Do antioxidant vitamins protect healthy people from free-radical damage, a process implicated in heart disease, stroke, and cancer, as well as such normal aspects of aging as wrinkled skin? Can some diseases be slowed or reversed with antioxidant compounds?
Perhaps surprisingly, researchers have yet to answer these seemingly straightforward questions, because no technique has existed to easily and directly measure the corrosive effects in the body of these highly reactive types of oxygen nor to assess the effectiveness of any countermeasures that might be taken.
Now, University of Pennsylvania Medical Center scientists have developed a new test to accurately and noninvasively measure free-radical activity in individuals. The method, detailed in the March 31 issue of the Proceedings of the National Academy of Sciences, is both simpler and more sensitive than one developed earlier by the same group. Taken together, the two assays corroborate each other and provide a powerful set of tools to address the role of free radicals in health and disease.
"Do healthy people derive any benefit from taking antioxidants if they have a strong native antioxidant defense?" asks Garret A. FitzGerald, MD, chairman of the department of pharmacology and senior author on the study. "Can antioxidants contribute significantly to the prevention or treatment of disease? This new test will allow us to answer these and other important questions about free-radical activity in individuals."
To date, the evidence linking free radicals to disease and aging -- through a biochemical process analogous to rusting -- and the supposition that antioxidants can limit the deleterious effects of free radicals have been based on statistical studies of groups of people and on test-tube experiments with cells in the laboratory.
These methods, although valuable, give no insight into variation between individuals, some of whom may possess highly effective inborn defenses against free-radical damage while others may be largely unprotected without vitamins or other external aid. Existing studies based on these necessarily indirect techniques have produced sometimes contradictory results, leading to debate and speculation among experts and confusion among members of the public.
"We presently have no rational basis for choosing a particular dose of a vitamin or for choosing a disease in which to evaluate the effects of a vitamin," says FitzGerald, who is also a professor of cardiovascular medicine at Penn. "And, indeed, we have reason to suspect that there might be quite a degree of inter-individual difference in susceptibility to the benefits of vitamins." The biochemical marker of free-radical activity identified by FitzGerald and his colleagues is an isoprostane called IPF2alpha-I, an abundant and stable byproduct of free-radical catalyzed oxidation of arachidonic acid that is easily detected in urine. Arachidonic acid is a fatty molecule found in cell membranes throughout the body. The marker identified in earlier studies by FitzGerald's team, also an isoprostane, is called 8-epi-PGF2alpha.
In several of these earlier studies, FitzGerald's team found the isoprostane markers to be elevated in several situations in which free-radical injury is thought to be a factor. In one set of experiments, levels of 8-epi-PGF2alpha were shown to be elevated in cigarette smokers, and vitamins C and E were shown effective in lowering those levels. In another study, 8-epi-PGF2alpha was found to be elevated during the critical period of reperfusion after bypass surgery or treatment for a heart attack.
In a report published in the October 15 issue of the Journal of Clinical Investigation, high levels of both 8-epi-PGF2alpha and IPF2alpha-I were identified in atherosclerotic plaque tissue removed from blocked neck arteries during a surgical procedure called an endarterectomy. This study involving both markers allowed the researchers to refine the newer test by cross-validating it with the older one, thus providing the technical underpinnings needed for a wide range of possible studies to come. Among these might be large-scale clinical trials of antioxidant vitamins.
The laboratory of chemist Joshua Rokach, PhD, at the Florida Institute of Technology collaborated with FitzGerald's group on the study. Primary funding for the work was provided by the National Institutes of Health. Further support came from the American Heart Association and the National Science Foundation.
The University of Pennsylvania Medical Center's sponsored research and training ranks third in the United States based on grant support from the National Institutes of Health, the primary funder of biomedical research and training in the nation -- $175 million in federal fiscal year 1997. In addition, for the third consecutive year, the institution posted the highest annual growth in these areas -- 17.6 percent -- of the top ten U.S. academic medical centers. News releases from the University of Pennsylvania Medical Center are available to reporters by direct e-mail, fax, or U.S. mail, upon request. They are also posted electronically to the medical center's home page ( http://www.med.upenn.edu), to EurekAlert! (http://www.eurekalert.org), an Internet resource sponsored by the American Association for the Advancement of Science, and to the electronic news services SciNews-MedNews and Quadnet.
Journal
Proceedings of the National Academy of Sciences