Unlocking the Mysteries of Free Radicals and Antioxidants

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Unlocking the Mysteries of Free Radicals and Antioxidants

 

Author: Alison Mack

September 30, 1996

 

 

OCA note:

 

Free radicals are small molecules broken off bigger molecules.

Irradiation, because of its intense energy, breaks molecules and

increases the amount of free radicals in food.

 

Antioxidants- are vitamins (like C) and other vitamins

that 'neutralize' free radicals and **decrease** their bad effects.

 

Aerobic [oxygen-breathing] organisms exist in a perpetual catch-22.

Oxygen sustains them, but it also poisons them via reactive

intermediates produced during respiration.

 

The powerful oxidants produced in this process -- including

the " superoxide " anion, hydroxyl radicals, and hydrogen peroxide --

 

are known as free radicals.

 

These highly reactive molecules have been fingered as agents not

merely of disease, but also of the aging 'process' itself.

 

But evolution has not left aerobes defenseless against reactive

oxygen species; their cells also produce 'antioxidants' to keep free

radicals in check.

 

Thus, scientists are trying to understand how free radicals cause

destruction as well as how antioxidants " protect " cells from damage,

which

could provide clues to treat or prevent disease and perhaps even

aging.

 

Reports on free radicals in living systems fill many specialized

journals and are featured prominently throughout the biochemical

literature.

 

Yet as recently as 30 years ago, reactive oxygen species were not

thought to occur in living cells,

recalls longtime researcher William Pryor, director of Louisiana

State University's Biodynamics Institute in Baton Rouge.

 

" The cant in the field [at that time] was that radicals were so

reactive

and unselective that they could not occur in biological systems, "

Pryor explains.

 

That view changed in 1967 when biochemist Irwin Fridovitch of

Duke University and Joe McCord (then a graduate student at Duke; now

a professor at the University of Colorado School of Medicine in

Denver) discovered the

 

antioxidant enzyme " superoxide dismutase " (SOD),

 

an important means of cellular 'defense' against free

radical " damage " .

 

Today, researchers agree that aerobically respiring cells are

veritable radical factories, producing " good radicals and bad

radicals both:

those that are under control and perform desirable biochemical

transformations, and those that cause pathology-

 

as well as toxins that work through radical reactions, " Pryor says.

 

Research concerning the cellular origins and physiological

consequences of free radicals now occupies thousands of

investigators worldwide.

 

Some of these scientists are examining the potential role of

reactive oxygen species in a long list of maladies, including

atherosclerosis, cancer,

inflammatory disease, and cataracts.

 

Free radicals are also thought to cause reperfusion injury, which

occurs when tissues are temporarily deprived of blood flow, such as

after heart attack, stroke,

and organ transplantation.

 

Recent explorations of possible links between 'oxidative' damage and

neurodegenerative disease have proved especially fruitful.

 

Yet, as Pryor mentions, free radicals aren't all bad. That's

particularly true of nitric oxide (NO), a molecule that's lately

achieved celebrity status.

 

Ubiquitous NO apparently regulates all manner of neurological,

vascular, and immunological functions; it even seems to

act as an antioxidant under certain conditions.

 

But NO also has its " dark side, " according to biochemist Bruce

Freeman, a professor in the department of anesthesiology at the

University of Alabama in Birmingham

(Hot Papers, The Scientist, Sept. 16, 1996, page 13).

 

Scientists are only beginning to explore that unknown territory.

 

 

 

'Radical' Aging Theories--

 

Theories of aging come and go, but one of the most enduring suggests

that free radicals play a significant role in biological senescence,

explains Pamela Starke-Reed, director of the Office of Nutrition at

the National Institute on Aging (NIA).

 

" It's far from being proven, " she says, " but it hasn't been

disproved, either. " That's mainly because there's no direct way to

measure free radicals in vivo, she elaborates, " but we're getting

close. "

 

Thus, NIA generously funds research in free radical biology. Starke-

Reed estimates that 15 percent of the institute's 1995-96 budget of

$71 million

supported research on oxidative damage related to aging; that figure

does not include studies of related topics such as 'genetic

mutation'.

 

As Starke-Reed indicates, the key challenge in this field is to

identify the mechanism by which oxidative " damage " induces age-

related

physiological phenomena.

