Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA.
J Biol Chem. 2021 Jan-Jun;296:100722. doi: 10.1016/j.jbc.2021.100722. Epub 2021 Apr 29.
Nicotine is the key addictive constituent of tobacco. It is not a carcinogen, but it drives smoking and the continued exposure to the many carcinogens present in tobacco. The investigation into nicotine biotransformation has been ongoing for more than 60 years. The dominant pathway of nicotine metabolism in humans is the formation of cotinine, which occurs in two steps. The first step is cytochrome P450 (P450, CYP) 2A6-catalyzed 5'-oxidation to an iminium ion, and the second step is oxidation of the iminium ion to cotinine. The half-life of nicotine is longer in individuals with low P450 2A6 activity, and smokers with low activity often decrease either the intensity of their smoking or the number of cigarettes they use compared with those with "normal" activity. The effect of P450 2A6 activity on smoking may influence one's tobacco-related disease risk. This review provides an overview of nicotine metabolism and a summary of the use of nicotine metabolite biomarkers to define smoking dose. Some more recent findings, for example, the identification of uridine 5'-diphosphoglucuronosyltransferase 2B10 as the catalyst of nicotine N-glucuronidation, are discussed. We also describe epidemiology studies that establish the contribution of nicotine metabolism and CYP2A6 genotype to lung cancer risk, particularly with respect to specific racial/ethnic groups, such as those with Japanese, African, or European ancestry. We conclude that a model of nicotine metabolism and smoking dose could be combined with other lung cancer risk variables to more accurately identify former smokers at the highest risk of lung cancer and to intervene accordingly.
尼古丁是烟草中主要的成瘾成分。它不是一种致癌物质，但它会促使人们吸烟，并持续接触烟草中存在的许多致癌物质。对尼古丁生物转化的研究已经进行了 60 多年。人类尼古丁代谢的主要途径是形成可替宁，这一过程分两步进行。第一步是细胞色素 P450（P450，CYP）2A6 催化的 5'-氧化，形成亚氨离子，第二步是将亚氨离子氧化成可替宁。P450 2A6 活性低的个体中尼古丁的半衰期更长，与“正常”活性的个体相比，活性低的吸烟者往往会减少吸烟强度或吸烟支数。P450 2A6 活性对吸烟的影响可能会影响一个人患与烟草相关疾病的风险。本文综述了尼古丁代谢，并总结了利用尼古丁代谢物生物标志物来定义吸烟剂量的情况。本文还讨论了一些较新的发现，例如鉴定出尿苷 5'-二磷酸葡糖醛酸转移酶 2B10 是尼古丁 N-葡糖苷酸化的催化剂。我们还描述了流行病学研究，这些研究确定了尼古丁代谢和 CYP2A6 基因型对肺癌风险的贡献，特别是在特定的种族/民族群体中，如具有日本、非洲或欧洲血统的人群。我们得出结论，尼古丁代谢和吸烟剂量模型可以与其他肺癌风险变量结合使用，以更准确地识别肺癌风险最高的前吸烟者，并进行相应的干预。
