Ah-receptor: impt. ciggie smoke cancer gene

[ttweed@wildrockies.org (Tony Tweedale)]

them good old aryl hydrocarbons in combustin products...
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Gene Is Vital Link Between Smoking And Cancer

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." - By Tom
Rickey

[Contacts: Tom Gasiewicz, Steve Dertinger]

24-Nov-1998

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