Nicotine metabolism may spawn carcinogen.

Chalk up another potential way for smoking tobacco to cause lung cancer. A new study indicates that the body can metabolize nicotine into products that the lungs subsequently may convert into a potent carcinogen.

This still speculative suggestion may Pose a challenge for companies trying to develop cigarettes with a reduced risk of causing cancer. The researchers say their work doesn't imply that people trying to quit smoking should abandon the short-term use of nicotine patches and gum.

"It's a heck of a lot better to use nicotine-replacement therapy than to smoke--by far," emphasizes study coauthor Sharon E. Murphy of the University of Minnesota Cancer Center in Minneapolis.

Nicotine underlies the addictive nature of cigarettes and other tobacco products. It also indirectly contributes to their carcinogenic properties. The curing of tobacco, for example, can produce tumor-causing compounds, called nitrosamines, from nicotine. Burning tobacco, as in a cigarette, has the same result.

Pure nicotine that enters the body has not been thought to be carcinogenic. Murphy and her colleagues, however, now offer evidence that enzymes in people can convert nicotine into aminoketone, the natural precursor of NNK. Animal tests have shown that this nitrosamine causes lung cancer.

Scientists have long known that the human body initially metabolizes about 90 percent of its nicotine load into cotinine, which is then further metabolized into a variety of other compounds. In previous work, Murphy, her colleague Stephen S. Hecht, and their coworkers had found that urine of smokers and people wearing nicotine patches contains two nicotine metabolites, keto acid and hydroxy acid, but that these compounds didn't derive from cotinine.

"If you give people cotinine and look for keto acid, you don't find it," says Murphy.

Reporting in an upcoming issue of the PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, the investigators show that bits of liver cells, which contain nicotine-metabolizing enzymes, can convert nicotine into keto acid without going through a cotinine stage. They further demonstrate that one of the enzymes, known as cytochrome P450 2A6, participates in this process by making aminoketone, NNK's precursor.

The investigators suspect that this novel metabolic pathway also functions in the lung. There's a lung-specific enzyme similar to 2A6, notes Murphy. Her group is now investigating whether this enzyme generates aminoketone from nicotine.

The medical relevance of this new-found metabolic pathway remains unclear. Scientists don't know how much of the aminoketone generated in the body becomes the carcinogenic NNK. Indeed, people using nicotine patches don't have elevated concentrations of NNK in their urine, Hecht finds.

It's hard to prove absolute safety, but this patch study is "reassuring," says Jack Henningfield of Johns Hopkins University School of Medicine. Henningfield, who has reviewed nicotine's safety record, notes that when people in Sweden switched to smokeless tobacco that's naturally low in nitrosamines, they drastically reduced their risk of mouth, head, and neck cancers.

"These people are still getting huge amounts of nicotine per day," says Henningfield.

However, such work doesn't dismiss the possibility that some lung cancer comes from NNK spawned in the lungs by nicotine. "It's not a major pathway in the total person. The question becomes, Is it important in a specific tissue?" says Murphy. The activity of nicotine-metabolizing enzymes varies considerably, so a subset of people might produce significant amounts of NNK, she adds.

Researchers suggest that concerns about nicotine itself may become important as companies begin to market cigarettes with tobacco prepared in ways that reduce nitrosamines. "What this [finding] implies is that even if you get tobacco free of nitrosamines, you can make a certain amount of them [in the body] just from the exposure to nicotine," notes Harold Seifried of the National Cancer Institute in Bethesda, Md.