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UW professor of environmental health David Eaton has solved the decades-old puzzle of why mice and rats differ by a factor of 100,000 in their susceptibility to liver cancer from the fungal toxin aflatoxin B1. The toxin, found on peanuts and corn, is the key member of a family of aflatoxin compounds that cause adverse human health effects including liver toxicity and liver cancer.

Eaton's research is one example of how researchers in the field of ecogenetics are attempting to sort out the genetic and environmental factors that influence an organism's response to carcinogenic agents and other imposed stresses. Arno Motulsky, UW professor of medicine and genetics, and Gilbert Omenn, dean of the UW School of Public Health and Community Medicine, have pioneered this burgeoning field of research and its policy implications at the University of Washington.

Worldwide, aflatoxins are considered a major public health problem, particularly in developing countries where food storage methods may be inadequate, under conditions of high heat and humidity, to prevent the growth of the mold that produces these toxic compounds. Aflatoxin Bsub 1 (AFBsub 1) is carcinogenic in several animal species, including poultry, trout, rats, and mice, in addition to humans.

It is not really the compound itself that is carcinogenic, but rather the biotransformed products of AFBsub 1 that exert their adverse effect. AFBsub 1 is oxidized to an epoxide called aflatoxin Bsub 1-8,9-epoxide, which then can either attach to DNA, causing mutations and cancer, or can further react to produce products that are toxic to liver cells. Eaton has elucidated how the differences in biochemical pathways between different species of animals give rise to vastly different sensitivities to the toxin.footnote 1

Rats and mice are quite similar in forming the epoxide, but in mice there is far greater detoxification of the epoxide owing to the protective activity of a particular enzyme, called glutathione S-transferase (GST). The human form of this enzyme resembles that of the rat more than the mouse enzyme, "suggesting that--on a biochemical basis--humans should be quite sensitive to the genotoxic effects of aflatoxins," says Eaton. Compounding the risk for humans is the finding that hepatitis B virus infection enhances the carcinogenic response of aflatoxin by about 30-fold. In fact, primary cancer of the liver is very common in Asia and Africa, where both the chemical and viral exposures are prevalent. Eaton's work suggests that a means of dietary or chemical intervention may be developed in the future to help protect high-risk populations from the effects of aflatoxins in their food.

Interestingly, the GST enzyme is also the agent that detoxifies carcinogens in tobacco smoke. In 1993, Motulsky, Eaton, and colleagues showed that smokers having high GST enzyme activity in their lung tissue had one third the risk for lung cancer as did smokers with low or no GST activity. The enzyme detoxifies another kind of epoxide in this case: the epoxides formed when the body metabolizes compounds from the smoke called polycyclic aromatic hydrocarbons.

  1. "Mechanisms of Aflatoxin Carcinogenesis," D. L. Eaton and E. P. Gallagher, Annu. Rev. Pharmacol. Toxicol., 34, 135 (1994).

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