Glutathione and oral cancer

虽然衰老和吸烟是口腔鳞状细胞癌的主要危险因素，但饮酒和营养在调节这种疾病的易感性方面也起着重要作用。大量饮酒和某些抗氧化剂/营养素摄入量减少增加口腔癌风险的机制(S)尚不清楚，但最近的研究表明，可能与氧化应激增加有关。谷胱甘肽(GSH)是在所有细胞和组织中发现的最丰富的细胞抗氧化剂，被认为在调节氧化还原状态和防止氧化应激中发挥关键作用。大量饮酒导致谷胱甘肽水平下降，也是生物老化过程的结果。最近的研究结果表明，谷胱甘肽在口腔癌的发生中具有保护作用。我们假设口腔上皮细胞中的GSH含量是致癌过程中的一个关键调节因素。我们的目标是研究提高或降低GSH水平对大鼠口腔癌发生的影响。为此，我们将确定口服GSH单乙酯(GSHME)或丁硫氨酸亚磺胺(BSO)对4-NQO的影响--口服GSH单乙酯(GSHME)或丁硫氨酸亚磺胺(BSO)对4-NQO诱导的舌癌形成的影响。此外，我们还将探讨GSH降低导致致癌性增强的一个可能机制，即通过激活NF-kappaB和随后上调COX-2活性来促进结肠细胞的增殖。在R-NQO大鼠模型的短期研究中，将使用特定的核因子-kappaB和COX-2抑制剂来研究这一机制。还将通过将血液和组织中的GSH水平与饮食中GSH及其前体的摄入量以及健康受试者中的其他口腔癌症风险因素(包括酒精摄入量和营养/抗氧化剂水平)相关联，来研究GSH与口腔癌症风险之间的关系。最后，我们将使用病例对照设计检查低GSH是否是口腔癌前病变的危险因素。这些结果将为人类口腔癌的病因和风险调控提供新的重要信息，并可用于设计有效和系统的口腔癌预防策略。此外，GSH水平可能有助于确定谁是这种疾病的高危个体。

While aging and tobacco are the major risk factors for squamous cell cancer of the oral cavity, alcohol consumption and nutrition also play an important role in the regulation of susceptibility to this disease. The mechanism(s) by which heavy alcohol intake and decreased intake of certain antioxidant/nutrients enhances the risk for oral cancer is unknown but recent studies have suggested than an increase in oxidative stress may be involved. Glutathione (GSH) is the most abundant cellular antioxidant found in all cells and tissues and is thought to play a key role in the regulation of redox status and protection against oxidative stress. Decreased GSH levels occur as a result of heavy alcohol consumption and are also a consequence of the biological aging process. Recent results have implicated a protective role for GSH in oral carcinogenesis. We hypothesis that the GSH content of the oral epithelium is a key regulating factor in the carcinogenic process. Our objectives are to examine the effects of increasing or decreasing GSH levels on oral carcinogenesis in the rat. To this end, we will determine the effects of oral administration of GSH monoethyl ester (GSHME) or butathionine sulfoximine (BSO) on 4-NQO- the effects of oral administration of GSH monoethyl ester (GSHME) or buthionine sulfoximine (BSO) on 4-NQO-induced tongue tumor formation. In addition, we will investigate one possible mechanism by which decreased GSH can lead to increased carcinogenicity, namely, the enhancement of colonic cell proliferation by activation of NF-kappaB and subsequent up-regulation of COX-2 activity. This mechanism will be investigated using specific inhibitors of NF-kappaB and COX-2 in short-term studies in the R-NQO rat model. The relationship between GSH and oral cancer risk in humans will also be examined by correlating blood and tissue GSH levels with dietary intake of GSH and its precursors, and other risk factors for oral cancer including alcohol intake and nutrient/antioxidant levels in healthy subjects. Finally, we will examine if low GSH is a risk factor for precancerous oral lesions using a case-control design. Results from these should provide new and important information on the etiology and regulation of risk of oral cancer in human subjects, and can be used to design effective and systematic preventive strategies for oral cancer. In addition, GSH levels may be useful in the identification of individuals who at high risk for this disease.