Trigger Of Deadly Food Toxin Discovered; Finding Could Help Prevent Liver Cancer

Because of lax or nonexistent regulation, 4.5 billion people in developing countries are chronically exposed to vast amounts of this toxin, called aflatoxin -- often hundreds of times higher than safe levels. In places such as China, Vietnam and South Africa, the combination of aflatoxin and hepatitis B virus exposure increases the likelihood of liver cancer occurrence by 60 times, and toxin-related cancer causes up to 10 percent of all deaths in those nations.

"It's shocking how profoundly these molds can affect public health," said Sheryl Tsai, UCI molecular biology & biochemistry, chemistry, and pharmaceutical sciences associate professor and lead author of a study appearing Thursday, Oct. 22, in the journal Nature that reports the finding.

Aflatoxin can colonize and contaminate nuts and grains before harvest or during storage. The U.S. Food & Drug Administration considers it an unavoidable food contaminant but sets maximum allowable limits.

The toxin wreaks havoc on a cancer-preventing gene in humans called p53. Without p53 protecting the body, aflatoxin can compromise immunity, interfere with metabolism, and cause severe malnutrition and cancer.

Tsai, graduate student Tyler Korman and undergraduate Oliver Kamari-Bidkorpeh, along with Johns Hopkins University researchers, found that a protein called PT is critical for aflatoxin to form in fungi. Previously, scientists didn't know what prompted the toxin's growth.

"The protein PT is the key to making the poison," Tsai said. "With this knowledge, perhaps we could kill the PT with drugs, inhibiting the mold's ability to make aflatoxin."

Destroying the mold -- rather than just the PT -- is the traditional method of decontamination, but it's expensive, costing hundreds of millions of dollars worldwide.

"This finding will lead to an increased understanding of how aflatoxin causes liver cancer in humans," said Dr. Frank Meyskens, Daniel G. Aldrich Jr. Endowed Chair and director of UCI's Chao Family Comprehensive Cancer Center. "It should allow for the development of inhibitors and, hopefully, a new chemoprevention approach to this deadly cancer."

Aflatoxin belongs to a class of organic compounds called polyketides. "Because polyketides provide the building blocks for both carcinogens and some of our most significant drugs, the importance of this study cannot be overemphasized," said Christopher Hughes, molecular biology & biochemistry professor and chair.

"This discovery provides insight into the mechanism of carcinogen production as well as an Achilles' heel that can be targeted by new generations of inhibitors. The basic understanding of polyketide synthesis that this work provides will be invaluable in the design of new polyketide-derived drugs."

The study was supported by the National Institutes of Health, the Pew Charitable Trusts, the U.S. Department of Energy, and the Damon Runyon Cancer Research Foundation.