabolite forms that have poor antioxidant effects.[105,107,108]
2.2.5 Thiols
Thiols are a class of molecules characterised by

the presence of sulfhydryl residues (SH) at their
active site.[109] Thiols are synthesised from sulphur
amino acids: cysteine or methionin, which is a cysteine precursor. They have numerous functions in
biological systems, e.g. protein synthesis, redox, cell
biogenesis and immunity. They also play a major
role in the antioxidant defence network.[109] GSH is
the major thiol present in an organism. It acts like a
substrate for GPX in peroxidase ROS inhibition.
GSH can also directly detoxify ROS and enhances
the functional antioxidant capacity of vitamins C
and E.[110,111] In the presence of oxidative stress, it is
possible to observe a decrease of the GSH/GSSG
ratio and of the total thiol quantity.[109,112,113] These
phenomena seem to be involved in the aetiology of
some neurodegenerative diseases such as Parkinsons or Alzheimers disease.[114] They are also observed in aging or after physical exercise.[112,113] A
low GSH concentration in cells may be associated
with cellular damage and decreased immunity efficiency, which can be compensated with a vitamin C
and E supplementation.[115] Such results tend to
show that these antioxidants have the same targets
and work together against them. Lipoic acid is a
thiol that inhibits lipid peroxidation and helps to
reduce vitamins C and E from their oxidised
form.[50,116,117] It can also reduce cystin (the oxidised
form of cysteine) into cysteine in order to promote
thiol genesis.[109,114,118] Therefore, lipoic acid supplementation helps to increase antioxidant protection and may have some therapeutic effects.[50,109]
Sports Med 2006; 36 (4)
2.2.6 Coenzyme Q10
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
Uric acid is an end-product of purine metabolism

in humans.[113,126,127] Intense physical exercise is
known to increase plasmatic concentrations of uric
acid.[90,128] Plasmatic uric acid can then diffuse into
muscles in order to protect them from FR oxidation.[129] Indeed, uric acid, in plasma and in muscle,
is also one of the more important antioxidants with
direct effects on singlet oxygen, HOCL, peroxyl
radical, peroxynitrite or ozone.[36,126,130-134] Some
studies demonstrated that uric acid represents a great
part (>50%) of the plasmatic antioxidant capacity.[131] Thus, uric acid helps to protect erythrocytes,
cell membranes, hyaluronic acid and DNA from FR
oxidation. Another important antioxidant property
of uric acid is the ability to form stable complexes
with iron ions. This process inhibits Fe3+, catalysed
vitamin C oxidation and lipid peroxidation.[135,136]
Therefore, uric acid is a vitamin C protector but is
also a vitamin E protector.[56] In vivo, it is possible to
detect and measure its FR-induced oxidation product (allantoin) in body fluids after episodes of oxidative stress, such as physical exercise.[113,127,137,138]
2.2.8 Heat Shock Proteins
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
ly with body temperature variations, inflammation

and oxidative stress.[139-141] HSP are considered antioxidants because they protect cells and intracellular
proteins against FR-induced damage.[17,139,140] Physical training and antioxidant supplementation promote a lower HSP basal level but the ability to have
a quick HSP liberation under stressful situations
remains unchanged.[140] Given the potential of ROS
to damage intracellular proteins during subsequent
bouts of muscle contractions, data suggested that,
under oxidative stress conditions, the pre-existing
antioxidant pathways may be complemented by the
synthesis of HSP.[141] Thus, HSP could represent an
important protection mechanism against exerciseinduced damage to muscle.[139-141]
2.2.9 Ferritin
Iron is required for normal cell growth and

proliferation and can have antioxidant effects as a
cofactor of catalase. However, iron ions can have
pro-oxidant effects in Fentons reaction or can oxidise vitamin C and reduce antioxidant protection
against FR.[136,142] Therefore, excess iron is potentially harmful and ferritin, one of the major proteins
of iron metabolism, plays an important part in the
maintenance of iron balance.[143] Several studies
support a protective role of ferritin against FRmediated damage because ferritin minimises FR
formation by sequestering iron in blood or in
cells.[142,144,145] In addition, an increase of ferritin
synthesis is observed in response to physical exercise, cellular damage and inflammation, which promote oxidative stress.[144-148] Indirect and direct
links between FR and genetic expression of ferritin
were shown in some studies.[142-145]
2.2.10 Albumin, Caeruloplasmin and Bilirubin
Albumin, caeruloplasmin and bilirubin act as

nonspecific chain-breaking antioxidants by giving
electrons to FR.[13] Albumin (a thiol protein) and
caeruloplasmin are implicated in copper transport
and so they reduce FR generation by Fentons reaction.[12,149] Bilirubin, a biliary protein coming from
haemoglobin, increases with oxidative stress and
has antioxidant effects in body fluids.[147,150,151]
However, these proteins have a limited antioxidant
action because their action is indirect and is effecSports Med 2006; 36 (4)
340
Finaud et al.
tive in body fluids such as blood, far from the major

