Murphy Sharon E
Department of Biochemistry, Molecular Biology, and Biophysics and Masonic Cancer Center, University of Minnesota , Minneapolis, Minnesota 55455, United States.
Chem Res Toxicol. 2017 Jan 17;30(1):410-419. doi: 10.1021/acs.chemrestox.6b00387. Epub 2016 Nov 22.
Nicotine is the primary addictive agent in tobacco, and P450 2A6 (gene name: CYP2A6) is the primary catalyst of nicotine metabolism. It was proposed more than 20 years ago that individuals who metabolize nicotine poorly would smoke less, either fewer cigarettes per day or less intensely per cigarette, compared to smokers who metabolize nicotine more efficiently. These poor metabolizers would then be less likely to develop lung cancer due to their lower exposure to the many carcinogens delivered with nicotine in each puff of smoke. Numerous studies have reported that smokers who carry reduced activity or null CYP2A6 alleles do smoke less. Yet only in Asian populations, both Japanese and Chinese, which have a high prevalence of genetic variants, has a link between CYP2A6, smoking dose, and lung cancer been established. In other ethnic groups, it has been challenging to confirm a direct link between P450 2A6-mediated nicotine metabolism and the risk of lung cancer. This challenge is due in part to the difficulty in accurately quantifying smoking dose and accurately predicting or measuring P450 2A6-mediated nicotine metabolism. Biomarkers of nicotine metabolism and smoking exposure, including the ratio of trans-3-hydroxycotine to cotinine, a measure of P450 2A6 activity and plasma cotinine, or urinary total nicotine equivalents (the sum of nicotine and six metabolites) as measures of exposure are useful for addressing this challenge. However, to take full advantage of these biomarkers in the study of ethnic/racial differences in the risk of lung cancer requires the complete characterization of nicotine metabolism across ethnic/racial groups. Variation in metabolism pathways, other than those catalyzed by P450 2A6, can impact biomarkers of both nicotine metabolism and dose. This is clearly important for smokers with low levels of UGT2B10-catalyzed nicotine and cotinine glucuronidation because the UGT2B10 genotype influences plasma cotinine levels. Cotinine is not glucuronidated in 15% of African American smokers (compared to 1% of Whites) due to the prevalence of a UGT2B10 splice variant. This variant contributes significantly to the higher plasma cotinine levels per cigarette in this group and may also influence the accuracy of the 3HCOT to cotinine ratio as a measure of P450 2A6 activity.
尼古丁是烟草中的主要成瘾成分，而细胞色素P450 2A6（基因名称：CYP2A6）是尼古丁代谢的主要催化剂。20多年前有人提出，与尼古丁代谢效率较高的吸烟者相比，尼古丁代谢能力较差的个体吸烟量会更少，要么每天吸烟支数更少，要么每支烟的吸烟强度更低。由于这些代谢能力较差的个体每次吸烟时接触到的与尼古丁一起的多种致癌物较少，他们患肺癌的可能性也较小。许多研究报告称，携带CYP2A6活性降低或无效等位基因的吸烟者吸烟量确实较少。然而，只有在日本人和中国人等遗传变异患病率较高的亚洲人群中，才确立了CYP2A6、吸烟剂量与肺癌之间的联系。在其他种族群体中，要证实细胞色素P450 2A6介导的尼古丁代谢与肺癌风险之间的直接联系一直具有挑战性。这一挑战部分归因于准确量化吸烟剂量以及准确预测或测量细胞色素P450 2A6介导的尼古丁代谢存在困难。尼古丁代谢和吸烟暴露的生物标志物，包括反式3-羟基可替宁与可替宁的比值（一种衡量细胞色素P450 2A6活性的指标）、血浆可替宁，或尿中总尼古丁当量（尼古丁和六种代谢物的总和，作为暴露的指标），有助于应对这一挑战。然而，要在肺癌风险的种族/民族差异研究中充分利用这些生物标志物，需要全面了解不同种族/民族群体的尼古丁代谢特征。除了由细胞色素P450 2A6催化的代谢途径外，其他代谢途径的变异也会影响尼古丁代谢和剂量的生物标志物。这对于UGT2B10催化的尼古丁和可替宁葡萄糖醛酸化水平较低的吸烟者显然很重要，因为UGT2B10基因型会影响血浆可替宁水平。由于UGT2B10剪接变异的普遍存在，15%的非裔美国吸烟者（相比之下白人中为1%）的可替宁不会发生葡萄糖醛酸化。这种变异在很大程度上导致了该群体中每支烟的血浆可替宁水平较高，并且可能还会影响3HCOT与可替宁比值作为细胞色素P450 2A6活性指标的准确性。
