Reactive oxygen species in living
systems: source, biochemistry, and role in human disease.
Antioxidants: Pathophysiologic Determinants and Therapeutic Agents)
Authors: Halliwell, Barry
Citation: American Journal of Medicine, Sept 30, 1991 v91 n3C p14S(9)
Subjects: Free radicals (Chemistry) Physiological aspects
Antioxidants Physiological aspects
Diseases Causes and theories of causation
Reference #: A12136862
Author's Abstract: COPYRIGHT Cahners Publishing Company 1991
Reactive oxygen species are
constantly formed in the human body and removed by antioxidant defenses.
An antioxidant is a substance that, when present at low concentrations
compared to that of an oxidizable substrate, significantly delays or
prevents oxidation of that substrate. Antioxidants can act by scavenging
biologically important reactive oxygen species
([O.sub.2].,[H.sub.2][O.sub.2], .OH, HOCl, ferryl, peroxyl, and alkoxyl),
by preventing their formation, or by repairing the damage that they do.
One problem with scavenging-type antioxidants is that secondary radicals
derived from them can often themselves do biologic damage. These various
principles will be illustrated by considering several thiol compounds.
Full Text COPYRIGHT Cahners
Publishing Company 1991
It is difficult these days
to open a medical journal and not find some paper on the role of
"reactive oxygen species" or "free radicals" in human disease. These
species have been implicated in over 50 diseases. This large number
suggests that radicals are not something esoteric, but that they
participate as a fundamental component of tissue injury in most, if not
all, human diseases.
What are "free radicals" and
"reactive oxygen species"? Do they cause disease? Are they produced in
increased amounts as a result of disease and then contribute to further
tissue injury? Are they merely an epiphenomenon of no relevance to
clinical medicine? This introductory article attempts to answer such
WHAT IS A FREE RADICAL?
Electrons in atoms occupy
regions of space known as orbitals. Each orbital can hold a maximum of
two electrons, spinning in opposite directions. A free radical can be
defined as any species capable of independent existence that contains
one or more unpaired electrons, an unpaired electron being one that is
alone in an orbital. Most biologic molecules are nonradicals, containing
only paired electrons.
An electron occupying an
orbital by itself has two possible directions of spin. Indeed, the
technique of measuring electron spin resonance detects radicals by
measuring the energy changes that occur as unpaired electrons ~relax'
following alignment in response to a magnetic field. Since electrons
are more stable when paired together in orbitals, radicals generally are
more reactive than nonradicals, although there is a considerable
variation in their reactivity. Radicals can react with other molecules
in a number of ways. If two radicals meet, they can combine their
unpaired electrons (symbolized by.) and join to form a covalent bond (a
shared pair of electrons). The hydrogen atom, with one unpaired
electron, is a radical and two atoms of hydrogen easily combine to form
the diatomic hydrogen molecule:
H. + H. [arrow right]
Radicals react with
nonradicals in several ways. A radical may donate its unpaired electron
to a non-radical (a reducing radical) or it might take an electron from
another molecule in order to form a pair (an oxidizing radical). A
radical may also join onto a nonradical. Whichever of these three types
of reaction occurs, the nonradical species becomes a radical. A feature
of the reactions of free radicals with nonradicals is that they tend to
proceed as chain reactions, where one radical begets another. For many
years, chemists have been interested in free radical reactions. Many
plastics, such as polythene, arise by free radical chain
polymerization. Combustion is a free radical reaction. The drying and
aging of paint also involves free radical reactions. Curators of museums
have studied the role of free radical damage in the age-dependent
deterioration of paintings and other items. Metabolism of toxins in
the human body can produce radicals. For example, carbon tetrachloride
([CCl.sub.4]) is metabolized in the endoplasmic reticulum of the liver
to produce the damaging trichloromethyl radical, [CCl.sub.3.].