 

Denham Harman, an emeritus professor of medicine at the University

of Nebraska Medical Center in Omaha and the originator of the free

radical theory of aging,

 

thinks that humans may decline along with their mitochondria.

 

There is, Harman says, a growing consensus among biogerontologists

that in mammals, aging -- defined as an increase in the risk of

death --

results from *deleterious* cellular 'changes' produced by free-

radical reactions.

 

These cell-damaging processes are largely initiated in the course of

mitochondrial respiration, he says, while life span is determined by

the rate of

damage to the mitochondria.

 

Numerous studies supporting that consensus were recently described

by Rajindar Sohal, a professor in the department of biological

sciences at

Southern Methodist University in Dallas, and Richard Weindruch, a

professor of medicine at the University of Wisconsin Medical School

in Madison (Science, 273:59-63, 1996).

 

Four conditions need to be met to validate the free radical theory

of aging, the authors wrote: first, oxidative damage must increase

as aging progresses;

second, longer-lived species must sustain lower rates of damage;

third, known life

span-lengthening regimes such as caloric 'restriction' must be shown

to reduce oxidative damage to cells;

and finally, experimental increases in " antioxidant " 'defenses'

should

lengthen life span.

 

On all of these counts, says Sohal, " there is enough evidence to

give good credence to the free radical theory of aging. "

 

Other scientists take a broader view of aging.

 

For example biogerontologist Leonard Hayflick, a professor at the

University of California, San Francisco, believes aging probably

results from multiple

causes, one of which is free radical damage.

 

" The most intriguing aspect of studies done with free radicals, "

Hayflick writes in his recent book, How and Why We Age (2d ed., New

York, Ballantine Books, 1996), " is, perhaps, not what they might be

telling us about aging, but what they are telling us about disease. "

 

 

 

Neurogenerative Links--

 

In particular, free radical studies are speaking volumes about the

link

between oxidative damage and neurodegenerative disorders such as

Huntington's (HD), Parkinson's (PD), and Alzheimer's diseases, as

well as amyotrophic lateral sclerosis (ALS), commonly known as Lou

Gehrig's disease.

 

" The more people have looked for free radical effects in

neurodegenerative diseases, the more they've found, " observes Dale

Bredesen, director of the program on aging at the Burnham Institute

in La Jolla, Calif.

 

Neurologists suspect that glutamate, a

neurotransmitter, sparks free radical production if it accumulates

in

the brain (J.T. Coyle, P. Puttfarcken, Science, 262:689-94, 1993).

 

The resulting reactive oxygen and nitrogen species may directly

damage cell membranes and proteins, Bredesen explains; they may also

act as signaling molecules to initiate programmed " cell death " ,

or apoptosis, a

process suspected to be involved in several neurodegenerative

disorders.

 

 

Free radicals may 'damage' compromised brain cells that might

otherwise resist such an attack.

 

For example, mutations in the copper-zinc form of

SOD are associated with a rare subtype of familial ALS, a

degenerative disease of motor neurons.

 

 

 

Nitric Oxide Reactions--

 

Besides mutation, another way that antioxidant proteins may be

weakened

is through the action of nitric oxide.

 

In this and other instances in which it plays the cellular villain,

NO is thought to react with

superoxide radicals to produce an even more reactive species,

peroxynitrite.

 

A combination oxidant and nitrating agent, peroxynitrate

subsequently reacts with the amino acid tyrosine in cellular

proteins, converting it to nitrosotyrosine.

 

Nitration may in turn affect protein function, according to Joseph

Beckman, a professor in the departments of anesthesiology and

biochemistry at the University of Alabama in

Birmingham. Beckman and colleagues recently raised antibodies that

recognize nitrated proteins and have used them to visualize nitrated

proteins in tissues affected by ALS, HD, and atherosclerosis (J.S.

Beckman et al., Biological Chemistry Hoppe-Seyler, 375:81-8, 1994),

among others.

 

Subsequently, Lee Ann MacMillan-Crow, a postdoctoral fellow in the

Alabama laboratory of Anthony Thompson in the department of surgery,

optimized an immunoprecipitation procedure that enabled her and

coworkers to isolate nitrated proteins from rejected kidney

transplant tissue.

 

Most interestingly, she reports, they recovered nitrated Mn SOD,

the mitochondrial form of the enzyme.

