What Is Oxidative Stress?
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䡵Oxidative Stress
What Is Oxidative Stress?
JMAJ 45(7): 271–276, 2002
Toshikazu YOSHIKAWA* and Yuji NAITO**
Professor* and Associate Professor**, First Department of Medicine,
Kyoto Prefectural University of Medicine
Abstract: Oxidative stress is well known to be involved in the pathogenesis of
lifestyle-related diseases, including atherosclerosis, hypertension, diabetes mellitus,
ischemic diseases, and malignancies. Oxidative stress has been defined as harm-
ful because oxygen free radicals attack biological molecules such as lipids, pro-
teins, and DNA. However, oxidative stress also has a useful role in physiologic
adaptation and in the regulation of intracellular signal transduction. Therefore, a
more useful definition of oxidative stress may be “a state where oxidative forces
exceed the antioxidant systems due to loss of the balance between them.” The
biomarkers that can be used to assess oxidative stress in vivo have been attracting
interest because the accurate measurement of such stress is necessary for inves-
tigation of its role in lifestyle diseases as well as to evaluate the efficacy of treat-
ment. Many markers of oxidative stress have been proposed, including lipid hydro-
peroxides, 4-hydroxynonenal, isoprostan, 8-hydroxyguanine, and ubiquinol-10. To
prevent the development of lifestyle diseases, advice on how to lead a healthy life
should be given to individuals based on the levels of oxidant and antioxidant activity
assessed by pertinent biomarkers. Individual genetic information should also be
taken into consideration.
Key words: Oxidative stress; Free radicals; Active oxygen; Biomarkers
and oxidative DNA damage, but also physi-
Introduction
ologic adaptation phenomena and regulation
The close association between oxidative of intracellular signal transduction. From a
stress and lifestyle-related diseases has become clinical standpoint, if biomarkers that reflect
well known. Oxidative stress is defined as a the extent of oxidative stress were available,
“state in which oxidation exceeds the antioxi- such markers would be useful for physicians to
dant systems in the body secondary to a loss of gain an insight into the pathological features of
the balance between them.” It not only causes various diseases and assess the efficacy of
hazardous events such as lipid peroxidation drugs.
This article is a revised English version of a paper originally published in
the Journal of the Japan Medical Association (Vol. 124, No. 11, 2000, pages 1549–1553).
JMAJ, July 2002—Vol. 45, No. 7 271T. YOSHIKAWA and Y. NAITO
Table 1 Major Active Oxygen Species true that the high reactivity of these oxygen
metabolites is utilized to control various bio-
O2䡠ⳮ Superoxide radical
H2O2 Hydrogen peroxide
logical phenomena.
HO 䡠 Hydroxyl radical From a biological viewpoint, various oxygen-
1
O2 Singlet oxygen derived free radicals have been attracting
HOO 䡠 Hydroperoxyl radical attention for the following reasons: Various
LOOH Alkylhydroperoxide active oxygen species are generated in the
LOO 䡠 Alkylperoxyl radical
body during the process of utilizing of oxygen.
LO 䡠 Alkoxyl radical
CIOⳮ Hypochlorite ion
Because the body is furnished with elaborate
Fe4ⳭO Ferryl ion mechanisms to remove active oxygen species
Fe5ⳭO Periferryl ion and free radicals, these by-products of oxygen
NO 䡠 Nitric oxide metabolism are not necessarily a threat to the
body under physiological conditions. However,
if active oxygen species or free radicals are
generated excessively or at abnormal sites, the
Free Radicals, Active Oxygen balance between formation and removal is lost,
resulting in oxidative stress. Consequently,
Species, and Oxidative Stress
active oxygen species and free radicals can
Usually, an atom is composed of a central attack molecules in biological membranes and
nucleus with pairs of electrons orbiting around tissues, thus inducing various diseases. In other
it. However, some atoms and molecules have words, oxidative stress is defined as a “state
unpaired electrons and these are called free harmful to the body, which arises when oxida-
radicals. Free radicals are usually unstable and tive reactions exceed antioxidant reactions
highly reactive because the unpaired electrons because the balance between them has been
tend to form pairs with other electrons. An lost.”
