REVIEW www.nature.com/clinicalpractice/gasthep Mechanisms of Disease: nicotine—a review of its actions in the context of gastrointestinal disease Gareth AO Thomas*, John Rhodes and John R Ingram INTRODUCTION Whilst the detrimental effects of smoking on health are both well known and overwhelming, there is increasing evidence that smoking actually protects against some conditions. Smokers have a lower incidence of some neuro- degenerative conditions such as Parkinson’s and perhaps Alzheimer’s diseases, 1 and gastro- intestinal disorders such as ulcerative colitis. 2 The tobacco smoker is exposed to a cocktail of over 4,000 chemicals, which makes it difficult to identify the agents responsible for the wide- ranging effects of smoking, both detrimental and otherwise. Nicotine, the best known and most ‘psychoactive’ pharmacologic ingredient, is often considered synonymous with smoking in the context of disease, but whilst some of the harmful or ‘negative’ effects might involve nico- tine, it is likely that most do not. Conversely, nicotine might be responsible for some protec- tive or ‘positive’ effects. By teasing out the role of nicotine in this conundrum it is to be hoped that we will gain a better understanding of disease mechanisms, and possibly open the door to therapeutic alternatives. THE METABOLISM AND PHARMACOLOGIC ACTIONS OF NICOTINE Nicotine is the principal alkaloid in tobacco. It is rapidly absorbed through the lungs, skin and gut, and metabolized mainly by the liver to coti- nine and other metabolites, some of which are also pharmacologically active. Nicotine is highly addictive, which explains a smoker’s craving for tobacco. An average cigarette contains 9–15 mg of nicotine, but only 1 mg or so is absorbed. Shortly after smoking, venous levels of nicotine range from 5 to 30 ng/ml, whereas arterial peaks can be as high as 80 ng/ml. The half-life of nico- tine is only about 2 h, whereas that of cotinine is about 18 h. Nicotine exerts its effects by activating nico- tinic acetylcholine receptors (nAChRs), which are classically found in the autonomic ganglia, central nervous system, neuromuscular junction, Smoking tobacco is associated with a number of gastrointestinal disorders. In some, such as Crohn’s disease and peptic ulcer disease, it increases the risk of disease and has a detrimental effect on their course. In others, such as ulcerative colitis, it decreases the risk of disease and can have a favorable effect on disease course and severity. In the eighteenth and nineteenth centuries, nicotine was used as a ‘panacea’ for various ailments, including abdominal symptoms—it is now under investigation to elucidate its role in gastrointestinal diseases that are associated with smoking. The actions of nicotine are complex; it is likely that its effects on the central nervous system, gastrointestinal tract and immune system interact with other risk factors, such as genetic susceptibility, to influence disease outcomes. This review focuses on the mechanisms of action of nicotine that might be relevant in gastrointestinal disease. KEYWORDS gastrointestinal disease, gastrointestinal tract, mechanisms, nicotine, smoking GAO Thomas is a Consultant Gastroenterologist, J Rhodes is a Professor emeritus, and JR Ingram is a doctor in the Department of Gastroenterology, at the University Hospital of Wales, Cardiff, UK. Correspondence *Department of Gastroenterology, University Hospital of Wales, Heath Park, Cardiff CF14 4XW, UK gareth.thomas2@uhw-tr.wales.nhs.uk Received 20 June 2005 Accepted 12 September 2005 www.nature.com/clinicalpractice doi:10.1038/ncpgasthep0316 REVIEW CRITERIA PubMed was searched in April 2005, using the terms “nicotine”, “gastrointestinal tract”, and “gastrointestinal disease” alone and in combination. 809 articles were identified relating to nicotine and the gastrointestinal tract; 262 referred to nicotine and gastrointestinal disease. Those articles potentially relevant to our review were obtained. In addition, review articles identified as part of the search were screened for relevant publications. Citations were chosen based on their relevance to statements in the text. SUMMARY 536 NATURE CLINICAL PRACTICE GASTROENTEROLOGY & HEPATOLOGY NOVEMBER 2005 VOL 2 NO 11 Nature Publishing Group ©2005