 

(Cu/Zn SOD is found in the cytosol, the fluid portion of the

cytoplasm.)

 

They also found decreased

Mn SOD activity in rejected transplant extracts, as compared with

healthy kidney tissue controls.

 

In follow-up experiments, the researchers found that the degree of

nitration in the extracts

paralleled enzyme inactivation, according to MacMillan-Crow.

 

Once Mn SOD is inactivated, she points out, superoxide-and thus

peroxynitrite-probably runs rampant in the cell.

 

" We think this positive-feedback mechanism is a realistic model

which may account for

end-stage kidney disease, and which could be operating in other

diseases as well, " she concludes.

 

Nitric oxide also reacts with thiol groups of proteins to form

powerful

compounds called S-nitrosothiols (SNOs), which have been shown to

regulate protein activity and even confer novel function on some

proteins.

 

Researchers led by Jonathan Stamler, an associate professor of

medicine at Duke University, recently demonstrated that SNOs are a

major

regulator of gas exchange and blood pressure (L. Jia et al., Nature,

380:221-6, 1996). And this month, Stamler and coworkers reported

that SNOs up-regulate genes encoding proteins that, in turn, destroy

excessive SNOs in the cell (A. Hausladen et al., Cell, 86:719-29,

1996).

 

 

Previously, only oxidative stress was known to activate such a

genetic feedback loop.

 

This discovery not only strengthens NO's reputation as a universal

molecular signal, but also indicates that it may rival oxygen as a

cellular toxin.

 

Thus, Stamler has coined the term " nitrosative stress " to describe

the cellular consequences of excess NO. Nitrosative stress,

Stamler asserts, " parallels oxidative stress in that it may lead to

a host of diseases, as well as the cumulative damage of aging. "

 

While oxidative and nitrosative stresses can be synergistic, he

says, the latter represents " a new type of stress that can occur in

the absence of oxygen. "

 

 

 

Antioxidant Treatments--

 

Although many studies focus on damage wrought by free radicals, a

significant body of research describes the many cellular defenses

deployed against this assault.

 

A small number of pharmaceutical researchers are engaged in

discovering

and designing chemical

antioxidants to treat disorders associated with oxidative stress.

 

Scientists continue to identify new natural 'antioxidants'.

 

 

 

Recent recruits to the ranks of SOD and vitamin E include the so-

called

thiol-specific antioxidant enzyme discovered by researchers at the

National Heart, Lung, and Blood Institute (M.B. Yim et al., Journal

of Biochemistry, 269:1621-6, 1994) and, perhaps, the hormone

melatonin (R.

Reiter, European Journal of Endocrinology, 134:412-20, 1996).

Chemical mimics of the active site of Mn SOD, developed by Eukarion

Inc., a Bedford, Mass.-based biotech company, have also been shown

to mediate beta-amyloid toxicity, thought to cause neuronal

degeneration in Alzheimer's disease (A.J. Bruce et al.,

 

Proceedings of the National

Academy of Sciences, 93:2312-6, 1996).

 

Based on observations that the steroid hormone methylprednisolone

reduced central nervous system injury in animal models, researchers

at Pharmacia and Upjohn Inc. of Kalamazoo, Mich., have developed a

series of chemical variants of this molecule, which they

dubbed " lazaroids, "

after the biblical character Lazarus, whom Jesus raised from the

dead, according to senior scientist Edward Hall.

 

Evaluating antioxidants' ability to prevent disease is a topic of

intense research.

 

 

Recently, however, researchers described a way to measure free

radical

byproducts in urine (M. Reilly et al., Circulation,

94:19-25, 1996) and therefore gauge the effect of various treatments

on free radical generation.

 

" The antioxidant field is extremely exciting because both animal and

in

vitro data have long suggested that antioxidants would be potent

protectors against chronic diseases-particularly cancer and heart

disease, " reflects Pryor.

 

Recent epidemiological and clinical studies

have been almost uniformly supportive of this hypothesis, he says.

 

Alison Mack is a freelance science writer based in Wilmington, Del.

(The Scientist, Vol:10, #19, p. 13, 16 , September 30, 1996)

 

http://www.organicconsumers.org/irrad/freeradicalarticle.cfm

 

 

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