FR production localisation, especially during physical exercise.
2.3 Antioxidant Supplementation in Athletes
2.3.1 Beneficial Effects of
Antioxidant Supplementation
Antioxidant supplementation among athletes is

well documented. The results of these studies are
often contradictory because of antioxidant compounds and quantity. Indeed, some studies showed
that the association of several antioxidants has better
effects than single-compound supplementation.[152-154] Moreover, the subjects profiles (age,
nutritional status, training level and physical activity
category) can influence the results.[33,44] In a large
majority of studies, antioxidant supplementation
does not enhance exercise performance or physical
capacity in non-deficient athletes.[7,44,78,103] In return,
antioxidant supplementation provides protection
against the negative health consequences of FR
caused by exercise. Thus, antioxidant supplementation helps athletes to maintain an optimal health,
which is a key condition to attaining the best performance. This is particularly important during periods of intensive training and/or competition, which
cause greater needs of antioxidants.[152-155] In this
case, a normal diet is not always sufficient.[6,33,156]
Some antioxidants (vitamins A, E and C) can protect
subjects from FR-induced muscle damage during
exercise or can have anabolic effects.[76,102] Results
tend to show that antioxidant supplementation can
have beneficial effects in athletes by preventing
against antioxidant deficiencies and FR harmful effects on tissues, particularly muscular tissues.[152,154]
2.3.2 Pro-Oxidant Effects of Overloaded
Antioxidant Supplementation
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
effects because long-term administration of quercetin significantly decreases glutathione concentration

and glutathione reductase activity in rats.[159] Moreover, antioxidants present in food are in a balanced
biochemistry state compared with supplement antioxidant compounds.[157]
2.4 Summary: Exercise and the
Antioxidant System
Both enzymatic and non-enzymatic antioxidants

play a vital role in protecting tissues from excessive
oxidative damages.[44,84] The respective actions of
the antioxidants are summarised in table III and
figure 2. This role is especially important during
exercise, which is associated with FR production, in
relation to intensity, duration and training status.[87]
Thus, because of low antioxidant dietary intakes and
exercise and training modifications on the antioxidant system, some antioxidant supplementation in
certain antioxidant nutrients seems to be justified.[22]
However, the theoretical basis for which antioxidants should enhance performance is not clear.
Studies have generally found that antioxidant supplements do not improve performance but improve
antioxidant status.[152,154] In return, large amounts of
antioxidant in nutrition could have negative effects.[44,79] Therefore, it seems that antioxidant supplementation must be extremely controlled for composition, duration and dose (depending on nutritional intakes) in order to be efficient for athletes health
and performance.
3. Methods to Assess Oxidative Stress in
Biological Systems
Oxidative stress can be estimated according to
the measurement of: (i) FR; (ii) radical-mediated
damages on lipids, proteins or DNA molecules; and
(iii) antioxidant enzymatic activity or concentrations. Results must be interpreted with caution because of possible contradictions.[44,160,161]
3.1 Direct Detection of FR
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)
lows the direct measurement of ROS from their

paramagnetic properties.[12,97,162] Measurements can
be made in vitro, in vivo or ex vivo. However, the
most precise measurements (in vivo) are not practicable in humans because of the toxicity of the products used for such methods.[12,44] Blood samples can
be collected in tubes containing a solution with spin
trappers, which are ROS stabilisers. After centrifugation, the serum is analysed by a spectroscopic
method. However, the results are to be interpreted
with caution because of the short half-life of the
ROS, their strong ability to react and their weak
concentration.[1,97,161] This direct method allows a
better understanding of the ROS reactions, and reagents used can also quantify ROS.[12] Realised ex
vivo, it raises the problem of the short ROS half-life,
these being stabilised in the serum after blood samples.
3.2 Measurement of Oxidative Damage to
Lipids, Proteins and DNA Molecules
3.2.1 Lipid Peroxidation
A basic approach to study oxidative stress would

be to measure the rate of peroxidation of membrane
lipids or fatty acids. Lipid peroxidation leads to the
breakdown of lipids and to the formation of a wide
array of primary oxidation products such as conjugated dienes or lipid hydroperoxides, and secondary
oxidation products including MDA, F2-isoprostane
or expired pentane, ethane or hexane.
Measurement of conjugated dienes is interesting
because it detects molecular reorganisation of polyunsaturated fatty acids during the initial phase of
lipid peroxidation. Because of this specificity, this
method is often used to assess oxidative stress.[18,44]
Lipid hydroperoxide is another marker of the initial
reaction of FR and is a specific marker of cellular
membrane damage.[12,97]
Other products are often used to measure oxidative stress but have the disadvantage of being secondary oxidation products. One of them, MDA, is
produced during fatty acid auto-oxidation. This substance is most commonly measured by its reaction
with thiobarbituric acid, which generates thiobarbituric acid reactive substances (TBARS). Although
341
TBARS assay is not specific to MDA (this induces

