Antioxidants May in Some Cases Do More Harm Than Good
http://www.washingtonpost.com/wp-dyn/articles/A39716-2001Aug6.html
Tuesday, August 7, 2001; Page HE01
It used to be so simple, a battle
between good and evil.
Rogue chemicals called free radicals
roam about the body like brazen street punks, the story went, smashing
cellular walls and roughing up innocent DNA molecules, causing cancers
and the diseases of middle and old age.
Their flagrant disregard for the
law would continue unchecked if it weren't for swashbuckling antioxidants
swooping in on the wings of dietary supplements, disarming the free radicals
of their menacing electrons and converting them into respectable molecular
citizens.
At least that's how the theory went.
And the public bought it -- both the story and millions of doses of antioxidant
supplements, which they believed would reduce disease, boost system performance
and maybe even slow the aging clock. But as a bewildering cascade of contradictory,
inconclusive and outright negative research reports over the past several
years suggests, the human body isn't governed by a B-movie script. The
antioxidant story isn't as simple as some -- largely, those who make and
sell them -- would have us believe.
"Free radicals are as good as they
are bad," says Walter Bortz of Stanford University Medical School. He is
a past president of the American Geriatric Society and author of several
popular books on aging and scientific articles on vitamins. He says that
antioxidants in high doses may do the body harm; in other cases they may
help. We simply don't know yet which ones do which and when.
"It's a very complicated story,"
he says.
You know many antioxidants by name,
whether you take them or not: vitamins C and E, beta carotene and selenium
are just the most common. Their purported health benefits adorn the packaging
for everything from cereals to cosmetics. One can easily walk through the
aisles of any grocery, drug or vitamin store thinking that antioxidants
are scientifically validated wonder pills. They're not, "although the data
don't seem to make any difference to the sales of supplements," says Richard
Veech, chief of the Laboratory of Membrane Biochemistry at the National
Institute on Alcohol Abuse and Alcoholism, who has reported on the interplay
of free radicals and antioxidants for more than 30 years.
Americans spent $31 billion on vitamin
supplements in 1999, according to the U.S. General Accounting Office. Nearly
$2 billion of that was for vitamins E and C, beta carotene and selenium,
according to Nutrition Business Journal. Up to 30 percent of the population
is taking antioxidant supplements regularly, according to the American
Heart Association.
While the efficacy of antioxidant
supplements remains gospel in the health-marketing community, Bortz says
the accumulating scientific record does not verify it. For every study
that shows benefits, he says, there is another study that doesn't.
So with antioxidants and free radicals
now seen as playing dual roles of good guys and bad guys, just what exactly
is the state of antioxidant research? And what health claims can you believe?
The experts -- you were about to guess this -- have a variety of opinions.
Armor All for the Body
It's generally recognized that antioxidants
have the ability to serve as sort of a rust protector for the body, putting
a stop to a process called oxidation.
Important molecules in the body,
such as those that form the walls of arteries, become oxidized when they
lose an electron. Once oxidized, they become unstable and easily break
apart.
The culprit, without a doubt, is
the free radical, Veech says. Free radicals are highly reactive molecules,
or single atoms with unpaired electrons, looking for a mate. So they steal
an electron from the first thing they encounter, perhaps a cell wall or
a strand of DNA. As free-radical damage mounts, cells can no longer perform
properly. Tissues degrade. Disease sets in. An excess of free radicals
has been cited in the development of cardiovascular disease, Alzheimer's
disease, Parkinson's disease and cancer. Aging itself
has been defined as a gradual accumulation
of free radical damage.
Yet not all free radicals are bad.
In fact, free radicals are necessary for life, according to Britton Chance,
professor emeritus of biophysics, physical chemistry and radiologic physics
at the University of Pennsylvania, a renowned expert on free-radical production.
The body cannot turn air and food into chemical energy without a chain
reaction of free radicals, for instance. Free radicals are also a crucial
part of the immune system, floating through the veins and attacking foreign
invaders. They help fight against bacteria.
