• 9/6/2005
  • New York, NY
  • editorial
  • Nature Structural & Molecular Biology 12, 729 (2005)

By now everyone ought to know that smoking is bad for you. Even the United States government is seeking to hold tobacco companies accountable for the health risks of their products. Why, then, do so many people continue to use tobacco? Simply put, nicotine can make a person feel happy and relaxed, and it is as addictive as heroine and cocaine. While over 30% of smokers say they want to quit, most relapse within a few days of avoiding their tobacco product of choice, right when nicotine withdrawal symptoms reach their peak.

Help is available for unhappy smokers, from nicotine patches to behavioral therapy, but the road to a nicotine-free life is still difficult for many. Therefore, researchers are working to develop drugs to inhibit nicotine metabolism. Such compounds would, in theory, keep the level of nicotine high in the blood, thus reducing nicotine cravings. On page 822 of this issue, we see the results of some of this work—the structure of the nicotine-metabolizing enzyme cytochrome P450 2A6 in complex with an inhibitor called methoxsalen. While methoxsalen, a drug currently approved for treating psoriasis, is not being touted as the holy grail of antismoking drugs, the authors of the study believe that their structure could aid in the design of other, more suitable inhibitors.

The cytochrome P450 family of proteins comprises over 50 enzymes involved in metabolism. Potentially toxic substances are often acted upon by these enzymes to make them more water soluble and thus easier to discharge from the body. Typical reactions catalyzed by these proteins are oxidations, hydroxlations and dealkylations, and it is estimated that half of all drugs are cleared by these enzymes. Cytochrome P450 2A6 metabolizes nicotine, and it is also responsible for converting certain tobacco-specific procarcinogens into mutagenic substances. In addition to nicotine, tobacco smoke contains tar, which is made up of more than 4,000 chemicals, over 60 of which are known carcinogens. Thus, inhibiting cytochrome P450 2A6 could also have the effect of reducing the overall toxicity of tobacco smoke.

The deleterious effects of tobacco use are well known. The recent death of Peter Jennings, a well-known journalist and longtime smoker, put the spotlight on lung cancer. However, many additional problems are associated with smoking, such as emphysema, chronic bronchitis, heart disease, diabetes and sudden infant death syndrome. In June of 2005, the Centers for Disease Control and Prevention released an estimate that smoking cost the United States $92 billion in lost productivity from 1997−2001. When coupled with their estimate of smoking-related healthcare costs, a figure of over $167 billion per year emerges. Smoking also takes an obvious toll on life expectancy, reducing it by an average of 14 years.

The percentage of adults in the United States who smoke declined from 42% in 1965 to 23% in 2002. That puts the number of former smokers at approximately the same level as current smokers, 45 million each. Unfortunately, the majority of new smokers are teenagers. In 2003, United States government surveys assessed that 28% of high school students used some type of tobacco product (primarily cigarettes). More upsetting is that even younger children are starting to experiment with tobacco; approximately 13% of middle school students have used cigarettes or some other tobacco-related products.

While the tobacco industry in the United States denies targeting children, antismoking activists as well as the United States government are currently challenging that notion, both in the media and in court. In 1999, the government filed a lawsuit against tobacco companies, seeking to hold them accountable for hiding the dangers and addictiveness of their products and for marketing to children. The nearly six-year trial ended in June of this year, and a final ruling by the judge is expected sometime after October 9, 2005. Most recently, critics of the tobacco industry’s marketing practices point to the introduction in 2004 of cigarettes and chewing tobacco that taste like candy, with flavors such as berry, mint, vanilla and toffee. They argue that those flavors, packaged in eye-catching, brightly colored boxes, would appeal primarily to young consumers trying their first cigarettes, not to adults or established users.

Preventing children from smoking should be a primary focus, but also important is getting adults, the role models for the younger generation, to stop smoking. Children living in households where adults smoke are far more likely to smoke themselves. Clearly, many people have the desire to stop smoking; they just need some help. At some point, research on nicotine-metabolizing inhibitors may give them another way to ease the transition to a tobacco-free lifestyle.