MDA overestimation), this method is accepted as a
general marker of lipid peroxidation but results are
subject to caution.[12,44,111,161] In addition, some studies tend to show that MDA is not an adapted method
to assess oxidative stress after exercise.[111]
A further technique for the measurement of lipid
peroxidation is the analysis of volatile hydrocarbon
end products such as pentane, hexane and ethane in
expired air. Such a method is non-invasive but is not
precise because these gases can be formed by other
ways than FR oxidation.[12]
More recently, it was found that F2-isoprostanes
are produced by FR catalysed peroxidation of
arachidonic acid.[18] Numerous recent studies have
shown that quantification of F2-isoprostane compounds could be a reliable method for endogenous
lipid peroxidation and oxidant injury assessment as
well as some other recent markers such as blood
oxidised LDL or antibodies against oxidised
LDL.[59,93,163]
3.2.2 Protein Modification
FR-induced modification of proteins causes the

formation of carbonyl groups into amino acid side
chains. An increase of carbonyl is present in every
phenomenon linked to oxidative stress.[66] Thus, the
measurement of carbonyl formation is the most usual method for determination of FR-damaged proteins.[65,66] Total proteins are often measured in order
to use the carbonyl/protein ratio, which is a more
precise index of protein oxidation.[164] This method
is particularly interesting because the half-life of
carbonyl is long. Thus, a high amount of carbonyl
can show cumulative effects of oxidative stress,
which is essential in some studies (e.g. longitudinal
following of athletes).
Oxidised amino-acid (e.g. o-o-dityrosine) quantification is an alternative method for oxidised protein measurement.[16] This method can be non-invasive (with the possibility of using urine samples) and
presents a methodological interest (high concentrations and stability of measured compounds). Nevertheless, there is a lack of knowledge in oxidised
amino acid kinetics, which limits the interpretation
of the results.[12,16]
Sports Med 2006; 36 (4)
342
Finaud et al.
3.2.3 DNA Modification
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
Creatine kinase (CK) and myoglobin are markers

of muscular cellular damage.[9,166] These parameters
can also be considered indirect markers of oxidative
stress because lipid peroxidation induces damage of
cellular membranes.[9,12] Thus, they are more permeable and allow the release of these intracellular
substances.[76] However, CK and myoglobin are not
specific markers of oxidative stress, especially in
athletes who can have high plasmatic CK and myoglobin values because of sports characteristics
(shocks, contacts), which induce cellular damage.[9]
Moreover, trained athletes have higher basal values
of CK and myoglobin.[76] Another effect on the
cellular membrane is an alteration of its pliability,
inducing a modification of blood rheology, which
has been used to evaluate states of fitness in athletes.[167]
3.3 Antioxidant Measures
3.3.1 Enzymatic Antioxidant Activity
Enzymatic antioxidant activity (SOD, CAT and

GPX) is quantified in a large majority of studies.
This method can evaluate the quality of antioxidant
protection at rest but can also show the importance
of oxidative stress, especially after physical activity.
After exercise, their evolution represents an adaptation upon FR production.[168,169] Antioxidant enzyme activity can be modified differently: increase
at first (adaptation) or decrease if oxidative stress is

important or long (utilisation).
3.3.2 Antioxidant Vitamins
Plasmatic quantification of antioxidant vitamins

(vitamin A, C and E) is a common method to assess
antioxidant protection and to detect vitamin deficiency.[12,13] As well as antioxidant enzymes, antioxidant vitamin concentrations are modified in the
presence of oxidative stress and can be indirect
markers of oxidative stress.[12] However, some precautions must be taken, especially for vitamin C. A
stabiliser must be added in samples in order to
stabilise this vitamin.[98] Vitamin E, in blood, is
transported linked to blood lipids. Therefore, cholesterol is often measured in order to obtain the
vitamin E/cholesterol ratio, which is a good marker
of vitamin E status.[59] Caution is recommended
when interpreting plasma antioxidant concentrations
because variations, during exercise or training, may
represent a redistribution between tissue and plasma.[87]
3.3.3 Other Antioxidants
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)
lantoin alone may have limited value as a marker of

oxidative stress because allantoin can be oxidised
and degraded by FR in blood samples. Thus, allantoin quantity can underestimate oxidative
stress.[137]
3.3.4 Total Antioxidant Capacity
The large number of antioxidants in human fluids