Without free radicals, says Chance,
"we couldn't have this conversation."
Free radicals are a natural byproduct
of breathing; antioxidants mop some of them up. A balancing act emerges,
says Veech. The body hopes to avoid excessive free-radical production,
but it certainly doesn't want to get rid of all of them.
A diet rich in fruit, vegetables,
nuts and some meats supplies most people with the antioxidants needed to
walk this tightrope, according to a report last year from the Institute
of Medicine. The IOM could find no convincing evidence that the bulk of
the American population needs additional armaments in the form of antioxidant
supplements to fight free-radical damage. The very notion that free radicals,
produced naturally, are some type of unwelcome houseguest is silly, according
to Veech.
Veech says that free radicals have
been incorporated into the functioning human system over millions of years
of evolution. The idea that they should be wiped out or minimized is nonsense,
he says.
"God," he says, "is no fool."
Low Levels, High Levels
Studies indicate fairly consistently
that having too few antioxidants is a bad thing. One study, published in
1983 in the British medical journal The Lancet, found that people with
low blood levels of selenium were twice as likely to develop cancer compared
with people with normal levels. Another study, published in 1986 in the
New England Journal of Medicine (NEJM), found that patients with a certain
type of lung cancer were four times more likely to be deficient in beta
carotene than a control group.
A 1989 study from the Netherlands
associated low selenium levels with an increased risk of heart attacks.
More convincingly, the Harvard-based Physicians Health Study -- which has
recorded the lifestyles of some 50,000 male health professionals for the
past 15 years -- found that men who ate a diet rich in vitamin E (from
nuts, seeds and soybeans) were half as likely to develop heart disease
as those with very low levels of dietary vitamin E.
Although these epidemiological studies
suggest an association between antioxidants and good health, this does
not mean that the antioxidants caused the improved health. Nor does it
imply that taking antioxidants in a pill form improves health. In the studies
cited above, it is not clear what is responsible for the lower levels of
the nutrients -- a poor diet, a certain environment, some unknown metabolic
factor.
Taking generous doses of antioxidant
supplements showed some promise in studies published in the mid-1990s.
Skin cancer patients given daily selenium supplements were twice as likely
to survive their cancer as those patients not given selenium, the Journal
of the American Medical Association (JAMA) reported in 1996. This was a
multi-center, double-blind, randomized, placebo-controlled study with more
than 1,300 patients -- all the markings of good science. The findings were
so dramatic, wrote the authors, that they stopped the study after six years
so that all patients could benefit from the selenium supplement.
Other studies showed similar positive
results: Vitamin E postponed the onset of debilitating Alzheimer's symptoms
in a small study published in the NEJM in 1997; slowed the progress of
coronary artery disease in a study at the University of Southern California
School of Medicine that was published in JAMA in 1995; cut the risk of
cataracts by half in a 1998 Stony Brook (N.Y.) Medical Center study published
in the journal Ophthalmology; and lowered the risk of prostate cancer in
a 1994 NEJM article. Vitamin C helped stave off blindness, kidney failure
and the need for amputation among diabetics, according to a 1998 Duke University
Medical Center report. Extra selenium, a mineral needed only in trace quantities,
reduced the risk of prostate, colorectal and lung cancer, according to
the National Institutes of Health's Clinical Center (as reported in 1997
and 1998 in journals such as the American Journal of Epidemiology, Cancer
Prevention and Nutrition Review).
Consumers tuned in to these results.
Sales of vitamin E grew from $590 million to $860 million from 1995 to
1999, according to Nutrition Business Journal. Sales of other antioxidants
climbed by millions of dollars as well.
But the story doesn't end there.
