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对这种疾病的易感性方面也起着重要作用。大量饮酒和减少摄入某些抗氧化剂/营养素增加口腔癌风险的机制尚不清楚，但最近的研究表明，氧化应激的增加可能与此有关。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方面发挥关键作用。谷胱甘肽水平的下降是大量饮酒的结果，也是生物衰老过程的结果。最近的研究结果表明谷胱甘肽在口腔癌变中具有保护作用。我们假设口腔上皮的谷胱甘肽含量是致癌过程中的关键调节因子。我们的目的是研究增加或减少谷胱甘肽水平对大鼠口腔癌变的影响。为此，我们将确定口服谷胱甘肽单乙酯（GSHME）或丁硫氨酸亚砜胺（BSO）对4-NQO的影响-口服谷胱甘肽单乙酯（GSHME）或丁硫氨酸亚砜胺（BSO）对4-NQO诱导的舌肿瘤形成的影响。此外，我们将研究GSH降低导致致癌性增加的一种可能机制，即通过激活NF-kappaB和随后上调COX-2活性来增强结肠细胞增殖。在R-NQO大鼠模型的短期研究中，将使用NF-kappaB和COX-2的特异性抑制剂来研究这一机制。谷胱甘肽与人类口腔癌风险之间的关系还将通过将血液和组织谷胱甘肽水平与饮食中谷胱甘肽及其前体的摄入量以及健康受试者中其他口腔癌风险因素（包括酒精摄入量和营养/抗氧化剂水平）的关系进行检验。最后，我们将使用病例对照设计检查低谷胱甘肽是否是癌前口腔病变的危险因素。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，谷胱甘肽水平可能有助于识别这种疾病的高风险个体。

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.