or in tissue makes it difficult to measure each antioxidant separately. Therefore, several methods have
been developed to measure the total antioxidant
capacity (TAC) of a biological sample.[162] The use
of a pro-oxidant in order to quantify the oxygen
radical absorbance capacity is one of the most used
techniques.[13,170] The TAC gave an overall value
corresponding to the sum of all antioxidants.[13,170]
However, the interpretation of the changes in the
antioxidant capacity is difficult because it can increase as a result of nutritional effects or because of
an adaptation of oxidative stress. Furthermore, some
antioxidant concentrations can be modified without
any evolution of the TAC.[171]
3.4 Summary: is There an Ideal Method?
In general, every method has its interests and its

limits, and because of this complexity, no single
measurement of oxidative stress or of antioxidant
status is going to be sufficient. Indeed, the interpretation of the values coming from a single marker
could be a source of error. Therefore, a battery of
measurements, including TAC, isolated antioxidant
and markers of FR-induced damage on lipids, proteins and DNA seems to be a reliable method to
assess oxidative stress.[13]
4. Oxidative Stress and Physical Activity
4.1 Oxidative Stress and Exercise
4.1.1 Aerobic Exercise
Effects on FR Production
In 1982, Davies et al.[172] were the first to show

that exercise increases FR production. Since then, a
lot of studies have investigated the effects of exercise on oxidative stress. Most of them were carried
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
Lovlin et al.[174] (1987)
Activity
2max)
MDA (at 40% VO
2max)
MDA (at 70% VO
2max)
MDA (at 100% VO
TBARS GSSG
MDA
CD
SOD GPX
CAT
Margaritis et al.[177] (1997)
Triathlon (long distance)
18 VT
Marzatico et al.[168] (1997)
Running (half-marathon)
6T
Vasankari et al.[53] (1997)
Running (marathon)
22 VT
Tocopherol TRAP
CD
Retinol CoQ10
Ashton et al.[162] (1998)
2max test (ergocycle)

VO
12 T
TAC
FR (ESR) MDA LH
Child et al.[173] (1998)
17 T
MDA
CK
TEAC UA
Liu et al.[58] (1999)
Running (marathon)
11 VT
10 UT
Oxidised LDL
TRAP UA
Thiols
Tocopherol vit C vit A
Hellsten et al.[138] (2001)
Two exercises to exhaustion at 90%

2max (cycling)
VO
Allantoin
UA (muscle)
GSH cysteine UA (plasma)
Inal et al.[178] (2001)
Swimming (800m)
10 T
CAT GPX
GSH
Mastaloudis et al.[90] (2001)
Running (50km)
11 T
Isoprostane
UA tocopherol vit C
Miyazaki et al.[169] (2001)
2max test (ergocycle)

VO
TBARS neutrophil FR
production
Protein carbonyls
SOD GPX CAT
Vider et al.[176] (2001)
2max test (treadmill)

VO
19 T
TBARS CD
TAC GSH CAT
GPX SOD
Dawson et al.[76] (2002)
Running (21km)
15 T
MDA
CK myoglobin
Chevion et al.[179] (2003)
Walking (50km)
Walking (80km)
29 T
16 T
CK
Protein carbonyls
UA
Palmer et al.[96] (2003)
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
trations (in plasma, urine or in tissues) are modified,

but results are often contradictory. For example,
Sports Med 2006; 36 (4)
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
Anaerobic exercise is a type of exercise that

includes a large variety of sport activities (e.g.
sprints, jumps or resistance exercise). Information
on the production of FR as a result of acute anaerobic exercise is lacking compared with aerobic exercise.[111] However, these studies generally show an
increase of the oxidative stress after supramaximal
exercise such as intermittent running, sprints, jumps
or sets of jumps, resistance exercise (eccentric or
concentric) or Wingate tests on an ergocycle (table
V).[94,111,163,164,182-185]
The increase of FR production, specific to anaerobic exercise, may be mediated through various
pathways in addition to electron leakage, such as
during aerobic exercise.[94,111,186] Xanthine oxidase
production, ischaemia reperfusion and phagocytic
respiratory burst activity seem to be implicated in
FR production during anaerobic exercise.[186] Moreover, the important increases of lactic acid, acidosis,
catecholamine and post-exercise inflammation,
characteristic in supramaximal exercises, are other
factors that can increase the production of FR.[183,186]
It seems possible that ischaemic reperfusion of
the active muscle is greatly involved in oxidative
stress during and after anaerobic exercise.[186] Precisely, this type of exercise significantly enhances
the catabolism of purins and provokes a fast deoxygenation (phenomenon of ischaemia reperfusion).
These two phenomena are known to increase the
activity of xanthine oxidase, which accelerates FR
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]
Studies about the effects of anaerobic exercise on

