Unlocking the Mysteries of Free Radicals and Antioxidants

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Unlocking the Mysteries of Free Radicals and Antioxidants JoAnn Guest Apr

23, 2003 17:41 PDT

Trying to Unlock the Mysteries of Free Radicals and Antioxidants

Stop Food Irradiation Project HOME

 

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 chemicals 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 scientist 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. To further study the role of this enzyme in

protecting motor neurons, a team led by scientists from Cephalon Inc., a

pharmaceutical company based in West Chester, Pa., and from the

Washington University School of Medicine in St. Louis created a Cu/Zn

knockout mouse (A.G. Reaume et al., Nature Genetics, 13:43-7, 1996).

Although " overtly normal " through young adulthood, these knockout mice

showed " increased vulnerability to neuronal death following injury, "

states author Richard Scott of Cephalon. Cu/Zn SOD, he concludes, while

unnecessary for normal development, " seems to protect neurons against

unexpected bursts of oxidative damage, " such as those known to occur

following injury.

 

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 also 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.

 

One of these compounds, tirilazad, is being tested in clinical trials

for the treatment of brain and spinal cord trauma and stroke-induced

injury. Hall says his company is also studying another class of

antioxidant molecules, the pyrrolopyrimidines, for the treatment of PD

and related diseases. Similarly, Centaur Pharmaceuticals of Sunnydale,

Calif., is developing a family of novel antioxidants based on

phenylbutylnitrone-a compound initially used as an indicator of free

radical activity in biological systems-primarily as therapeutics for

neurodegenerative disorders, reports founder and chief technical officer

John Carney.

 

Evaluating antioxidants' ability to prevent disease is also a topic of

intense research. Although mounting evidence testifies to the benefits

of eating antioxidant-rich foods, more studies are required to confirm

whether supplementing a healthy diet with the antioxidant vitamins E, C,

and beta-carotene actually reduces free radical levels in vivo, notes

NIA's Starke-Reed. 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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