Chemists and biologists have
examined in detail the role of free radical reactions in the damage done
to living cells by high-energy radiation. When tissues are exposed to,
for example, gamma radiation, most of the energy taken up is absorbed by
the cell water, largely because there is more water there than any other
molecule. The radiation causes one of the oxygen - hydrogen covalent
bonds in water to split, leaving a single electron on hydrogen and one
on oxygen, thus creating two radicals:
H. is a hydrogen radical (or
hydrogen atom), and .OH is a hydroxyl radical. The latter is the most
reactive radical known to chemistry. It can attack and damage almost
every molecule found in living cells at a diffusion-controlled rate,
i.e., .OH reacts as soon as it comes into contact with another molecule
in solution. Since it is so reactive, .OH generated in vivo does not
persist for even a microsecond and rapidly combines with molecules in
its immediate vicinity. Reactions of .OH with biologic molecules, must
of which are nonradicals, set off chain reactions. Reactions of .OH
include its ability to interact with the purine and pyrimidine bases of
DNA, leading to radicals that have a number of possible chemical
fates. .OH can also abstract hydrogen atoms from many biologic
molecules, including thiols:
R - SH + .OH [arrow right]
RS. + [H.sub.2.O]
The resulting sulfur
radicals (thiyl radicals) have many interesting chemical properties.
They can combine with oxygen to generate oxysulfur radicals, such as
[RSO.sub.2.] and RSO., a number of which damage biologic molecules[7-9].
For example, sulfur-containing radicals derived from the drug
penicillamine are able to attack and damage certain proteins. When
discussing the use of thiol compounds as free radical scavengers, it is
essential to ask what may happen to the resulting sulfur radicals in
biologic systems. Perhaps the best-characterized biologic damage
caused by .OH is its ability to stimulate the free radical chain
reaction known as lipid peroxidation. This occurs when the .OH is
generated close to membranes and attacks the fatty acid side chains of
the membrane phospholipids. It preferentially attacks polyunsaturated
fatty acid side chains, such as arachidonic acid. The .OH abstracts an
atom of hydrogen from one of the carbon atoms in the side chain and
combines with it to form water:
CH - + .OH [arrow right] - C
Reaction (4) removes the
.OH, but leaves behind a carbon-centered radical ( - C - ) in the
membrane. Carbon-centered radicals formed from polyunsaturated fatty
acid side chains usually undergo molecular rearrangement to give
conjugated diene structures, which can have various fates. Thus, if two
such radicals collided in the membrane, cross-linking of fatty acid side
chains could occur as the two electrons joined to form a covalent bond.
Reaction with membrane proteins is also a possibility. However, under
physiologic conditions, the most likely fate of carbon-centered radicals
is to combine with oxygen, creating yet another radical, the peroxyl
radical (sometimes abbreviated to the peroxy radical):
Peroxyl radicals are
reactive enough to attack adjacent fatty acid side chains, abstracting
radical is generated, and so the chain reaction [equations (5) and (6)]
continues. One .OH can result in the conversion of many hundred fatty
acid side chains into lipid hydroperoxides. Accumulation of lipid
hydroperoxides in a membrane disrupts its function and can cause it to
collapse. Lipid hydroperoxides can also decompose to yield a range of
highly cytotoxic products, among the most unpleasant of which are
aldehydes. A great deal of attention in the literature has been
focused on malonaldehyde (malondialdehyde), but this is much less
noxious than such products as 4-hydroxynonenal[12,13]. Peroxyl radicals
and cytotoxic aldehydes can also cause severe damage to membrane
proteins, inactivating receptors and membrane-bound enzymes.
SOURCES OF OXYGEN RADICALS IN VIVO
Biochemists (apart from
those with a special interest in "background" free radical generation in
vivo, due to exposure to ionizing radiation) became interested in
radicals only in the 1970s. This interest followed from the discovery in
1968 of superoxide dismutase (SOD), and enzyme specific for a free
radical substrate. SOD removes superoxide radical, a species that is
formed by adding an extra electron onto the oxygen molecule:
SOD removes O2 by catalyzing
a dismutation reaction, involving oxidation of the O2 to oxygen and
reduction of another O2 to hydrogen peroxide:
In the absence of SOD,
reaction (8) occurs nonezymically but at a rate approximately four
orders of magnitude less at pH 7.4.