antioxidants are scarce compared with those concerning submaximal exercise. Some studies show an
increase of the enzymatic antioxidant activity in
plasma or in muscle after anaerobic exercise.[79,168,178] In turn, a Wingate test provokes a
decline of SOD activity without any GPX activity
change.[111] According to the authors, the decline of
the SOD activity would result from an increase of
FR production. Those differences could be explained by the differences in exercise intensity.
Sports Med 2006; 36 (4)
346
Table V. Human studies on the effects of anaerobic exercise on markers of oxidative stress
Study (year)
Activity
Sahlin et al.[186] (1992)
Isometric knee extension at 60% 1RM

intermittent 80 min
Saxton et al.[187] (1994)
Elbow flexion 70 max eccentric or concentric

actions
6 150m sprints
Ortenblad et al.[166] (1997)
6 bouts of jumping 30 sec each bout
McBride et al.[94] (1998)
Resistance training programme (8 exercises, 3

sets of each failure)
Childs et al.[79] (2001)
Eccentric arm flexion (cybex)

3 10 reps at 80% RM
Inal et al.[178] (2001)
100m swim
Groussard et al.[188] (2003)
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
Cycling Wingate tests (30 sec)
7T
UA vit C
Tocopherol vit A
Groussard et al.[111] (2003)
Cycling Wingate tests (30 sec)
8T
ESR signals
TBARS
SOD GSH
GPX
Ramel et al.[185] (2004)
Resistance programme (10 exercises max of

reps at 75% 1RM)
7T
10 UT
MDA
CD (trained group)
CD (untrained group)
Vit A tocopherol
Goldfarb et al.[184] (2005)
Eccentric resistance exercise
18 UT
Protein carbonyls MDA

GSSG
GSH
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.
Sports Med 2006; 36 (4)
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
100 min of intermittent exercise

on legs and arms
Subjects
Chang et al.[189] (2002)
Rugby match (2 40 min)
Svensson et al.[113] (2002)
50 min of aerobic exercise and 15 T

intermittent 1020 sec anaerobic
exercise (ergocycle)
7T
15 VT vs 6 T and 10 UT
Markers
Effect
UA (blood)
UA (muscle)
TBARS
CD
GPX SOD
GSH
UA
Running shuttle (20m) during 90 16 T

MDA
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).
Thompson et al.[99] (2003)
There are few data on the effects of anaerobic

exercise on non-enzymatic antioxidants. Nevertheless, it was shown that a Wingate test induced an
increase in plasmatic uric acid and vitamin C concentrations and a drop of the plasmatic vitamin A
and E concentrations.[188] In this study, a decline of
GSH was also observed, which could be explained
by its use in the regeneration of vitamins C and
E.[188] In turn, a recent study shows that fat-soluble
plasma antioxidants (vitamins A and E) increase
after acute resistance exercise.[185] Therefore, further
studies are needed for a better understanding of nonenzymatic antioxidant response to anaerobic exercise.
4.1.3 Mixed Exercises
General Findings about Mixed Exercise
A mixed activity can be defined as an activity

that involves both aerobic and anaerobic metabolism in a balanced ratio. Team sports such as football, rugby and basketball are some examples of this
type of exercise, which include aerobic phases (intermittent running at different intensity) and anaerobic phases (jumps, sprints). Therefore, the effects
of this type of exercise on oxidative stress have been
the source of few investigations and are more centred on training effects.[156,188]
Mixed Exercise Effects on FR Production
and Antioxidants
The literature tends to show that mixed exercise

has logically the same effects as aerobic and anaerobic exercise on FR production. Such results were
reported after an intermittent running session and

after a rugby match (table VI).[99,189]
In turn, the effects on antioxidants are more contradictory. Indeed, a rugby match does not modify
enzymatic antioxidant activity.[189] This result is surprising in regard to aerobic and anaerobic exercise
effects on SOD, GPX and CAT, and must be confirmed by further study. In contrast, some studies
suggest that non-enzymatic antioxidants may have
the same evolution after mixed exercise compared
with aerobic and anaerobic exercise: an increase of
uric acid and a decrease of GSH.[99,113,129,138] However, there is an important lack of knowledge about
other non-enzymatic antioxidant responses (vitamins A, E and C).
Summary: Oxidative Stress and Exercise
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
Ohno et al.[191] (1988)
Running >5km 6 wk 10wk
Accominotti et al.[192] (1991)
Cycling (follow up)
Tessier et al.[112] (1995)
2max 3 wk 10wk
Running <80% VO
Blood samples at rest
Bergholm et al.[193] (1999)
2max 4 week
Running 60 min at 7080% VO
3mo
Liu et al.[58] (1999)
Running (marathon)
Post-exercise blood samples
Miyazaki et al.[169] (2001)
Running
2max
60 min at 80% VO
5 wk 12wk
Elosua et al.[190] (2003)
Running
50 min 5 wk 16wk
Blood samples after 30 min aerobic exercise
Palazzetti et al.[153] (2003)
Triathlon overload training (4wk)

