The system hinges on a sharp boost in protective enzymes, called phase II enzymes, which can dispose of toxic chemicals. The enzymes effectively neutralize toxins' ability to damage DNA and trigger cancer, the researchers say.

In two studies appearing in the current Proceedings of the National Academy of Sciences, they've not only demonstrated the fundamental workings of the system, but have also pinpointed the key "switch" that regulates it. "We've gained long-awaited proof of a basic mechanism that can reduce the risk of cancer," says molecular pharmacologist and team member Paul Talalay, M.D.

Scientists already know that natural substances in plants, such as the sulforaphane in broccoli, as well as some man-made chemicals, can tap into this system — that they're somehow "chemoprotective" — but the route hasn't been clear. The new work, a result of 20 years' research, "confirms that raising the levels of phase II enzymes can offer a highly effective way to achieve protection against carcinogenesis," says Talalay. "We always had faith," he adds; "Now, in our animal studies, we have a direct demonstration."

"Our precise understanding of this system should make it fairly easy to design drugs that can fine-tune it," says researcher Thomas W. Kensler, Ph.D., a Hopkins toxicologist who's now overseeing early clinical trials of one such drug in China. "We have evidence that we can increase the system's levels of protection in people," he says, "and are planning long-term studies that would reveal any lowered incidence of cancer."

In the study, the researchers focused on strategies cells use to control activity of the phase II enzymes. "The levels of these enzymes are tightly controlled by the cellular equivalent of a dimmer switch," says Kensler. The scientists knocked out the switch — a protein called Nrf2 — in genetically engineered mice and saw the activity of phase II enzymes drop dramatically compared with mice whose "switch gene" was intact.

When they exposed both the knockout mice and normal mice to benzpyrene, a potent carcinogen in cigarette smoke, both developed tumors, but the knockouts — apparently disconnected from the protective system — had significantly more.

In a more telling demo of the system, the scientists gave both the normal and the knockout mice a drug called oltipraz along with the benzpyrene carcinogen. Oltipraz has been used for parasite infections. But it was also shown in earlier Hopkins studies to raise levels of phase II enzymes and lower cancer risk.

In the study, carcinogen-exposed normal mice on oltipraz had their tumor number cut by half. But the knockout mice were tumor-ridden, even with the protective drug. "This shows the great importance of the Nrf2 ‘switch,'" says Tsukuba University molecular biologist Masayuki Yamamoto, M.D., Ph.D.; "Without it, the mice couldn't be protected."

Earlier work by Yamamoto showed that protective chemicals, such as those in plants, work by sparking cells' release of Nrf2. Then Nrf2 activates a common DNA sequence on the genes of all phase II enzymes, switching them on.

"Scientists have tried to learn what makes some people more susceptible to cancer," Kensler adds. "They've looked at genes for single phase II enzymes here and there. But with NRf2, you have the control for all of them. With slight changes in the ‘switch,' you can get a tremendous step up in a body's sensitivity to cancer agents."

Turning the system up or down might have value, says Yamamoto. "By turning down an organism's ability to squelch carcinogens, you could get an exquisitely sensitive model for testing, say, which pollutants in the Chesapeake Bay cause tumors to form. Likewise, you could turn it up and, in theory, increase any animal's resistance to cancer or, perhaps, other diseases."

The researchers believe the system is a common, general one in many animals. "Also," says Kensler, "we think it may be part of a broader way animals deal with many types of toxicity — not just carcinogens. Toxicity plays a role in many conditions such as atherosclerosis and neurodegenerative diseases."

The studies were funded by grants from the National Institutes of Health and by gifts from the Lewis and Dorothy Cullman Foundation, New York.

The Nrf2-depleted mice were developed by Masayuki Yamamoto, M.D., Ph.D. Others on the research teams were Minerva Ramos-Gomez, Sc.M., Mi-Kyoung Kwak, Ph.D., Patrick M. Dolan, B.S. and Albena Dinkova-Kostova, Ph.D., from Hopkins; and Ken Itoh, M.D., Ph.D., from Tsukuba University in Japan.

You can access some fairly dramatic photos from this study, showing the difference in the stomach lining of normal mice given the benzpyrene carcinogen–they have some natural protection–and the knockout mice where the protective system has been destroyed. The large mass in the knockouts, which looks like mashed potato, is tumor. Go to: http://www.hopkinsmedicine.org/brocosystem.htm

Note: If no author is given, the source is cited instead.

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