Scientists Finger A Molecular Kingpin In Body's Response To Cigarettes

November 23, 1998

Using genetically modified "knock-out" mice, scientists at the University of Rochester have produced the strongest evidence yet implicating a specific gene -- the same one that makes us susceptible to the pollutant dioxin -- as a vital link in the chemical cascade whereby cigarette smoke causes cancer. The finding comes thanks to a batch of genetically engineered mice normal in every way except for the deletion of the gene for the aromatic hydrocarbon, or AH, receptor; these mice had no damage from the same levels of cigarette smoke that caused significant gene damage in their normal brethren.

The work, reported in the November issue of Carcinogenesis, clarifies how cigarette smoke has an impact on our molecular machinery and should help researchers in their efforts to prevent genetic damage from the biochemical assault posed by smoking.

The team at the University's Environmental Health Science Center cautions that researchers must perform longer-term, larger studies and check in additional ways for evidence of gene damage to understand precisely how cigarette smoke damages our DNA, including the AH receptor's role. However, "It's quite possible that the AH receptor is one of the body's master switches that governs those pathways that control much of the gene damage from cigarette smoke," says principal author Tom Gasiewicz, professor of environmental medicine.

With every breath of cigarette smoke, the body is confronted by more than 4,000 chemicals; animals like humans and mice break some down into harmless byproducts and turn others into more dangerous compounds that wreak havoc throughout the body, breaking up or binding to our DNA and turning on or off important genes. Cancer typically develops because of such damage to several genes. While scientists have long known that every puff of cigarette smoke causes a molecular melee that plays a role in one-third of all cases of cancer, sorting out the primary culprits has been difficult.

Enter the dioxin research group headed by Gasiewicz, an internationally recognized expert on dioxin who occasionally sports a cap embossed with the words, "Team Dioxin." The chemical is now found in low levels in all animals, including humans; it enters the body mainly through the foods we eat, with its ultimate source in the production of plastics and electronic equipment, herbicides, and combustion from automobiles, power plants and incinerators.

For two decades Gasiewicz has studied how dioxin binds to and manipulates the AH receptor, which plays a key role in determining how our body reads its DNA and controls many genes. Graduate student Stephen Dertinger, who had recently helped develop a technique that uses lasers to assess gene damage while working at Litron Laboratories, suggested taking a look at the effects of cigarette smoke, which counts dioxin-like compounds among its constituents. So the team set out, with funding from the National Institute of Environmental Health Sciences.

Gasiewicz and Dertinger studied "knock-out" mice, animals that scientists have especially crafted for research by deleting a specific stretch of DNA. These mice were supplied by long-time collaborator Allen Silverstone of the SUNY Health Science Center in Syracuse; the animals trace their lineage back to the National Cancer Institute, whose researchers were the first to knock out the AH receptor. For three days the team exposed 20 young adult mice to the equivalent amount of smoke particulates that a human receives from smoking six or seven cigarettes a day.

"These animals were exposed to the same complex mixture of chemicals found in cigarette smoke, not just one highly purified chemical constituent. This is a more realistic model of exposure and is an important distinction between this and many other studies," says Dertinger. After exposure the team analyzed each animal's blood cells, using a laser to measure gene damage faster and with greater sensitivity than conventional microscope-based methods.

While normal mice showed significant amounts of gene damage, mice without the AH receptor showed none. "We were very surprised. This suggests that the genes responsible for DNA damage from cigarettes are controlled predominantly by this receptor," says Gasiewicz.

Gasiewicz and Dertinger note that the result covers only one type of gene damage in a single type of tissue. Specifically, the team measured chromosome breaks in blood cells created in the bone marrow. The team plans to study damage in other tissues, such as the liver and lungs. Gasiewicz also says that longer-term studies to look for some of the ultimate products of damaged genes -- tumors -- are necessary.

"Our results show that the AH receptor definitely plays an important role, but more work is necessary before we conclude that it's the most important factor mediating genetic damage from cigarettes," adds Dertinger.

The findings complement recent work by other researchers who have shown that people with an abundance of enzymes known as CYP1A1 or P450 cytochrome molecules are more prone to developing cancer from smoking. The AH receptor turns on these enzymes, and it's long been considered a prime suspect in smoking-related gene damage; a few years ago a team from the University of California at Davis showed in the laboratory that the receptor seems to play an important role in the process. The Rochester team's results are the first to demonstrate the link so dramatically in animals.

"This is a significant study," says Gary Gairola, research professor in the College of Pharmacy at the University of Kentucky and an expert on cigarette smoke toxicology. "The team has used a clear endpoint, micronucleus formation, to cleverly demonstrate the role of the AH receptor in cigarette smoke-induced genetic damage."

The team also discovered a synergistic effect between cigarette smoke and dioxin-like chemicals: The more that such chemicals bind to the AH receptor, the more the receptor churns out enzymes that make cigarette smoke harmful to our bodies. "It's a double whammy," says Gasiewicz: "The dioxins now present in our environment may strengthen cigarettes' cancerous kick."

Intimate knowledge of the molecular targets of cigarette smoke suggests an intriguing line of research: a smoking vaccine, a compound that would somehow protect against the ravages of tobacco smoke. The team has published several papers on designs of AH receptor antagonists, molecules that would tie up the body's receptors and make the body immune to chemicals in cigarette smoke that target the receptor. The team's compounds are very similar to molecules known as "flavonoids" found in foods like broccoli, cabbage and soybeans, all known cancer fighters.

"We all know people who smoked their whole lives but never got lung cancer," says Gasiewicz. "One of the reasons may be differing amounts of receptors such as the AH receptor. Or those people may be exposed to drugs or chemicals in their diet, similar to the antagonists we're designing, that alter the metabolism of cigarette smoke.

"Of course, the best way to limit the harmful effects of cigarette smoke is to avoid exposure completely. Don't smoke: It's that simple."

University of Rochester

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