Blood samples at rest or after a duathlon)
Subjects
Markers
Effect
GSH GPX SOD

GR CAT
12 T
GSH (after intensive training)

GSH (after long-term intensive training)
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.
Sports Med 2006; 36 (4)
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
4.2.1 Aerobic Training

Effects on Oxidative Stress and FR Production
The majority of studies show that endurance

training reduces post-exercise oxidative stress and
muscular damage (table VII).[16,22,53,60,112,169,190]
These findings agree with the general thinking that
regular aerobic exercise permits fighting against cell
aging and the apparition of some cancers. This reduction can be so important that oxidative stress did
not increase in highly trained triathletes despite an
important triathlon-induced inflammation.[177] However, from these results, it has not been determined
yet whether this decrease of oxidative stress comes
from a decrease of FR production during exercise or
from an increase of the antioxidant system efficiency.
The effects of aerobic training on antioxidant

enzymes are situated at the muscular, plasmatic,
hepatic and cardiac levels.[179,194] In muscle, some
studies suggest that a specific antioxidant enzyme
adaptation exists in muscle having a strong oxidative power, thus a strong percentage of type 1 fibres.[16,178,195] In plasma and other tissues, an increase
in antioxidant enzyme activity was observed following a controlled protocol of endurance training.[110,168,169,190,196] However, it seems that this adaptation is not correlated with the increase of
2max observed during these studies and that SOD
VO
and GPX increase more than CAT.[16,169,191,195,197]
The results concerning the effects of endurance
training on the non-enzymatic antioxidants are more
controversial with studies showing an improvement
or a reduction of the total antioxidant capacity or of
an isolated antioxidant in trained subjects compared
with sedentary subjects.[22,58,112,197] Some studies
have also shown that the antioxidant adaptation can
be correlated with the training volume or with
2max.[177,198] However, it seems that the training
VO
protocol must be sufficiently long and intense in
order to create an adaptive answer.[169] For example,
2max without inan 8-week protocol increases VO
creasing the antioxidant potential, whereas a
10-week protocol (longer and more intensive) in 2max and the activity of some antioxicreases VO
Table VIII. Human studies on effects of anaerobic training on markers of oxidative stress
Study (year)
Activity
Markers
Effect
15 10 sec of anaerobic exercise 11 UT

(50 sec rest) 3 wk 7wk
Subjects
GPX CAT
SOD
Ortenblad et al.[166] (1997)
Jump training: blood samples at

8 T vs 8 UT
rest and after 6 30 sec jumping
CK (after exercise)
MDA (after exercise)
SOD GPX (at rest)
CAT (at rest)
Running (sprint): blood samples

at rest
6 T vs 6 UT
MDA
CD
SOD GPX
CAT
Rall et al.[199] (2000)
Progressive resistance strength

training 12wk
8 UT elderly, 8 T and 8 UT
with rheumatoid arthritis
8-OHdG (in both groups)
Muscular exercise (5080% 1RM) 84 UT elderly

TBARS LH
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).
Vincent et al.[200] (2002)
Sports Med 2006; 36 (4)
350
Finaud et al.
dants.[73,112] During such studies, the measure of the

nutritional antioxidant contribution is essential because the efficiency of the antioxidant system largely depends on it.
4.2.2 Anaerobic Training
Few data about the effect of anaerobic training on

oxidative stress are available. However, it has been
shown that anaerobic-trained subjects have a lower
oxidative stress and lower muscular damage at rest
or after exercise when compared with non-trained
subjects.[166,196] Moreover, these improvements are
comparable with those observed in endurancetrained sportsmen.[196] These results are controversial because other studies did not show a diminished
oxidative stress following an anaerobic training protocol.[199,200] The methodological differences (populations characteristics, training protocols, biological measurements) can explain some of these discrepancies (table VIII).
According to some studies, the anaerobic-trained

subjects have a better antioxidant enzyme activity in
blood, in tissues and especially in working muscle
(table VIII);[166,168,200,201] however, this improvement
was not found in every study.[196] The differences
between the results can be explained by the location
of dosages and by the training protocol. Indeed, as
for aerobic training, it seems that the length of the
protocol is important because the adaptation phenomenon only appears after several weeks of intense
practice.[201]
For non-enzymatic antioxidants, it seems that the
anaerobic practice increases their concentrations.[202] According to Cazzola et al.,[202] this adaptation would be a result of the repeated FR production during ischaemia reperfusion and inflammation
provoked by this type of exercise at muscular level.
4.2.3 Mixed Training
Little research has been carried out on the influence of mixed training effects on oxidative stress.
Nevertheless, recent studies suggest that trained
football or rugby players have a lower oxidative

