Bagchi M, Bagchi D, Hassoun E A, Stohs S J
Department of Pharmaceutical and Administrative Sciences, Creighton University Health Sciences Center, Omaha, NE 68178, USA.
Toxicology. 1998 May 15;127(1-3):29-38. doi: 10.1016/s0300-483x(98)00021-3.
The oral use of moist smokeless tobacco products (snuff) is causally associated with cancer of the mouth, lip, nasal cavities, esophagus and gut. The mechanism by which smokeless tobacco constituents produce genetic and tissue damage is not known. Recent studies in our laboratories have shown that an aqueous extract of smokeless tobacco (STE) activates macrophages with the resultant production of reactive oxygen species (ROS), including nitric oxide. Furthermore, the administration of acute doses of STE (125-500 mg/kg) to rats induces dose dependent increases in mitochondrial and microsomal lipid peroxidation, enhances DNA single strand breaks, and significantly increases the urinary excretion of the lipid metabolites malondialdehyde, formaldehyde, acetaldehyde and acetone. Since the use of tobacco is a chronic process, the effects of an aqueous extract of STE in rats following low dose exposure were examined. Female Sprague-Dawley rats were treated orally with 25 mg STE/kg every other day for 105 days. The effects of subchronic treatment of STE on hepatic microsomal and mitochondrial lipid peroxidation and the incidence of hepatic nuclear DNA damage were assessed. Lipid peroxidation increased 1.4- to 3.3-fold in hepatic mitochondria and microsome with STE treatment between 0 and 105 days with respect to control animals while hepatic DNA single strand breaks increased up to 3.4-fold. Maximum increases in lipid peroxidation and DNA single strand breaks occurred between 75 and 90 days of treatment. Urinary excretion of the four lipid metabolites malondialdehyde, formaldehyde, acetaldehyde and acetone was monitored by high pressure liquid chromatography (HPLC) with maximum increases being observed between 60 and 75 days of treatment. The results clearly indicate that low dose subchronic administration of STE induces an oxidative stress resulting in tissue damaging effects which may contribute to the toxicity and carcinogenicity of STE.
口服使用湿的无烟烟草制品（鼻烟）与口腔癌、唇癌、鼻腔癌、食道癌和肠道癌存在因果关联。无烟烟草成分产生基因和组织损伤的机制尚不清楚。我们实验室最近的研究表明，无烟烟草的水提取物（STE）可激活巨噬细胞，从而产生包括一氧化氮在内的活性氧（ROS）。此外，给大鼠急性注射STE（125 - 500毫克/千克）会导致线粒体和微粒体脂质过氧化呈剂量依赖性增加，增强DNA单链断裂，并显著增加脂质代谢产物丙二醛、甲醛、乙醛和丙酮的尿排泄量。由于烟草使用是一个慢性过程，因此研究了低剂量暴露后STE水提取物对大鼠的影响。雌性斯普拉格 - 道利大鼠每隔一天口服25毫克STE/千克，持续105天。评估了STE亚慢性治疗对肝微粒体和线粒体脂质过氧化以及肝细胞核DNA损伤发生率的影响。与对照动物相比，在0至105天的STE治疗期间，肝线粒体和微粒体中的脂质过氧化增加了1.4至3.3倍，而肝DNA单链断裂增加了高达3.4倍。脂质过氧化和DNA单链断裂的最大增加发生在治疗的75至90天之间。通过高压液相色谱法（HPLC）监测丙二醛、甲醛、乙醛和丙酮这四种脂质代谢产物的尿排泄量，在治疗的60至75天之间观察到最大增加。结果清楚地表明，低剂量亚慢性给予STE会诱导氧化应激，从而产生组织损伤效应，这可能导致STE的毒性和致癌性。
