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Free Radicals Mediate Arsenic's Harmful Effects

Tom K. Hei

Arsenic, a cancer-causing metal that poisons millions of people worldwide, exerts its harmful effects by boosting the body's production of damaging chemicals called free radicals, Columbia researchers report.

The new research, published in the Feb. 13 issue of "Proceedings of the National Academy of Sciences," adds to growing evidence that nutrients called antioxidants, which eliminate free radicals, may help prevent cancer and other illnesses caused by such environmental toxins as arsenic, cadmium, and asbestos. Sources of antioxidants include vitamins and micronutrients commonly found in the human diet, such as vitamin C, vitamin E and selenium.

"Arsenic is among the top environmental contaminants on the EPA Superfund list," says Tom K. Hei, the lead author of the study. "This piece of research provides the first clear-cut evidence that an environmental carcinogen acts predominantly through a free-radical pathway." Hei is professor of radiation oncology and public health at the Center for Radiological Research at Columbia's College of Physicians and Surgeons.

"If we understand how arsenic causes cancer, we'll have better means of prevention." Antioxidants are a leading candidate for such preventive measures, he said.

The study, which also involved P&S dermatology researchers and researchers at Albert Einstein College of Medicine and Colorado State University, showed that cells cultured in the laboratory sharply increased their free radical production within five minutes of being exposed to an arsenic compound. The compound, sodium arsenite -- the main toxic form of arsenic in the environment -- also boosted the rate of mutations among the cells. Mutations are a key step in cancer development. The mutation rate shot up still higher when researchers added a chemical that reduced the cells' production of natural antioxidants. This was consistent with previous research suggesting that antioxidants can protect cells from arsenic-induced genetic damage.

Close to a million U.S. residents are exposed to unsafe levels of arsenic, especially in the Southwest, says Hei. And the problem is substantially worse in some other countries. One study showed arsenic contaminates 27 percent of drinking wells in certain parts of Bangladesh and India, at levels more than 10 to 20 times higher than the maximum level the EPA has deemed safe.

Arsenic, a natural component of the Earth's crust, can enter the body primarily in two ways. One is through ingestion, such as through contaminated water, food, or drugs. Another is by inhalation, usually resulting from workplace exposure in industries such as ore smelting, semiconductor and glass manufacturing, and the burning of arsenic-tainted coal. Diseases associated with chronic arsenic exposure include lung, skin, bladder, and liver cancers, diabetes, atherosclerosis, kidney failure, liver and nervous system damage, and keratosis, a skin disease.

"In addition to the gene and chromosomal mutations that we have illustrated in this study, the oxidative damage is likely to contribute to other arsenic-associated human diseases as well. This includes cardiovascular and renal abnormalities," says Hei.

How arsenic induces human cancer has been somewhat of a mystery for two reasons. First, arsenic is an oddball among human carcinogens in that it has not been shown to cause cancer in laboratory animals. Second, laboratory research on the mutagenic effect of arsenic in mammalian cells has turned up nothing. This has puzzled scientists because epidemiological studies have established that arsenic is a human carcinogen, and mutations are generally a crucial first step in the development of cancer.

Hei and colleagues believe rodents such as those used for research have cellular mechanisms that protect them from arsenic damage. They also speculate that the types of mutations induced by arsenic are large chromosomal losses that are hard to detect with conventional mutation assays. When arsenic deletes the monitored gene, it also might delete crucial genes nearby, thus killing the cells.

To circumvent these problems, Hei and colleagues used a line of hybrid human-animal cells. These are hamster ovary cells containing a copy of human chromosome No. 11 in addition to their own chromosomes. Since these cells can live despite damage to the human chromosome, the number of mutants can be measured by the absence or presence of surface antigens that are coded by the human chromosome.

Using these and other techniques, Hei and colleagues developed data suggesting arsenic acts through a series of chemical reactions in the cell that produce free radicals. Free radicals form naturally in the body during oxygen metabolism, but their levels rise with the presence of some toxins. They are harmful because they tend to interact strongly with nearby molecules, changing the structure of cellular components such as DNA.

Using a spin trapping assay, Hei's team showed that arsenic acts by first spurring production of superoxide, a very unstable free radical species that is rapidly being converted into hydrogen peroxide by enzymes in the cells. The hydrogen peroxides are in turn converted into hydroxyl radicals, extremely reactive and damaging free radicals that attack cell membranes and DNA to create mutations.

"As such, antioxidants could be an interventional approach in patients who have been subjected to chronic arsenic exposure," says Hei. He plans to extend the study to determine the source of these radical species, in particular the role of mitochondria in mediating the genotoxic effects of arsenic.

The research was supported by the EPA and the National Institutes of Health.

--Office of External Relations, Columbia University Health Sciences Division, hsdnews@columbia.edu.

Published: Feb 15, 2001
Last modified: Sep 18, 2002


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