oxygen molecule (O2) undergoes four-electron However, oxidative stress is actually useful
reduction when it is metabolized in vivo. Dur- in some instances. For example, oxidative stress
ing this process, reactive oxygen metabolites induces apoptosis to prepare the birth canal for
are generated by the excitation of electrons delivery. Also, biological defense mechanisms
secondary to addition of energy or interaction are strengthened by oxidative stress during
with transition elements. The reactive oxygen appropriate physical exercise and ischemia.
metabolites thus produced are more highly Therefore, a more useful definition of oxidative
reactive than the original oxygen molecule and stress may be a “state where oxidation exceeds
are called active oxygen species. Superoxide, the antioxidant systems because the balance
hydrogen peroxide, hydroxyl radicals, and between them has been lost.”
singlet oxygen are active oxygen species in the
narrow sense. Active oxygen species in a broad
Biomarkers of Oxidative Stress
sense are listed in Table 1. Only active oxygen
species having an unpaired electron, indicated The biomarkers that can be used to assess
with a dot above and to the right of the chemi- oxidative stress have been attracting interest
cal formula in the table, are free radicals. because the accurate assessment of such stress
For aerobic organisms, a mechanism to is necessary for investigation of various patho-
remove these highly reactive active oxygen logical conditions, as well as to evaluate the
species is essential to sustain life. Therefore, efficacy of drugs. Assessment of the extent of
various antioxidant defense mechanisms have oxidative stress using biomarkers is interesting
developed in the process of evolution. It is also from a clinical standpoint. The markers found
272 JMAJ, July 2002—Vol. 45, No. 7OXIDATIVE STRESS
O2 · been the most frequently used marker of oxi-
oxygen radical LOO
· · IH dative stress partly because lipid peroxidation
LH L LOO stable
products (Fig. 1) is a very important mechanism of cell
membrane destruction. Lipid peroxidation is a
chain reaction by which unsaturated fatty acids
LOOH LH (cell membrane components) are oxidized in
various pathological conditions.
membrane injury When a hydrogen atom is removed from a
cellular injury fatty acid molecule for some reason, the free
tissue injury
radical chain reaction proceeds as shown in
Fig. 1 The chain reaction causing lipid peroxidation Fig. 1. Thus, radicals that can be involved in
the extraction of hydrogen atoms from lipids
include the hydroxyl radical (HO 䡠), the hydro-
peroxyl radical (HOO 䡠), the lipid peroxyl radi-
in blood, urine, and other biological fluids may cal (LOO 䡠), and the alkoxyl radical (LO 䡠).
provide information of diagnostic value, but it Metal-oxygen complexes, particularly iron-
would be ideal if organs and tissues suffering oxygen complexes, are also important in vivo.
from oxidative stress could be imaged in a man- The peroxidation chain reaction propagates
ner similar to CT scanning and MR imaging. In itself once it has started. The process by which
recent years, attempts have been made to use lipid radicals (L 䡠) are generated from lipids
electron spin resonance techniques for this pur- (LH) is called the chain initiation reaction.
pose, but it will take time before such methods Lipid radicals (L 䡠) thus generated react imme-
can be applied to humans. diately with oxygen, resulting in the formation
Because the body is not necessarily fully of LOO 䡠, which attacks another lipid and
protected against oxidative damage, some of removes a hydrogen atom from it, resulting in
its constituents may be injured by free radicals, the formation of lipid hydroperoxide (lipid per-
and the resultant oxidative products have oxide; LOOH) and another L 䡠. This new L 䡠 also
usually been used as markers. Many markers reacts with oxygen and forms LOO 䡠, which
have been proposed, including lipid peroxides, attacks another lipid to generate lipid peroxide,
malondialdehyde, and 4-hydroxynonenal as so lipid peroxide accumulates as the chain reac-
markers for oxidative damage to lipids; iso- tion proceeds.
prostan as a product of the free radical oxi- Gastric mucosal injury occurs in patients
dation of arachidonic acid; 8-oxoguanine with extensive burns. Before the development
(8-hydroxyguanine) and thymineglycol as indi- of mucosal lesions, the blood level of skin-
cators of oxidative damage to DNA; and vari- derived substances that react with thiobarbi-
ous products of the oxidation of protein and turic acid shows an increase. Then these sub-
amino acids including carbonyl protein, stances also increase in the gastric mucosa,
hydroxyleucine, hydrovaline, and nitrotyro- leading to the development of mucosal lesions.
