Beyond Vitamins

YOU THERE-YOU BREAKFASTING ON A CHOCOLATE doughnut with a chaser of vitamin E. And you-scarfing down the burger and fries and feeling virtuous with your dessert of high-potency megadose stress-formula multivitamins. You, too-thinking that that nightly aperitif of vitamin C absolves you of the nutritional sins you commit every dinner time with a consenting T-bone.

You should have listened to your mother.

Having shown that Mom was right about chicken soup curing colds, and cranberry juice helping bladder infections, scientists are catching up on an even more important front: by "balanced diet," she certainly did not mean one vitamin from the white pile, and one from the red, and one from the yellow. It is whole foods-especially fruits and vegetables-that pack the disease-preventing wallop. That's because they harbor a whole ratatouille of compounds that have never seen the inside of a vitamin bottle for the simple reason that scientists have not, until very recently, even known they existed, let alone brewed them into pills.

The compounds are called "phytochemicals" ("phyto" is derived from the Greek word for plant). Every slice of tomato and every bite of apricot contains thousands of them, chemical tongue twisters that evolved because they protect plants from sunlight but which, through a beneficent quirk of nature, turn out to affect people. In the world where science merges with health, phytochemicals are the next big thing. The National Cancer Institute is so excited it has launched a multimillion-dollar project to find, isolate and study them. Private firms are eying them as a health blockbuster. For among their most intriguing talents is an apparent ability to block the multiple processes that lead to cancer. "There is growing evidence," says Devra Lee Davis, senior science adviser at the U.S. Public Health Service, "that these natural products can take tumors and defuse them ... They can turn off the proliferative process of cancer."

This pioneering science couldn't have hit at a better time. People healthier than butter (or not); oat bran will save you (or won't); a little alcohol will keep heart attacks at bay (but give you breast cancer). just last week, in The New England Journal of Medicine, a long-awaited study of the effects of the popular vitamins known as antioxidants delivered a decidedly pessimistic message. "We should have a moratorium on unsubstantiated health claims for antioxidants and cancer," says Dr. Julie Buring of Brigham and Women's Hospital in Boston. Amid all the debate, phytochemicals offer the next great hope for a magic pill, one that would go beyond vitamins.

Last week researchers nailed down the cancer-preventing value of one of the phytochemicals. It is a compound in broccoli called sulforaphane, and it seems to keep lab animals from getting breast cancer. "The results are quite dramatic," says Dr. Paul Talalay of Johns Hopkins Medical Institutions. "Far fewer animals [given sulforaphane] developed tumors." Two years ago Talalay added sulforaphane to human cells growing in a lab dish and showed that it boosted synthesis of anticancer enzymes. Now, in the current Proceedings of the National Academy of Sciences, his team reports that the broccoli compound protects living animals against cancer. Of 25 rats injected with a carcinogen known as DMBA, 68 percent got mammary tumors. Of 39 animals that were also injected with low or high doses of sulforaphane, only 35 percent and 26 percent, respectively, did. Sulforaphane is found not only in broccoli but in cauliflower, Brussels sprouts, turnips and kale. Neither microwaving nor cooking nor hollandaise seems to destroy it.

Even more intriguing, Hopkins chemistry professor Gary Posner made a synthetic version of sulforaphane. Chalk one up to better living through chemistry: Posner's sulforaphane look-alike is even better than nature's. Only one quarter of the animals injected with the lab-made compound got breast tumors. "And the synthetic versions are easier to produce than sulforaphane and are more stable," says the proud Posner. Now all he has to do is figure out how to put it into rum-raisin ice cream.

Early '90s research with cells in a lab dish led biochemists to suspect that both sulforaphane and its synthetic version work their magic by boosting the activity of "phase 2 enzymes." These enzymes detoxify carcinogens by hooking them up to molecules that act like a furniture mover's dolly. Within hours of the broccoli's arrival in the stomach, carcinogens are wheeled out of the cells before they can cause harm (diagram).

If biologists have learned anything about cancer over the last two decades, it is that the disease is a multistep process. In fact, a cell has to jump through so many biochemical hoops to become malignant, it is amazing anyone ever gets cancer (page 48). But people do-1,170,000 new cases in this country last year alone. And while the multiplicity of steps has frustrated biologists seeking the cause of malignancies, it is a rich lode for researchers trying to prevent cancer. Phytochemicals seem able to throw a biochemical wrench into one or more of the mechanisms leading to a tumor. "At almost every one of the steps along the pathway leading to cancer," says epidemiologist John Potter of the University of Minnesota, "there are one or more compounds in vegetables or fruit that will slow up or reverse the process."

Just-discovered chemicals in tomatoes have perfected a first-strike capability. Scientists at Cornell University reported this year that two of tomatoes' estimated 10,000 phytochemicals, called p-coumaric acid and chlorogenic acid, snuff out the formation of cancer-causing substances. During digestion, the body routinely makes compounds, called nitrosamines, out of nitric oxide and components of protein called amines. The tomato acids act like Dustin Hoffman in "The Graduate": they grab hold of the nitric acid and whisk it out of the church-er, cell-before it can go through with its chemical marriage to amines. juice fanatics take note: when Cornell's Joseph Hotchkiss gave volunteers tomato juice, their bodies made fewer nitrosamines. "The whole tomato is more effective against [carcinogen] formation than just the vitamin C component," says Hotchkiss. "You can't have a lousy diet and take a few vitamins and get the same benefit." P-coumaric and chlorogenic acids are in many fruits and vegetables, including green peppers, pineapples, strawberries and carrots. They hold up fine with cooking. But what good do cancer-fighting molecules do for the humble tomato? They seem to protect it from otherwise harmful sunlight.