The discovery of SOD led to
the realization that [O.sup.-.sub.2] is formed in vivo in living
organisms, and SOD removes it. Some of the O2 formed in vivo arises from
a chemical accident. For example, when mitochondria are functioning,
some of the electrons passing through the respiratory chain leak from
the electron carriers and pass directly onto oxygen, reducing it to
O2[15,16]. Many molecules oxidize on contact with oxygen, e.g., and
epinephrine solution left on the bench "goes off" and eventually forms a
pink product. The first stage in this oxidation is transfer of an
electron from the epinephrine to [O.sub.2], forming O2. Such oxidations
undoubtedly proceed in vivo as well. For example, several sugars,
including glucose, interact with proteins to produce oxygen radicals. It
has been suggested that decades of exposure of body tissues to elevated
blood glucose can result in diabetic patients suffering "oxidative
stress" that may contribute to the side effects of hyperglycemia.
Glycation of proteins involves not only direct reaction with the sugar
but also free radical reactions.
Thiols can also be oxidized
in the presence of oxygen, generating sulfur-containing radicals as well
as O2 and .OH. Thiol oxidation is favored by alkaline pH values and by
the presence of transition metal ions, especially copper ions. Thus,
mixtures of copper ions and thiols can be cytotoxic, as shown for
cysteine. Iron ions can also promote free radical generation from
thiols under certain circumstances. Attempts to use thiols as
anti-oxidants in systems containing iron or copper ions may even result
in stimulation of oxidative damage.
Superoxide and Phagocyte Action
Some of the O2 production in
vivo may be accidental but much is functional. Activated phagocytic
cells generate O2 as shown for monocytes, neutrophils, eosinophils, and
macrophages of all types. Radical production is important in
allowing phagocytes to kill some of the bacterial strains that they
engulf. This can be illustrated by examining patients with chronic
granulomatous disease, a series of inborn conditions in which the
membrane-bound reduced nictotinamide adenine dinucleotide phosphate (NADPH)
oxidase system in phagocytes that makes the O2 fails to work. Such
patients have phagocytes that engulf and process bacteria normally, but
several bacterial strains are not killed and are released in viable form
when the phagocytes die. Thus, patients suffer sever, persistent, and
multiple infections with such organisms as Staphylococcus aureus.
Another killing mechanism used by neutrophils (but not by macrophages)
is the enzyme myeloperoxidase. It uses [H.sub.2.O.sub.2] produced by
dismutation of O2 to oxidize chloride ions into hypochlorous acid (HOCl),
a powerful anti-bacterial agent:
[H.sub.2.O.sub.2] + [Cl.sup.-
arrow right] HOCl + [OH.sup.-]
Thiol groups are easily
oxidized by HOCl. Hence, low molecular mass thiol compounds such as
glutathione (GSH), N-acetylcysteine, and mercaptopropionylglycine are
very effective at protecting, for example, proteins against oxidative
damage by HOCl[23.24]. Superoxice formed in vivo, whether functionally
or accidentally, is disposed of by SOD [equation (8)]. Recent studies
using genetic engineering techniques to manipulate SOD levels of
organisms, or to delete the genes encoding SOD, provide further evidence
of the importance of SOD. It is interesting to note that no complete
inborn deficiencies of SOD have been reported in humans, perhaps because
they would be lethal mutations.
Reactive Oxygen Species
SOD removes O2 by converting
it into hydrogen peroxide ([H.sub.2.O.sub.2]) and [O.sub.2] [equation
(8)]. [H.sub.2.sub.2] itself can be quite toxic to cells. For example,
incubation of cells with [H.sub.2.O.sub.2] causes deoxyribonucleic acid
(DNA) damage, membrane disruption, and release of [Ca.sup.2+] ions
within the cells, leading to activation of [Ca.sup.2+]-dependent
proteases and nucleases. At least some of this damage may be
mediated by a reaction of [H.sub.2.O.sub.2] with O2 in the presence of
iron or copper ions, to form highly reactive radicals, one of which .OH.
