Oxidant Exposure and Related Harm from Tobacco Smoke

摘要 吸烟的毒性和对健康的负面影响是由于吸入了一种复杂的 7000种化学品，包括许多有毒物质和致癌物质，被列入FDA有害和潜在的 有害成分(HPHCs)。氧化剂是烟草烟雾中富含的一种主要毒物， 被认为在慢性阻塞性肺疾病、心血管疾病和癌症等与烟草相关的疾病的发展中发挥关键作用 通过产生氧化应激/损伤和炎症。然而，特定的氧化剂最 责任仍不清楚。虽然几种氧化剂包括在HPHC清单上(例如，羰基)，一种 大多数反应性的、破坏性的和丰富的类，自由基类，没有被代表。最近我们发现， 不同卷烟品牌之间的自由基传递差异很大(12倍)，受产品的影响很大 设计(如烟草品种)和吸烟行为，在其他受欢迎的易燃产品中也很高 包括一些过滤过的雪茄。自由基的传递也与其他氧化剂高度相关，包括羰基 (例如，丙烯醛)。基于这些发现，我们认为烟草衍生的氧化剂，包括自由基， 是制定旨在减少以下危害的监管战略的重要目标 使用可燃烟草。这一方法得到了我们的初步发现的有力支持，即 从高氧化剂转换为低氧化剂的吸烟者氧化应激生物标志物显著减少 香烟。该项目的目标是确定特定的氧化剂对产生 烟草相关危害和确定氧化剂还原对烟草相关毒性终点的影响。至 为此，我们提出了三个具体目标。在目标1中，我们将确定自由基和 使用先进电子技术由不同可燃烟草产品/品牌提供的其他氧化剂 顺磁共振(EPR)波谱和液-质联用(LC-MS) MS/MS)方法。在目标2中，我们在相关的小鼠模型中进行暴露研究，以确定 烟草烟雾氧化剂对肺损伤和炎症的影响；比较高和低氧化剂的效果 品牌和烟草品种。在目标3中，我们将进行老鼠暴露研究，以确定 炭过滤香烟烟雾对氧化剂所致小鼠肺损伤的影响。总体而言，这些研究将 通过关注烟草的毒理学重要性，为烟草监管科学领域做出重大贡献 接触氧化剂。这些数据将对FDA制定监管政策具有特别的价值 旨在减少烟草使用造成的危害。

Abstract Toxicity and negative health effects of tobacco smoking results from the inhalation of a complex mixture of over 7000 chemicals including many toxicants and carcinogens included on the FDA list of Harmful and Potentially Harmful Constituents (HPHCs). Oxidants are a major class of toxicant abundant in tobacco smoke and are thought to play a critical role in the development of tobacco related diseases including COPD, CVD and cancer through the generation of oxidative stress/damage and inflammation. However, the specific oxidants most responsible remain unclear. While several oxidants are included on the HPHC list (eg. carbonyls), one of the most reactive, damaging and abundant classes, free radicals, are not represented. Recently we found that delivery of radicals varied greatly (>12-fold) across cigarette brands, was substantially impacted by product design (e.g. tobacco variety) and smoking behaviors and was high in other popular combustible products including little filtered cigars. Radical delivery was also highly correlated with other oxidants including carbonyls (eg. acrolein). Based upon these findings, we propose that tobacco-derived oxidants, including free radicals, represent an important target for developing regulatory strategies aimed at reducing the harm from combustible tobacco use. This approach is strongly supported by our preliminary findings that levels of oxidative stress biomarkers are significantly reduced in smokers who switch from high to low oxidant cigarettes. The objectives of this project are to identify specific oxidants responsible for the generation of tobacco related harm and determine the impact of oxidant reduction on tobacco-related toxicity endpoints. To this end, we propose 3 specific aims. In Aim 1, we will determine the levels and identity of free radicals and other oxidants delivered by different combustible tobacco products/brands using advanced electron paramagnetic resonance (EPR) spectroscopy and liquid chromatography-tandem mass spectrometry (LC- MS/MS) methodologies. In Aim 2 we conduct exposure studies in a relevant mouse model to determine the impact of tobacco smoke oxidants on lung damage and inflammation; comparing effects of high vs. low oxidant brands and tobacco varieties. In Aim 3, we will conduct mouse exposure studies to determine the impact of charcoal filtration of cigarette smoke on oxidant-induced lung damage in the mouse. Overall, these studies will significantly contribute to the field of tobacco regulatory science by focusing on the toxicological importance of oxidant exposure. These data will be of particular value to the FDA for the development of regulatory policies aimed at reducing harm imposed by tobacco usage.