sine. Lipid peroxide was assessed in clinical The free radical peroxidation of lipids is an
samples even in relatively early studies, and important factor in local injury to cell mem-
the analytical methods for this substance have branes and impairment of the activity of
improved. enzymes and receptors bound to the mem-
The famous method of Yagi, which measures brane, and the lipid peroxide thus produced
substances that react with thiobarbituric acid, can affect even remote organs.
has been widely used in both clinical and Among the agents that protect the body
experimental studies. Such substances have from lipid peroxidation, vitamin E is consid-
JMAJ, July 2002—Vol. 45, No. 7 273T. YOSHIKAWA and Y. NAITO
0.8 40 quently, plasma vitamin E levels seem unlikely
CoQH2-10 [without Cu 2Ⳮ]
to be a useful biomarker of oxidative stress. In
0.6 30
Ubiquinol-10 and lipid hydroperoxide (애M)
VE
addition, vitamin E is lipid soluble, so its blood
level varies depending on the lipid content.
Vitamin C and vitamin E (애M)
0.4 20
When human plasma is incubated at 37°C
VC
0.2 10 in air, the concentrations of antioxidants and
PC-OOH CE-OOH lipid peroxides change as shown in Fig. 2. Of
0.0 0
the three antioxidants, vitamin C decreases
0.8 40
CoQH2-10 [with 5애M Cu 2Ⳮ]
first, followed by reduced coenzyme Q-10
0.6 30 (ubiquinol-10). This suggests that vitamin C
VE and ubiquinol-10 are the antioxidants that are
0.4 20 most sensitive to oxidative stress. Vitamin E
CE-OOH may be protected by vitamin C and ubiquinol-
0.2 VC 10
10 because it is an important antioxidant. Vita-
PC-OOH min C and ubiquinol-10 levels were measured
0.0 0
0 10 20 30 40 50 to assess oxidative stress in patients with vari-
Time (hr) ous liver diseases. In patients with chronic
CoQH2-10; coenzymeQ10 hepatitis, liver chirrhosis, and liver cancer, the
VC; vitamin C, VE; vitamin E
PC-OOH; phosphatidylcholine hydroperoxide vitamin C and ubiquinone-10 (oxidized coen-
CE-OOH; cholesterylester hydroperoxide zyme Q-10) levels were significantly decreased
Fig. 2 Changes of antioxidants and generation of lipid and increased, respectively, when compared
peroxides during incubation of human plasma with those in the control group, with a signifi-
at 37°C in air
Source: Yamamoto, Y. et al.: Oxidative Damage and cant percent increase of oxidized coenzyme
Repair. ed. Davies, K.J.A., Pergamon Press, 1991; Q-10. In contrast, there was no significant dif-
pp. 287–291. ference of the vitamin E level.
Oxidative Stress as a Biological
ered to be the most important. This vitamin has
Modulator and as a Signal (Fig. 3)
attracted attention as an antioxidant because it
can scavenge lipid peroxyl radicals and hence Oxidative stress not only has a cytotoxic
stop the propagation of the free radical chain effect, but also plays an important role in the
reaction. The lipid peroxyl radical removes a modulation of messengers that regulate essen-
hydrogen atom from the phenyl group of vita- tial cell membrane functions, which are vital for
min E and the molecule that has accepted the survival. It affects the intracellular redox status,
hydrogen atom is stabilized. In turn, vitamin E leading to the activation of protein kinases,
is converted into a radical, which is also stable including a series of receptor and non-receptor
and less reactive. Consequently, this vitamin E- tyrosine kinases, protein kinase C, and the
derived radical is unlikely to attack lipids and MAP kinase cascade, and hence induces vari-
perpetuate the chain reaction. Instead, it is ous cellular responses. These protein kinases
thought to react with another peroxyl radical play an important role in cellular responses
and thus become stable. This antioxidant reac- such as activation, proliferation, and differen-
tion protects biological membranes from injury tiation, as well as various other functions.
caused by free radicals and lipid peroxides. Accordingly, the protein kinases have attracted
However, lipid peroxides are still generated the most attention in the investigation of
in the plasma despite the presence of an the association between oxidative stress and
adequate concentration of vitamin E. Conse- disease.