This reaction proceeds in a number of stages, but the overall process is
Thus, removal of
[H.sub.2.O.sub.2], as well as of O2, is biologically advantageous.
SOD therefore works in
conjunction with two enzymes. catalase and glutathione peroxidase,
that remove [H.sub.2.O.sub.2] in human cells. The study of inborn errors
of metabolism suggests that glutathione peroxidase (GSH-Px) is the more
important of the two in removing [H.sub.2.O.sub.2], probably because it
is located in the same subcellular compartments (cytosol and
mitochondria) as SOD. GSH-Px has the distinction of being the only human
enzyme known requiring the element selenium for its activity; a
selecnocysteine residue (side chain -SeH instead of -SH, as in normal
cysteine) is present at its active site. However, it is unlikely that
the sole function of selenium in humans is to act as a cofactor for
GSH-Px. GSH-Px removes [H.sub.2.O.sub.2] by suisng it to oxidize
reduced glutathione (GSH) into oxidized glutathione (GSSG):
2GSH + [H.sub.2.O.sub.2
arrow right] GSSG + [2H.sub.2O
[H.sub.2.O.sub.2] has no
unpaired electrons and does not qualify as a radical. Hence, the term
reactive oxygen species has been introduced to describe collectively not
only O2 and .OH (radicals) but also [H.sub.2.O.sub.2] (nonradical).
Hypochlorous acid (HOCl) produced by myeloperoxidase is also a nonradical,
having no unpaired electrons. [H.sub.2.O.sub.2.], .OH, and HOCl are
sometimes collectively called "oxidants." This is valid description of
[H.sub.2.O.sub.2], .OH, and HOCl, which are oxidizing agents. However,
O2 has both oxidizing and reducing properties. The latter property is
used in a popular assay for O2, the SOD-inhibitable reduction of
cytochrome c, often applied to measure [O.sup.-.sbu.2.] production by
cyt c (Fe.sup.3+] + [O.sup.-.sub.2
[arrow right] O.sub.2] + cyt c (Fe.sup.2+
TRANSITIONS METAL IONS AND FREE
Many transition metals have
variable oxidation numbers, e.g., iron has [Fe.sup.2+] and [Fe.sup.3+]
ions and copper has [Cu.sup.+] and [Cu.sup.2+] ions. Changing between
oxidation states involves accepting and donating single electrons, e.g.,
Transition metal ions are
remarkably good promoters of free radical reactions. Polymer
scientists and food chemists have been aware of this for years[4,30],
and biochemist are learning it too [1,17-20,26,31-34]. It has already
been noted that copper ions promote oxidation of thiols:
R-SH + [Cu.sub.2+ arrow
right R-S.] + [Cu.sup.+] + [H.sup.+]
and that [Fe.sup.2+] ions
reduce [H.sub.2.O.sub.2] to give * OH [equation (10)].
Transition Metals and Lipid
Transition metal ions are
involved in lipid peroxidation in two ways. They can participate in
first-chain initiation, which involves attack by any species capable of
abstracting a hydrogen atom. .OH, which has this property, is produced
by the reaction of O2 and [H.sub.2.O.sub.2] with iron ion catalysis
[equation (10)]. It is also be produced by reaction of [H.sub.2.O.sub.2]
with copper ions, probably in addition to oxidizing copper(III)-oxygen
complexes[26,31]. Several iron ion-oxygen complexes, such as perferryl,
ferryl, or [Fe.sup.2+]/[Fe.sup.3+]/[O.sup.2] complexes, have also been
claimed to initiate peroxidation, although their ability to do so is
Transition metal ions also
affect lipid peroxidation by decomposing peroxides. Commercial fatty
acids are heavily contaminated with peroxides. Cell disruption to
isolate membrane fractions increases rates of nonenzymic free radical
reactions and activates enzymes (cyclooxygenases and lipooxygenases)
that produce peroxides (Figure 1). When transition metal ions are added
to lipid systems already containing peroxides, their main action is to
decompose these peroxides into peroxyl and alkoxyl (lipid-O *) radicals
that in turn abstract hydrogen and perpetuate the chain reaction of
lipid peroxidation. This may be represented by the following
simplified equations, in which lipid * symbolises a carbon-centered
lipid O. + lipid-H [arrow
right] lipid-OH + lipid.
