Publications

Federal District Judge Gladys Kessler found that the major American tobacco companies violated the Racketeer Influenced and Corrupt Organizations Act, defrauding the public by deceptively marketing "light" cigarettes. Judge Kessler's ruling prohibits the defendant tobacco companies from implying health benefits through using misleading terms such as "light", "mild" or "low-tar", or through other indirect means. This ruling could be interpreted narrowly as simply prohibiting certain words, or could be interpreted broadly as prohibiting implying health benefits by any other means, including colour, numbers or images. It is important to include indirect communications, as tobacco companies easily circumvent narrow advertising bans. A narrow interpretation would be inconsistent with the court's comprehensive factual findings of fraudulent intent by the industry. A broad interpretation of the Order, including existing brands, line extensions and new tobacco products such as potential reduced exposure products that are marketed as "cigarettes", Judge Kessler's order could make a substantial contribution to protecting health.

Research has shown that the toxicity of sidestream cigarette smoke, the primary constituent of secondhand smoke, increases over time. To find potential mechanisms that would explain the increase in sidestream smoke toxicity over time, we analyzed unpublished research reports from Philip Morris Co. using the internal tobacco industry documents now available at the University of California San Francisco Legacy Tobacco Documents Library and other Web sites. Unpublished research from Philip Morris Tobacco Company shows that 4-(methylnitrosamino)-I-(3-pyridyl)-1-butanone (NNK), a highly carcinogenic tobacco-specific nitrosamine, can form in sidestream cigarette smoke after it has been released into ambient air. In experiments done between 1983 and 1997, Philip Morris scientists measured the concentration of NNK in sidestream smoke in a sealed stainless steel test chamber at initial particle concentrations of 24 mg/m(3) over the course of 6 to 18 h. They repeatedly showed that airborne NNK concentrations in sidestream cigarette smoke can increase by 50% to 200% per hour during the first 6 h after cigarettes are extinguished. Two experiments done in a real office showed that NNK concentrations increase for the first 2 h after cigarettes are extinguished. If NNK formation also occurs in the lower smoke concentrations observed in real smoking environments, these results suggest that nitrosation of nicotine and/or nicotine breakdown products in aging secondhand smoke is a significant contributor to nitrosamine exposure in humans.

The molecular and functional diversity of G protein-coupled receptors is essential to many physiological processes. However, this diversity presents a significant challenge to understanding the G protein-mediated signaling events that underlie a specific physiological response. To increase our understanding of these processes, we sought to gain control of the timing and specificity of G(s) signaling in vivo. We used naturally occurring human mutations to develop two G(s)-coupled engineered receptors that respond solely to a synthetic ligand (RASSLs). Our G(s)-coupled RASSLs are based on the melanocortin-4 receptor, a centrally expressed receptor that plays an important role in the regulation of body weight. These RASSLs are not activated by the endogenous hormone alpha-melanocyte-stimulating hormone but respond potently to a selective synthetic ligand, tetrahydroisoquinoline. The RASSL variants reported here differ in their intrinsic basal activities, allowing the separation of the effects of basal signaling from ligand-mediated activation of the G(s) pathway in vivo. These RASSLs can be used to activate G(s) signaling in any tissue, but would be particularly useful for analyzing downstream events that mediate body weight regulation in mice. Our study also demonstrates the use of human genetic variation for protein engineering.