Cigarettes' Smoking Gun?

Acrolein, one of the 4,000 constituents of cigarette smoke, has been found unexpectedly to cause DNA damage in the gene for the infamous tumor-suppressor p53, which is often disrupted by cancer. In particular, the pattern of DNA mutations caused by acrolein mimics what is often found in human lung cancer samples (Proc. Natl. Acad. Sci. USA, DOI: 10.1073/pnas.0607031103).

"If cigarette smoke is the weapon that causes lung cancer, then these mutations are fingerprints on the knife," says author Moon-shong Tang of New York University School of Medicine, in Tuxedo. Tang was also involved in identifying another cigarette-smoke component that can induce such mutations: a metabolite of a polycyclic hydrocarbon called benzo[a]pyrene. Acrolein is present in cigarette smoke in levels of up to 1,000 times greater than benzo[a]pyrene.

Acrolein alkylates guanine residues in DNA, causing a pattern of DNA damage that is "remarkably similar to that observed in the commonly mutated p53 gene isolated from lung tumors in smokers," comments Stephen S. Hecht of the University of Minnesota Cancer Center.

"These results are tantalizing," Hecht says. "But there is also a conundrum." Hecht points to an exhaustive review by the International Agency for Research on Cancer that did not find acrolein to be carcinogenic to laboratory animals.

"It is possible that rodent metabolism of acrolein is different than in humans, but much more research is warranted," Hecht says. "Collectively, Tang's data provide intriguing leads pertinent to a possible role of acrolein in smoking-induced cancer in spite of its apparently low carcinogenicity in laboratory animals."

Gerd P. Pfeifer of Beckman Research Institute suggests looking directly for acrolein-DNA adducts in lung biopsy samples from smokers. "The carcinogenicity of acrolein in animal models may need to be reevaluated," he says.

There are 45 million smokers in the U.S. and 1.2 billion worldwide. Careful analysis of all harmful compounds in cigarettes could ultimately lead to regulations that would decrease the possibility of cancer development, Hecht says.