Gene Linked to Cancer-Causing Chemicals

UCLA researchers have identified and cloned the gene for a protein that plays a key role in the cancer-causing process of many chemicals, including those in cigarette smoke--a development that could lead to tests to identify people at highest risk from smoking.

It may also lead to new ways to protect people who are exposed to chemical carcinogens in industrial environments, thereby making the workplace safer.

Among the chemicals that the protein interacts with are dioxins, widely considered the world’s most toxic chemicals. Dioxins, for example, are thought to have caused cancer among U.S. troops in Vietnam exposed to the herbicide Agent Orange.

The identification of the gene, reported in today’s Science by UCLA pathologist Oliver Hankinson and his associates, “is a valuable contribution,” said pharmacologist Donald Barnes of the Environmental Protection Agency. “This is the first chapter of the story and we’re only just beginning to learn about the cast of characters.”

“This will give us a much better idea of what is actually going on in the nucleus of the cell,” the key site of attack for cancer-causing chemicals, said pharmacologist Allan Okey of the University of Toronto.

The discovery also comes at a time when the EPA is reconsidering the process by which it regulates the amount of dioxins in the environment. A variety of new research at UCLA and elsewhere has suggested that there is a certain “threshold” level of dioxins, below which humans may not be adversely affected.

In the wake of this new understanding, EPA officials are considering changing the rules governing the amount of dioxins to which people can be exposed, perhaps increasing the limits.

Dioxins are contaminants produced in extremely small amounts as byproducts of various industrial processes, such as the manufacture of herbicides and paper, as well as in the combustion of a variety of materials.

In March of last year, the U.S. Department of Veterans Affairs agreed to compensate about 1,600 Vietnam veterans who developed non-Hodgkin’s lymphoma, a cancer of the lymph glands that was thought to have been produced by their exposure to Agent Orange--although the government has never admitted that was the cause.

Environmentalists have also opposed the construction of many municipal and industrial incinerators because of the likelihood that they would emit dioxins.

Dioxins and other chemicals have been associated with as many as 80% of all cancers in the United States, Hankinson said, with the chemicals in cigarette smoke alone accounting for 30%.

Cloning the gene and the newly identified protein, which Hankinson calls by the acronym arnt, gives researchers large quantities of the materials to work with.

Hankinson has shown that the arnt protein works in conjunction with the dioxin receptor, a protein on the surface of cells that binds specifically to dioxin and certain other toxic chemicals. The complex of the arnt protein and the receptor carries the toxic chemicals to the nucleus of cells. Once there, they interact with the individual’s DNA to initiate a complex process that leads to tumor formation.

The arnt protein works with three broad classes of cancer-producing chemicals:

* Polychlorinated aromatic hydrocarbons, a family that includes dioxins, polychlorinated biphenyls or PCBs, and the pesticide DDT.

* Polycyclic aromatic hydrocarbons, which are found in cigarette smoke and smog. They are also produced by smelters, coke ovens and roofing compounds.

* Heterocyclic amines, which are found in cooked meats.

At least 10 laboratories have been searching for the arnt protein and the dioxin receptor.

One reason is because a variety of evidence suggests that people at the greatest risk of developing lung cancer have the highest number of dioxin receptors on their cells. Because the receptor has not yet been isolated, however, there was no way to identify these people.

But identification of the arnt protein should make it possible to screen populations for such people because their protein level will also be elevated. They could then be given extra encouragement to quit smoking.

Furthermore, Hankinson has shown in animals that blocking the activity of the arnt protein prevents cancer-causing chemicals from reaching the nucleus of the cells, where they do damage. It might be possible to block the activity of the protein in humans with drugs, thereby protecting people from cancer.

Researchers also have another intriguing mystery to solve, Barnes said. No one has been able to identify a natural function for the dioxin receptor or the arnt protein.

“Why did God put that there?” he asked. “Obviously he had something in mind, and it was probably not (dioxin). That’s been the subject of active investigation for more than a decade and we still don’t know.”