274 JMAJ, July 2002—Vol. 45, No. 7OXIDATIVE STRESS
Activation of protein kinases
Tyrosine kinase
Src family
Oxidative stress Syk/ZAP-70 family
Active oxygen EGF receptors Cellular responses
species
Protein kinase C Activation
Ischemia
Glutathione system MAP kinase cascade Proliferation
Inflammation
Thioredoxin system Inflammatory
Radiation MEK-ERK pathway reaction
Ultraviolet light SEK1-JNK pathway Stress
Anticancer drugs MKK3/6-p38 pathway protection
Heavy metals Death
Cytokines
Activation of
transcription factors
AP-1
NF-B
Nrf2
Fig. 3 Oxidative stress and cellular responses
Oxidative stress can influence many biologi- plays in the activation of NF-B, many new
cal processes such as apoptosis, viral prolifer- findings have been obtained recently. Stimu-
ation, and inflammatory reactions. In these lation with tumor necrosis factor (TNF)-␣,
processes, gene transcription factors such as phorbol myristate acetate (PMA), interleukin
nuclear factor-B (NF-B) and activator (IL)-1, lipopolysaccharide, viral infection, and
protein-1 (AP-1) act as oxidative stress sensors ultraviolet light leads to the generation of active
through their own oxidation and reduction oxygen species, which function as a second
cycling. This type of chemical modification of messenger in the activation of NF-B. The
proteins by oxidation and reduction is called mitochondrial respiratory chain is considered
reduction-oxidation (redox) regulation. to be the major source of active oxygen species.
The transcription factor NF-B undergoes In cells lacking mitochondria, damage caused
translocation from the cytoplasm to the nucleus by TNF-␣ and NF-B dependent IL-6 produc-
in response to an extracellular signal. This tion is suppressed. It has also been shown that
translocation induces its ability to bind to DNA, antimycin A, an inhibitor of mitochondrial elec-
leading to transcriptional up-regulation of the tron transport, increases the intracellular gen-
expression of many genes related to inflamma- eration of active oxygen species and enhances
tion and immunity. Thus, NF-B seems to be the activation of NF-B. In resting cells, NF-B
involved in development and aggravation of is bound to IB and remains in the cytoplasm.
many diseases. Recently, it was also suggested An extracellular signal causes the dissociation
that this factor may be involved in the process of these two molecules and IB decomposes,
of carcinogenesis because it is located upstream whereupon NF-B migrates to the nucleus and
to a series of transcription regulation factors activates transcription.
and because it possesses the ability to suppress The phosphorylation cascade that produces
apoptosis. the NF-B/IB complex has been shown to
With respect to the role that oxidative stress depend on the interaction between proteins
JMAJ, July 2002—Vol. 45, No. 7 275T. YOSHIKAWA and Y. NAITO
derived from activation of IL-1 and TNF recep- store massive amounts of genetic information
tors. The activation of NB-B requires a signal on DNA microchips and has provided various
derived from active oxygen species. The possible efficient computer programs for analysis, thus
involvement of active oxygen species in the promising rapid progress in this field.
release of NF-B is partly suggested because Many daily habits are closely associated with
IB undergoes phosphorylation via a group of oxidative stress, which is augmented by smok-
kinases involved in a phosphorylation cascade. ing, drinking, and an irregular diet. In Japan,
Induction of the expression of thioredoxin by dietary habits have undergone a marked change
active oxygen species is also involved in the over the years. When the energy intake related
activation of NF-B, since thioredoxin gives to major nutrients is calculated, lipids provide
NF-B the ability to bind to DNA in a process over 25%, reflecting this change. Many envir-
that is regulated by redox reactions. onmental factors can generate active oxygen
NF-B seems to be the key transcription species and DNA damage caused by such oxy-
factor for elucidating the relationship of oxida- gen radicals is extremely serious because it may
tive stress to lifestyle diseases and identifica- be related to carcinogenesis. To prevent the
tion of the precise mechanisms involved may development of lifestyle diseases, instructions
lead to the development of new therapies for on how to lead a healthy life should be given
such diseases. individually depending on the level of antioxi-
dant activity assessed by pertinent biomarkers.
Individual genetic information should also be
Conclusion
taken into consideration when giving such
The causes of lifestyle diseases can be divided instructions. Such health issues may become
into three major categories, which are genetic, central to medical care in the 21st century.
habitual, and environmental. Many of the genes
that are associated with biological oxidative
stress have been identified, with the genes for REFERENCES
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causative factors. Recent progress in the field 3) Yoshikawa, T.: Science of Free Radicals. Kou-
of molecular biology has made it possible to dan Sha Saientifikku, Tokyo, 1997.
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