Fast enzymes and cancer

IN ANY LARGE POPULATION EXposed to the same low levels of carcinogens–the toxins in car exhaust, for example–some individuals will succumb to cancer while others escape. The reasons for this variable vulnerability have long been a mystery. But now researchers may have solved at least part of the puzzle for one type of cancer: people with “fast” versions of an enzyme that rapidly clears carcinogens from the body are more likely to resist the effects of such toxins than are those with “slow” forms of the same enzyme.

The enzyme in question–N-acetyltransferase–is abundant in the liver. Its job is to add a molecule called an acetyl group onto toxic molecules–particularly the aromatic amines, chemicals found in cigarette smoke, automobile exhaust, and other pollutants. The acetyl group makes these compounds more soluble in water and easier to excrete in urine. But if the amines escape acetylation–as they may in people who possess a slow-acting form of the enzyme–the toxins may run into other enzymes in the liver. These enzymes tack on an oxygen atom instead of an acetyl group, which makes the molecules highly reactive. As the oxidized toxins sit in the bladder waiting to be excreted, they can bind to bladder-cell DNA and cause it to mutate, setting the stage for bladder cancer later on.

An international research team recently took a close look at this process. The study focused on 97 healthy men, 47 of whom smoked. Each man drank a cup of coffee and then supplied a urine sample. To see which were slow acetylators and which were fast, the researchers measured levels of acetylated caffeine in their urine. (Caffeine is acetylated in the liver, but unlike the aromatic amines, it isn’t oxidized, so it doesn’t harm the bladder’s DNA.) At the same time, they measured how much of a common aromatic amine had bound to DNA in the men’s bladder cells. Because the men all came from the same city–Turin, Italy’s leading car-manufacturing center–they were presumably all exposed to similar amounts of the toxin in the ambient environment. But the smokers would have inhaled a lot more of it than the nonsmokers.

The results were just what you’d expect. The researchers found that the men who smoked and had slow versions of the enzyme–evidenced by low levels of acetylated caffeine in their urine–also had the highest levels of the amine air pollutant stuck to their DNA, indicating that toxins weren’t being efficiently flushed out of their bodies. Those who smoked and were fast acetylators had lower levels of the bound pollutant. Nonsmoking slow acetylators had still lower levels, while nonsmoking fast acetylators had the lowest of all.

Glenn Talaska, a toxicologist at the University of Cincinnati who participated in the study, emphasizes that exposure to toxic chemicals is still far more important than a person’s acetylator status: heavy smokers, for instance, are at high risk of bladder cancer even if they are fast acetylators. Nevertheless, such new diagnostic tools can be lifesavers. “Previously you had to wait for the epidemiology to show you individuals who are going to be at risk, and then it’s too late for those folks–they’ve got cancer already,” says Talaska. “What we’re finding is that we’ve got molecular tools now with which we can screen populations before they develop the disease.”

Humans Are Too Bony

Popular lore and thriller movies like Jaws portray white sharks as indiscriminate hunters that eat anything in sight, leaving behind only a pool of blood. But according to Peter Klimley, the creatures are in fact very picky eaters and may not even eat humans. Klimley, an animal behaviorist at Bodega Marine Laboratory near San Francisco, first noticed the fastidiousness of white sharks as he was trying to trick one into swallowing a sound transmitter hidden in a sheep carcass. (The transmitter would allow Klimley to track the shark’s movements.) Nine times a shark bit the carcass, swam with it awhile, but then released it. Puzzled, Klimley started asking his sharkbiologist colleagues how they got the animals to swallow. He noticed a trend: White sharks swallowed only bait with a high fat content, such as blubbery whale meat, seals, and sea lions. Leaner animals, such as birds, otters, and sheep, were bitten but then released. One experiment used four seal carcasses, including one that had been stripped of its fat; the sharks swallowed all but the fatless carcass. Sharks, Klimley suspects, favor fat because it has twice the energy content of muscle; their selective bite may explain why they are able to grow twice as fast as related species. It may also explain why humans are bitten but not eaten (although Robert Maxwell must have been tempting). Says Klimley: “You don’t hear about instances of a whole person being pulled out of a white shark stomach.”

COPYRIGHT 1994 Discover

COPYRIGHT 2004 Gale Group

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