Rejuggling Act

By Quinn Eastman | Illustration by Richard Borge

Move over, free radicals. A new theory puts sulfur center stage in understanding how the body responds to oxidative stress.

A stroll through an Atlanta supermarket illustrates the awareness consumers have for the promise offered by antioxidants. Fruit juices, herbal teas, yogurts, even cookies are advertised as containing an “antioxidant advantage” that might strengthen your immune system, fight aging, and lower the risk of various diseases. Many consumers seem convinced that whether taken in a pill or a glass of juice, the more antioxidants, the better.

Antioxidants such as vitamins C and E are supposed to soak up free radicals and cushion cells from their damaging effects, known collectively as oxidative stress.

With this idea in mind, doctors designed large clinical studies to test the theory that supplementing the diet with antioxidant vitamins could protect against conditions such as heart disease and cancer. Unfortunately, the theory doesn’t work.

“It appears that much recent research on antioxidants has been misdirected,” says Dean Jones, biochemist and director of the clinical biomarkers lab at Emory. “Studies with thousands of patients over several years keep showing the same thing: free-radical scavengers do little to prevent disease. Yet antioxidant supplements are a multi-billion-dollar industry.”

Jones has been developing an alternative theory: When it comes to oxidative stress, the focus should be less on free radicals and more on sulfur. Molecules containing sulfur are the body’s most important control points for regulating oxidative stress. Jones’ work is guiding the development of tests to gauge a patient’s risk for conditions such as heart failure and may lead to better understanding of how to supplement the diet with more effective antioxidants targeting sulfur.

Sulfur: the currency of oxidative stress

Why is sulfur so important? Antioxidants come in many forms, but by far the most abundant and important ones are glutathione and cysteine. Both contain sulfur, which  gives these compounds the ability to quench oxidants. In fact, sulfur gives them the ability to allow other non-sulfuric antioxidants like vitamin C to quench free radicals as well. When vitamin C absorbs free radicals, for example, glutathione and cysteine use sulfur to cycle the vitamin back to its original unoxidized form. Without sulfur, antioxidants like vitamin C would be inoperative.

“Cells use sulfur to settle their debts in oxidative stress,” says Jones. “Glutathione and cysteine help supply the currency to pay those debts.”

If glutathione and cysteine and their sulfur are so central to countering oxidative stress, why not give these compounds as dietary supplements instead of vitamins? “It’s not that simple,” says Jones. “We’re still trying to sort that out.”


Antioxidants come in many forms, but by far the most abundant ones

are glutathione and cysteine. Both contain sulfur, which gives

these compounds their ability to quench oxidants.


For one thing, glutathione (located inside cells) and cysteine (located outside cells) are important as antioxidants in different parts of the body. Each one comes in two forms: reduced (ready to go) and oxidized (used up). Jones and clinical nutrition expert Tom Ziegler have found that oxidized cysteine and glutathione levels rise and fall in daily cycles in response to meals but peak at times several hours apart. They also found that increasing cysteine levels in the bloodstream has little or no effect on glutathione levels inside cells. In addition, glutathione is broken down quickly in the intestines, and once swallowed, it becomes cysteine.

In clinical trials in which patients with heart and lung disease took a form of cysteine, it seemed to help in some cases, but the actual dose taken was smaller than the amount of cysteine found in the average diet. Some studies also suggest that giving the body a pulse of cysteine tips the balance toward the less helpful oxidized form, the opposite of what was intended.

Determining the best way to take sulfur-based antioxidants may require careful timing of intake with respect to sleep and meals and calibration of dose depending on age and metabolism. Other nutrients such as zinc, which affects the body’s ability to use cysteine and glutathione, may need to be worked in as well.

In addition to its potential as part of a highly regimented dietary supplement, cysteine has promise as a biomarker for inflammation and heart disease, says Jones. When he and his colleagues exposed white blood cells in culture to high levels of the less helpful (oxidized) form of cysteine, the cells showed signs of inflammation and displayed “sticky” molecules on their surfaces that would make them more likely to adhere to vessel walls and form atherosclerotic plaques. It appears that enzymes important for driving inflammation become more or less active depending on the state of the sulfurs on their cysteines, Jones says.

“This is some of our most exciting work,” he adds. “It shows that there’s a direct mechanistic link between oxidative stress, inflammation, and early events in atherosclerosis.”


Viola VaccarinoBack to the Mediterranean

Instead of taking supplements found in pills, the best way to reduce oxidative stress may still be a diet rich in fruits, vegetables, and whole grains.

Viola Vaccarino, who leads Emory’s cardiovascular epidemiology research group, and former doctoral student Jun Dai, now a faculty member at Indiana University, recently studied the connection between diet and oxidative stress in a group of approximately 300 twins.

Studying twins allowed the scientists to separate out genetic influences and factors from environmental ones.

The twins’ diets were scored for how closely they resembled the classic Mediterranean diet, which includes large amounts of fruit, vegetables, whole grain breads, fish and poultry, small or moderate amounts of dairy products, and small amounts of red meat.

The higher their Mediterranean diet score, the lower the twins’ oxidative stress levels—as measured by the proportion of oxidized glutathione—tended to be.

Dai and Vaccarino point out that their study did not gauge the effects of participants’ consumption of specific fruits or vegetables or the antioxidants in them. The idea that certain antioxidants are responsible for the Mediterranean diet’s protective effects needs further testing.

The proportion of cysteine-rich legumes, sources of fats, and amount of fried foods may also influence oxidative stress, Dai adds.—Quinn Eastman


Measuring oxidative stress

Redefining oxidative stress points the way for cardiology researchers who are trying to develop better techniques to measure oxidative stress in the body.

“There are many markers of oxidative stress, but there is little agreement on which ones are useful,” says cardiologist David Harrison, who studies the relationship between oxidative stress and hypertension.

Focusing on sulfur as a measurement isn’t always practical or affordable. Testing for cysteine and glutathione requires storing samples in a preservative and then analyzing them with a mass spectrometer. And as Jones has shown, looking at glutathione and cysteine is useful but may not tell the whole story.

Measuring free radicals themselves is hard because they exist only for milliseconds. Harrison and colleagues have had success with measuring another form of reactive oxygen, lipid peroxides, which can cause cell injury or generate free radicals. Measuring lipid peroxides is surprisingly convenient, Harrison says, requiring only a finger prick and a bench-top measuring instrument.

Collaborators Jones and cardiologist Sam Dudley have shown that levels of both lipid peroxides and oxidized cysteine provide strong indicators of patients’ risk of cardiac arrhythmias such as atrial fibrillation.

Jones believes that the best measurements of a patient’s oxidative stress level will include a profile of several different markers. “The goal is to develop a profile comparable in practicality and affordability to that used to determine whether one needs anti-cholesterol medication,” he says. “Having such a profile for oxidative stress and a protocol for how to respond could potentially prevent or forestall many kinds of illnesses and save many lives.”

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Emory Medicine - Spring 2009