Side by side, over the years, came a wave of neutral and even negative
reports about the benefits of antioxidant supplements. One study, reported
in NEJM in 1994, found that Finnish male smokers were 18 percent more likely
to develop lung cancer after taking a beta carotene supplement. In 1997,
The Lancet published a study of nearly 2,000 men receiving vitamin E, beta
carotene, both or a placebo after suffering their first heart attack. The
two beta carotene groups were about twice as likely to die from a second
heart attack or heart disease as the placebo group, and the vitamin E-only
group was about 1.5 times as likely to die.
Other studies showed similar negative
results: no evidence that vitamins C and E or beta carotene prevented colorectal
cancer; no evidence that these "big three" prevented arteries from re-clogging
after angioplasty; no evidence that beta carotene prevented cancer or heart
disease in more than 22,000 physicians over 12 years; no evidence that
extra selenium prevented cancer in 60,000 nurses; and more bad news for
smokers taking beta carotene, this time with a 28 percent higher incidence
of lung cancer. These studies were reported in NEJM from 1994 to 1997.
Criticisms naturally flowed back
and forth, with the pro-supplement camp finding methodological errors in
studies casting doubt on pills, and the anti-supplement folks finding similar
problems in the work that seemed to contradict their findings. .
Strangely, Veech says, all these
studies might be absolutely right, pointing to the complex heart of the
matter -- that we don't understand the intricate relationship between certain
types of antioxidants and certain types of free radicals at different moments
over the course of one's lifetime.
"You can't talk about antioxidants
en masse," says Veech. "They all have different potentials."
The Antioxidant Paradox
Barry Halliwell of the National University
in Singapore wrote a short article in The Lancet last year entitled "The
Antioxidant Paradox." Halliwell was lamenting the fact that although diets
rich in antioxidants seem to have a positive effect on health, popping
antioxidant supplements can be either beneficial or harmful, and the results
are not at all predictable.
If the chemistry is all the same
(that is, pairing up free electrons and converting free radicals to neutral
molecules), why would a given antioxidant have different effects at different
times on different regions of the body? Several entirely different mechanisms
might be taking place, researchers say:
• Extra amounts of antioxidants might
be turning into pro-oxidants (which promote the removal of electrons from
atoms), fueling free-radical production and its damage.
• Supplements might do nothing at
all because they can't get to where they are needed.
• Or antioxidants might not be the
magic beneficial chemical in the food we eat after all.
Can antioxidants turn on you? Several
studies have shown that people who did not get the daily recommended allowance
of vitamin C had an increase in free-radical damage to their DNA. But,
paradoxically, people who took megadoses of C also had an increase in DNA
damage. The second scenario might happen, Halliwell says, because vitamin
C can worsen cell damage once it has already started.
Within a cell, certain metal compounds
are released as a result of free-radical damage. These metals themselves
can act as a catalyst for further free-radical damage when they are in
a "reduced" state, with a missing oxygen or extra hydrogen atom. Antioxidants
place metals in this reduced state. Thus, in this environment, antioxidants
become pro-oxidants, Halliwell says.
This was demonstrated in laboratory
animals exposed to the pesticide paraquat, a known carcinogen. Animals
that received vitamin C before exposure were largely protected from cancer.
Animals that received vitamin C after exposure didn't fare so well: The
antioxidant aggravated the damage caused by the herbicide and led to more
cancers.
The American Cancer Society (ACS)
advises cancer patients not to prescribe themselves antioxidants because
of this potential effect, although it has never been demonstrated convincingly
in human studies.
"Think of antioxidants as drugs,"
says Michael Thun, who heads epidemiological research for the ACS in Atlanta.
There are gaps in our understanding, Thun says, and "antioxidants are not
necessarily safe or beneficial."
Compounding this is the fact that
free radicals can kill cancer cells; that's how some cancer treatment works.
And rapidly multiplying cancer cells can use antioxidants to their advantage
to fuel their growth, Thun says. So taking antioxidants at the wrong time
essentially arms the bad guy with the weapons to stay alive and multiply.