stress at rest than sedentary subjects (table
IX).[189,202,203] Moreover, after a rugby match, players with a high fitness level have a lower oxidative
stress elevation when compared with players with a
lower fitness level.[189] Thus, the training level
seems to have an important influence on oxidative
stress in this type of activity.
Studies showed that football or rugby players

have an increased enzymatic antioxidant system.[189,202,203,205,207] These results are verified in top
athletes as well as in subjects with a lower level.[202,205] Mixed training also increases the total
antioxidant capacity and some non-enzymatic antioxidants such as vitamin C, vitamin E or uric acid.[202,205,207] Thus, the improvement of the antioxidant system protects players from the deleterious
effects of oxidative stress. However, the increase of
the training and competitive load can induce the
opposite effect as shown with basketball players.[156]
Contrary results have been obtained with high-level
football players.[202] Differences could be explained
by nutritional status. The football players had sufficient nutritional antioxidant contributions, whereas
the basketball players diet was not controlled.
4.2.4 Relationship Between Training Load and
Oxidative Stress
The markers of the oxidative stress and of the

antioxidant status might be important parameters in
the biological follow-up. However, although numerous data concerning a classical biological check-up
of sportsmen are available, few studies have been
done concerning the longitudinal follow-up of oxidative stress markers and antioxidant status.
A longitudinal follow-up of high-level cyclists
shows a significant increase of the GPX activity
during the training periods and a reduction during
the recovery periods.[192] Besides, it is important to
note that the authors noticed a decrease in the GPX
activity and in selenium plasmatic concentrations
during the periods of intensive training. In the same
way, a recent study with professional American
footballers suggests that antioxidant status and oxidative stress evolve during a sport season according
Sports Med 2006; 36 (4)
Activity
Subjects
Markers
Effect
Balakrishnan and Anuradha[204]

(1998)
Football (6 wk), hockey

(20 h/wk), running (23y)
26 T vs 27 UT
TBARS CD
Tocopherol CAT
Vit C GSH GPX
SOD
Brites et al.[205] (1999)
Football regular training

30 T vs 12 UT
TEAC vit C UA vit E

SOD
Pincemail et al.[59] (2000)

Basketball regular training
21 T (top soccer players)

9 T (basketball players)
Autoantibodies against oxidised

LDL
Vit C (results in half the players)
Subudhi et al.[206] (2001)
Alpine ski
Blood samples before and after a
10d training camp
12 VT
TEAC
MDA LH protein carbonyls
Svensson et al.[113] (2002)
3d of aerobic and anaerobic

training on ergocycle
15 T
GSH
UA
Chang et al.[189] (2002)
Rugby regular training

Blood samples after a rugby match
(2 40 min)
15 VT vs 6 T and 10 S
TBARS CD
SOD GPX
Evelson et al.[207] (2002)
Rugby regular training

15 T vs 15 UT
TRAP SOD vit C tocopherol
Schippinger et al.[208] (2002)
American football regular training

Blood samples at rest (follow-up
before and during competitive
season)
8 VT
LH
LP
Tocopherol vit A
Vit C
Cazzola et al.[202] (2003)

20 VT vs 20 UT
Tocopherol vit C UA SOD

LP
LH
Metin et al.[203] (2003)

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
Sports Med 2006; 36 (4)
Study (year)
Table IX. Human studies on effects of mixed training on markers of oxidative stress
352
Finaud et al.
to the training load and competition.[208] Thus,

through a sport season, a decrease of the efficiency
of the antioxidant system and an increase of oxidative stress can be observed. However, these two
studies should be completed by other investigations
in order to provide a better understanding of the
relationship between training load and oxidative
stress. Although they are not based on longitudinal
follow-up, other studies tend to prove that oxidative
stress can increase during an intense period of training. Numerous studies have shown that training
improves antioxidant status (see sections
4.2.14.2.3); however, in the study by Pincemail et
al.,[59] half of the subjects (high-level football and
basketball players) presented with a low antioxidant
status and an important oxidative stress. These results can be explained by individual low antioxidant
intakes and by the frequency of training and competition that lead to an important mobilisation and
utilisation of antioxidant compounds. These results
are confirmed by other studies in various sports and
populations.[156,193,204,206] Recently, it was also
demonstrated that overloaded training compromises
the antioxidant defences, leading to an increase of
the exercise-induced oxidative stress.[153,155]
4.2.5 Oxidative Stress and Overtraining
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
biological variables in athletes in order to detect and