lipid-OO. + lipid-H [arrow
right] lipid-OOH + lipid.
lipid. + [O.sub.2] [arrow
Reducing agents, such as
ascorbic acid or [O.sup.2-*], accelerate these metal ion-dependent
peroxidation reactions because [Cu.sup.+] and [Fe.sup.2+] ions seem to
react with peroxides faster than do [Cu.sup.2+] and [Fe.sup.3+]
respectively. The end products of these complex metal ion-catalyzed
breakdowns of lipid hydroperoxides include the cytotoxic aldehydes
mentioned previously (malonaldehyde, 4-hydroxynonenal), as well as
hydrocarbon gases such as ethane and pentane. Some thiyl compounds
can also reduce metal ions and accelerate peroxidation of lipids, e.g.,
cysteine. It has been suggested that some thiyl radicals (RS.]
initiate peroxidation by abstracting hydrogen atoms from lipids .
Different thiols behave differently in peroxidizing lipid systems,
presumably depending on their metal ion-reducing ability and the
reactivity of their thiyl radicals.
Organisms use superoxide
dismutases, catalase, and glutathione peroxidase as protection against
generation of reactive oxygen species. Organisms also keep as many iron
and copper ions as possible safely bound in storage or transport
proteins[37-39]. There is three times as much transferrin iron-binding
capacity in plasma as iron needing to be transported, so that there are
essentially no free iron ions in the plasma. Iron ions bound to
transferrin cannot stimulate lipid peroxidation or formation of free .OH
radicals. The same is true of copper ions bound to the plasma proteins
ceruloplasmin or albumin[37-40]. The value of this sequestration is
shown by an inspection of the pathology suffered by patients with
iron-overload disease, in whom iron ion-citrate chelates circulate in
the blood. These patients can suffer liver damage, diabetes, joint
inflammation, and hepatoma, among other problems. Metal ion
sequestration is an important antioxidant defense. For example, recent
papers have referred to ascorbic acid as a major antioxidant in plasma.
However, ascorbate can only exert antioxidant properties in the absence
of transition metal ions.
As well as the primary
defenses (scavenger enzymes and metal-ion sequestration), secondary
defenses are also present. The cell membranes and plasma lipoproteins
contain [alpha]-tocopherol, a lipidsoluble molecule that functions as a
chain-breaking antioxidant. Attached to the hydrophobic structure of
[alpha]-tocopherol is an -OH group whose hydrogen atom is easily
removed. Hence, peroxyl and alkoxyl radicals generated during lipid
peroxidation preferentially combine with the antioxidant, e.g.,
instead of with an adjacent
fatty acid side chain. This therefore terminates the chain reaction,
whence the term chain-breaking antioxidant. It also converts the
[alpha]-tocopherol into a new radical, tocopherol-O., which is poorly
reactive and unable to attack adjacent fatty acid side chains,
consequently stopping the chain reaction. Evidence exists[43,44] that
the tocopherol radical can migrate to the membrane surface and reconvert
to [alpha]-tocopherol by reaction with ascorbic acid (vitamin C). Both
vitamin C and [alpha]-tocopherol seem to minimize the consequences of
lipid peroxidation in lipoproteins and in membranes, should this process
begin. Some thiol compounds, such as GSH, might also be involved in
regenerating [alpha]-tocopherol from its radical in vivo.