If you can't keep carcinogens from forming in the first place, as tomatoes do, or boot them out of the cell, as broccoli does, it helps to disarm them. Enter a photochemical with the no-nonsense name phenethyl isothiocyanate (PEITC). A cousin of the broccoli chemical, it, too, lurks in vegetables such as cabbage (where it survives the conversion to cole slaw and sauerkraut) and turnips. PEITC inhibits lung cancer caused by chemicals in mice and rats, reports Gary Stoner of Ohio State University, by offering itself as a sacrificial lamb to voracious enzymes in cells called P450s. P450s munch on substances arriving via food, drink, smoke or air, breaking them into fragments that bind to a cell's DNA. That can cause mutations in critical genes and, in the worst case, unleash the runaway growth of cancer. But the turnip chemical throws itself into the biochemical jaws of P450s, keeping these enzymes from creating carcinogens. In fact, PEITC can protect DNA from a potent carcinogen in tobacco smoke. A phytochemical in strawberries, grapes and raspberries also neutralizes carcinogens before they can invade DNA. It is called ellagic acid.

Even if these early defenses fail, there is yet another step on the road to cancer where phytochemicals can intervene. One little tumor never killed anyone; the danger lies in lumps that grow, invade the bloodstream and send colonists throughout the body. That is how breast, prostate and other solid tumors kill. But the original lump cannot grow without supply lines-capillaries that bring oxygen and other nutrients. Last year German researchers announced that they had isolated a chemical in soybeans that prevents these vital supply lines from forming. Called genistein, it might one day be copied in the lab and given to people to prevent small tumors from growing. In fact, the lack of genistein may explain why Japanese men who relocate to the West and adopt a soy-poor diet for even a few years have a greatly elevated risk of prostate cancer: without genistein, tiny tumors are no longer deprived of the blood vessels that let them grow.

Almost every bin in the produce aisle offers a rich lode for phytochemists to mine. A phytochemical in cauliflower and its ilk seems to cut the risk of breast cancer by acting on a precursor to the female hormone estrogen. Called indole-3-carbinol, it triggers enzymes that nudge the precursor to break down into a harmless form of estrogen rather than the form linked to breast cancer. An amount equal to that in half a head of cabbage might do the trick. But in case anyone wants to make a mega-indole-3 pill, food-science professor George Bailey of Oregon State University warns that in some cases indole-3 may actually increase the risk of other cancers. Onion and garlic contain allylic sulfide, which ratchets up a family of enzymes that detoxifies carcinogens. Capsaicin, in hot peppers, keeps toxic molecules from attaching to DNA, which can initiate cancer; so does a phytochemical in turmeric and cumin. And almost every fruit and vegetable, from berries to yams to citrus and cucumbers, contains flavonoids. In a cellular version of musical chairs, these compounds race to sites on the cell where cancer-causing hormones (including estrogen) attach themselves. When the music stops, the flavonoids keep the hormones from sitting down on the cell's surface.

For all their talents, phytochemicals are not omnipotent. Even lifelong vegetarians get cancer. But if further evidence were needed that the best bet for health is a whole mix of foods and the phytochemicals therein, it came last week. A study by researchers at NCI and Finland's National Public Health Institute showed that a few vitamins won't undo the damage caused by heavy smoking. The study followed 29,000 Finnish men over 50, long-term smokers all, who received vitamin E, beta carotene, both or neither for five to eight years. Although both C and E are antioxidants-its boosters claim that they fight aging and cancer and just about everything else short of communism-they proved no match for cigarettes. The men on beta carotene got 18 percent more lung cancers than those receiving placebos; those on vitamin E suffered 50 percent more fatal strokes. "These supplements," write the researchers, "may actually have harmful as well as beneficial effects."

Which is not to say that those who refrain from assaulting their lungs with the 43 carcinogens in tobacco smoke should write off antioxidants. The press has a tendency to treat every new scientific study as the Virgin Birth, as if no other research had come before. in this case, lots of antioxidant studies have (box, page 47). It always pays to take a single scientific study with a grain of salt (unless you have high blood pressure).

If there is a take-home message in all this, it is the old saw about eating a diet rich in fruits and vegetables. "That's what your mother told you, but you never believed there was good scientific research supporting it," says epidemiologist Gladys Block of the University of California, Berkeley. "Now there is." Although no long-term study in humans has shown that any particular phytochemical retards cancer, the lab results dovetail perfectly with about 200 studies linking diets rich in all sorts of fruits and vegetables with a lower risk of cancer. It's not necessary to hold your nose and gulp a stalk of broccoli, George Bush: even raspberries and pineapples harbor these lifesavers. And since every leaf of arugula and bunch of grapes contains thousands of phytochemicals, the produce aisle should offer successful prospecting for years to come. Will the phytochemicals one day be synthesized and put into pills? Will the sun rise tomorrow? "Everyone is looking for one magic compound," says NCI's Dr. Carolyn Clifford. "That may be wishful thinking." But perhaps Americans will realize that taking a tablet, be it an old-fashioned vitamin or a fancy new phytochemical, instead of the recommended five daily servings of fruits and vegetables, is nutritional madness. If nothing else, the smoking Finns have raised a cautionary flag about isolated supplements. Better you should listen to Mother.

Within hours after being eaten, sulforaphane, one of broccoli's cancer-fighting phytochemicals, enters the blood stream. It circulates and triggers one of the body's defense systems.

The road to cancer can begin with a carcinogenic molecule-from food, drink, air or smoke-invading a cell.

When sulforaphane reaches the cell, it activates a group of proteins called phase 2 enzymes.

The enzymes burst into action, attaching the carcinogen to a molecule that whisks it out of' the cell, headed for oblivion.

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