prevent overtraining.[209] Oxidative stress markers
could be interesting, complementary with biological
variables, because of the possible links between
oxidative stress and overtraining.[9,82]
The causes of the overtraining syndrome are
complex and there are divergent hypotheses based
on structural, metabolic, immunological or inflammatory phenomenon.[9,82] A period of intense training, as described in the previous paragraphs, is associated with a decrease of the antioxidant status, an
increase of the ROS production and a proportional
increase of oxidative stress.[204] Although there is no
direct evidence, the increase of oxidative stress can
be implied in the appearance of the overtraining
syndrome.[8,9] Cell damage, in particular at the muscular level, could be an important explanatory element of overtraining by reducing the muscular cells
metabolic capacities.[8,73,82] Besides, the accumulation of muscular lesions is associated with inflammation (increase of cytokines and neutrophils) in
order to repair damaged tissues. Inflammation can
induce an enhanced oxidative stress caused by the
increase of the FR production by neutrophils and
macrophages.[73,82]
4.3 Summary: Oxidative Stress, Training
and Overtraining
Aerobic, anaerobic or mixed training provokes a

decrease of oxidative stress, which is caused by an
increase if the efficiency of the antioxidant system
in response to the supplementary production of FR
during exercise. Nevertheless, the training programme must be sufficiently long and intense to
trigger a consequent adaptive response of the antioxidant system and a decrease of oxidative stress.
Moreover, this adaptation is more important when
the training level of the subjects is low at the beginning of the protocol.
This training-induced improvement of the antioxidant status and decrease of oxidative stress are
extensively documented in the literature. However,
some studies report a decrease of the antioxidant
system efficiency, particularly in high-level athletes
subjected to an important training and competitive
Sports Med 2006; 36 (4)
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).
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Biologie Interuniversitaire des Activites Physiques et Sportives, Bat Biologie B. Campus des Cezeaux. 63177, Aubi`ere
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E-mail: J.finaud@tiscali.fr
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Sports Med 2006; 36 (4): 327-358

3.2.1 Lipid Peroxidation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 341

tigue, many diseases and aging.[2,3] However, they

Oxidative Stress and Physical Activity

Physical activity increases the FR production and

1. Free Radicals (FR) and

Table I. Classification and main effects of free radicals

Reactive oxygen species

Lipid oxidation and peroxidation

Reactive nitrogen species

Reactive sulphur species

2006 Adis Data Information BV. All rights reserved.

Sports Med 2006; 36 (4)

trons. Dioxygen prefers to receive one electron at a

tive and very toxic ROS and there is no specific

1.1.2 Superoxide Ion

the addition of one electron

1.1.3 Hydrogen Peroxide

Equation 3 summarises the first and the second

Hydroxyl radical (OH) is the end product of

1.3.1 ROS Formation During Oxygen Metabolism

Oxidative Stress and Physical Activity

Electron chain transport

vealed that about 50% of O2 production arises

chondrial DNA (mtDNA) induces alterations to the

The second major source of ROS is ischaemia

Oxidative Stress and Physical Activity

Myoglobin can also be oxidised by auto-oxidation

ROS are involved in the immunity phenomenon,

Despite some helpful effects, ROS have possible

aract, cancers, Alzheimers or Parkinsons diseases

Lipoprotein oxidation is an important factor in

proteolysis blocking and an accumulation of oxidised proteins.[64,65] Consequently, protein turnover,

ROS are also known to cause DNA strand breaks

A minimal amount of ROS is necessary for muscular contraction.[47,49,50] Nevertheless, oxidative

Oxidative Stress and Physical Activity

CAT is present in every cell and in particular in

Table II. Localisation and actions of antioxidant enzymes

Cytosol mitochondria (membrane)

Peroxysome, cytosol and mitochondria

Cytosol and mitochondria

CAT = catalase; GPX = glutathione peroxide; SOD = superoxide dismutase.

H2O2.[86] Catalase converts H2O2 into water and

2.2 Non-Enzymatic Antioxidants

2.2.1 Vitamin E (Tocopherol)

Antioxidant enzymes are endogenous (table II).

2006 Adis Data Information BV. All rights reserved.

Vitamin E is a fat-soluble vitamin made up of

Sports Med 2006; 36 (4)

Oxidative Stress and Physical Activity

Table III. Localisation and actions of the main non-enzymatic antioxidants

Lipid peroxidation inhibition

Lipid peroxidation reduction

Vitamin C (ascorbic acid)

Substrate for GPX

Lipid peroxidation inhibition

Linked with glucids

Pro-oxidant enzymes inhibition

Vitamin C and E regeneration

Protection of proteins (cells)

Free iron trapping

SOD cofactor (Cu-Zn-SOD)