The terms "[alpha]-tocopherol"
and "vitamin E" are often used synonymously, which is not strictly
correct. Vitamin E is defined nutritionally as a factor needed in the
diet of pregnant female rats to prevent resorption of the fetus and
compounds other than [alpha]-tocopherol (e.g., [beta-, gamma-, and
delta-tocopherols) have some effect in this assay. However, [alpha]-tocopherol
is the most effective, and it seems to be the most important
lipid-soluble chainbreaking antioxidant in vivo in humans. The
content of [alpha]-tocopherol in circulating low-density lipoproteins
helps to determine their resistance to lipid peroxidation and thus may
affect the development of atherosclerosis, a disease in which lipid
peroxidation is involved. Low plasma levels of f [alpha]-tocopherol
and vitamin C correlate with an increased incidence of myocardial
infarction and of some forms of cancer.
Other Antioxidants and Repair Systems
Some other compounds may
also function as antioxidants in vivo, such as uric acid, ubiquinol, and
bilirubin (reviewed in.). Antioxidant defenses are not quite
perfect. Cells contain systems that can repair DNA after attack by
radicals, degrade proteins damages by radicals, and metabolize
WHAT CAN WE EXPECT FROM ANTIOXIDANTS
IN THE THERAPY OF HUMAN DISEASE?
What Is an Antioxidant?
"Antioxidant" can be define
in various ways. Often, the term is implicitly restricted to
chainbreaking antioxidant inhibitors of lipid peroxidation, such as
vitamin E. However, the author prefers a broader definition - an
antioxidant is any substance that, when present at low concentrations
compared with those of an oxidizable substrate, significantly delays or
prevents oxidation of that substrate. The term "oxidizable substrate"
includes almost everything found in living cells, including proteins,
lipids, carbohydrates, and DNA.
Antioxidants act in many
different ways (Table I). In proposing antioxidants for use in human
disease, it is important to note the following: (a) the precise role
played in the disease pathology by reactive oxygen species; and (b) the
molecular targets of oxidative damage that need protecting. Thus,
oxidative stress can damage a multiplicity of targets in living cells
and the initial damage to one target can then affect others. Figure
2 attempts to illustrate some of the complex interacting mechanisms by
which express production of reactive oxygen species can produce cell
damage. If, for example, the primary event in damage to DNA, then an
inhibitor of lipid peroxidation might offer little or no protection. !!!
TABLE TABLE I Questions to Ask When Evaluating the Proposed Role of an
"Antioxidant" In Vivo
1. What biomolecule is the
compound supposed to protect? An inhibitor of lipid peroxidation is
unlikely to be useful if the oxidative damage is mediated by an attack
on proteins or DNA.
2. Is the compound present
in vivo at or near that biomolecule at sufficient concentration? For
example, many compounds have been suggested to act as .OH scavengers in
vivo. In order to compete with biologic molecules for .OH, a scavenger
must be present in at least millimolar concentrations in vivo. Most
drugs never achieve this sort of concentration.
3. How does it protect: by
scavenging reactive oxygen species, by preventing their formation, or by
4. For naturally occurring
antioxidants, is antioxidant protection the primary biologic role of the
molecule or a secondary one? For example, SOD has probably evolved as an
antioxidant enzyme. By contrast, transferrin has probably evolved as an
iron transport protein, although the binding of iron ions to transferrin
prevents them from accelerating radical reactions, giving this protein
an important secondary role in extracellular antioxidant defense.
5. If the antioxidant acts
by scavenging a reactive oxygen species, can the antioxidant-derived
radicals themselves do biologic damage?
6. Can the antioxidant cause
damage in biologic systems different from those in which it exerts
Free Radicals and Human
Disease: Causation or Consequence?
Does increased formation of
free radicals and other reactive oxygen species cause any human disease?
Radiation-induced carcinogenesis be initiated by free radical
damage. The signs produced by chronic dietary deficiencies of
selenium (Keshan disease) or of vitamin E (neurologic disorders seen in
patients with inborn errors in the mechanism of intestinal fat
absorption) could also be mediated by reactive oxygen species[28,50]. In
the premature infant, exposure of the incompletely vascularized retina
to elevated concentrations of oxygen can lead to retinopathy of
prematurity, which in its most severe forms can result in blindness.