We should point out that none of
this has convinced some practitioners of alternative medicine not to prescribe
antioxidants for cancer. Many do, and insist mainstream medicine is depriving
patients of valuable cures and treatments.
Another baffling complication is
that -- despite the assurances of pill makers who advise simply taking
their pills by mouth and feeling confident that the body will know what
to do with them -- no one knows how to get antioxidants to travel where
they are needed, when they are needed.
Most free-radical damage occurs in
the mitochondria, according to the University of Pennsylvania's Chance.
The process of making energy in the mitochondria, called the respiratory
chain, depends on the availability of free radicals. And extra free radicals
are made in the process.
The mitochondria house a tiny, circular
strain of DNA that contains 30 genes. This is separate from the double-helix
DNA in the cell's nucleus. The mitochondrial DNA, called mDNA, is often
the free radical's first point of attack. When mDNA is damaged, it cannot
do its job of creating the proteins (molecular messengers) needed for daily
bodily maintenance.
This is where a magic bullet could
come in handy, Chance says -- something that could penetrate the mitochondria
and mop up a rogue free radical set on doing damage, while steering clear
of the intricate respiratory chain. Yet mitochondria are veritable fortresses
with tough outer walls, moat-like inner barriers and meandering inner walls
protecting their precious contents. Proteins get out, but antioxidants
have a tough time getting in.
"This is where the problem is," Harmon
says, "getting into the mitochondria."
No one is sure whether brute force
-- which is to say, a megadose of antioxidants -- is the way into the mitochondria,
says Bortz, who was a colleague of Linus Pauling, the Nobel laureate who
recommended megadoses of vitamin C to ward off colds, flus and even cancer.
Perhaps the body has more subtle ways of permitting entry.
Diet Vs. Supplements
And so it is that doctors are split
on whether to recommend antioxidant supplements to their patients. The
camps are broken down into those who believe there are not enough data
to make blanket recommendations; those who feel that Americans (particularly
children) have such a poor diet that they need a supplement to ensure adequate
levels for basic function; and those who say that anyone can benefit from
increased antioxidants regardless of how healthy the diet is. A smaller
camp sees in the reports about negative effects of antioxidant pills reason
enough not to take any.
For Bortz, who is in his sixties
and runs a marathon once a year, whether or not to take an antioxidant
supplement is "an intellectual issue."
"Anything that will work, I'm for,"
Bortz says. "I just don't want people spending their money on false hopes.
. . . Exercise is the master therapy."
Bortz says "maybe" to vitamin E;
"nah" to vitamin C; and "no way" to beta carotene.
Halliwell argues that a varied diet
seems to be more healthy than simple supplement-taking because the isolated
antioxidant might not be the superhero. Fruit and vegetables are rich in
antioxidants, but these plants contain hundreds of other chemicals. Any
single chemical or combination of chemicals might pack the therapeutic
punch.
Nutrients from food enable the body
to make its own antioxidants. Veech says that a chemical produced by the
body called glutathione is ultimately responsible for neutralizing free
radicals, and the glutathione concentration in cells dwarfs that of the
free-radical scavengers such as vitamin C and E. So diet and energy demands
determine the amount of free radical generation and removal, with supplements
playing a minuscule role, if any.
"The production of free radicals,
absent genetic defects, results from normal metabolic processes," says
Veech. "Likewise, the destruction of free radicals in a non-harmful manner
is also the result of normal metabolic processes.
"People don't want to exercise. They
don't want to eat healthy food. They don't want to stop drinking; they
don't want to stop smoking; they don't want to stop having dangerous sex.
They want to take a pill. Well, good luck."
Resources
• NIH Clinical Center: www.cc.nih.gov/ccc/supplements/
• NIH Office of Dietary Supplements:
dietary-supplements.info.nih.gov/
• FDA Guide to Dietary Supplements:
www.fda.gov/fdac/features/1998/598_guid.html
© 2001 The Washington Post Company
By Christopher Wanjek
Special to The Washington Post