Several controlled clinical trials have documented the efficiency of
[alpha]- tocopherol in minimizing the retinopathy, suggesting a role
for lipid per-oxidation.
For most human diseases,
increased formation of reactive oxygen species is secondary to the
primary disease process. For example, activated neutrophils produce
[O.sub.2-], and HOCl in order to kill bacteria. If a large number of
phagocytes become activated in a localized area, they can produce tissue
damage. The synovial fluid in the swollen knee joints of rheumatoid
patients swarm with activated neutrophils. There is evidence that
reactive oxygen species and other products derived from neutrophils
contribute to the joint injury. Whether this is a major or a minor
contribution to joint damage remains to be established. In some
forms of adult respiratory distress syndrome (ARDS), lung damage seems
to be mediated by an influx of neutrophils into the lung, where they
become activated to produce prostaglandins, leukotrienes, proteolytic
enzymes such as elastase, and reactive oxygen species. Among other
effects, reactive oxygen species inactivate proteins (such as [alpha
1]-antiproteinase) within the lung that normally inhibit the action of
elastase and prevent it from attacking lung elastic fibers. The precise
contribution of oxidative damage to lung injury in ARDS is unknown, but
deserves investigation in view of the high mortality rate.
In both ARDS and in
rheumatoid arthritis, increased generation of reactive oxygen species is
secondary to the processes that cause neutrophil infiltration, but they
then may make an additional detrimental contribution to tissue injury.
There are several examples
in which injury, by a nonradical mechanism, leads to increased free
radical reactions. Mechanical (e.g., crushing) or chemical injury to
tissues can cause cells to rupture and release their contents, including
transition metal ions (Figure 1), into the surrounding area.
Administration of cytotoxic drugs to patients with acute myeloid
leukemia has been shown to create a temporary "iron-overload" state,
probably due to extensive drug-induced lysis of the leukemic cells. This
increased iron availability could contribute to the side effects of
Perhaps the greatest
interest in this area lies in the sequelae of traumatic or ischemic
injury to the brain. Some Areas of the human brain are rich in iron.
Cerebrospinal fluid has no significant ironbinding capacity, since its
content of transferrin is low. It has been proposed that injury to
the brain by mechanical means (trauma) or by oxygen deprivation (stroke)
can result in release of iron ions into the surrounding area. These ions
facilitate further damage to the surrounding areas by accelerating free
radical reactions. This proposal has been given some support from animal
studies, using antioxidants such as chelating agents that bind iron ions
and prevent from catalyzing radical reactions. Promising results have
been obtained with amino-steroid-based antioxidants. Thus, one such "lazaroid,"
U74006F, has been observed to decrease the effects of reperfusion injury
upon the brain of cats to decrease post-traumatic spinal cord
degeneration in cats and to minimize neurologic damage after head
injury in mice.
Free Radicals in Human
Disease: A Triviality?
Tissue destruction and
degeneration can result in increased oxidative damage, by such processes
as metal-ion release, phagocyte activation, lipoxygenase activation, and
disruption of mitochondrial electron transport chains, so that more
electrons "escape" to oxygen to form [O.sub.2-] . (Figure 1). If follows
that almost any disease is likely to be accompanied by increased
formation of reactive oxygen species. It is not therefore surprising
that the list of diseases in which their formation has been implicated
is long and is growing longer. For atherosclerosis[43,59], rheumatoid
arthritis, some forms of ARDS, reoxygeneration injury[60,61], and
traumatic or ischemic damage to the central nervous system, there is
reasonable evidence to suggest that free radical reactions make a
significant detrimental contribution to the pathologic process. As
previously stressed, it is equally likely that in some (perhaps
most) diseases, the increased ROS formation is an epiphenomenon, making
no significant contribution to the progression of the disease. Each
proposal must be subject to stringent examination, because the likely
clinical value of "antioxidant therapy" will depend on how well the
exact role of reactive oxygen species is known.
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