UDPGLUCURONOSYLTRANSFERASE GENOTYPE AND ORAL CANCER RISK

描述(改编自申请人的摘要)：UDP 葡萄糖醛酸基转移酶(UGT)可能在细胞中发挥重要作用，如 防止致癌化合物积累的遗传保护酶 它可以与细胞大分子反应，导致氧化 将外源物质转化为活性致癌亲电物质。几种主要烟草 致癌原，如多环芳烃的代谢物 (PAHs)，如苯并[a]芘(BaP)和烟草特有的亚硝胺(TSNAs) 像耐克(4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone)一样，都是通过 UGT通过增加这些试剂的亲水性来诱导葡萄糖醛酸化反应， 从而使它们更易溶于水，更容易排泄，而且更少 生物活性。拟议工作的主要目标是通过以下方式审查戒毒 UGT作为口腔癌不同易感性的机制， 特别关注主要NNK代谢物的葡萄糖醛酸化反应， 纳斯达克(4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanol)。NNK和NNAL是 被认为是诱发口腔癌的主要因素 空洞和肺。这一比例在个体间存在很大的差异 葡萄糖醛酸化形式的NNAL(NNAL-Gluc)：游离NNAL表明个人 它们对NNK代谢物的葡萄糖醛酸化能力和 让NNK解毒。这与最近的研究一致，这些研究表明，种族 肺癌和潜在的口腔癌的发病率和死亡率的差异可能， 在一定程度上，可以用个体受试者的能力差异来解释 通过NNAL葡萄糖醛酸化作用使NNK解毒。初步研究已确定在 至少两个具有NNAL-葡萄糖化活性的人UGT(1A9和2B7) 并证明该活性可被苯巴比妥和酚类物质诱导。 老鼠体内的抗氧化剂。因为新陈代谢激活和 NNK等致癌物的解毒作用可能受 参与烟草致癌物质活化的酶的宿主表达， 建立了一种假设，即一个人对NNAL葡醛酸化的能力是 与个人患口腔癌以及其他疾病的风险相关 呼吸消化道癌。因此，这项拟议工作的目标是 为了(1)充分表征人类的NNAL葡萄糖醛酸化途径，(2) 阐明、功能评估和确定潜在的 人类UGT基因的重要遗传多态可能反映了一种 个人将NNAL转换为NNAL-Gluc的能力，作为衡量一个人的能力 解毒NNK的能力，以及(3)检查这些多态的重要性 口腔癌易感性的病例对照研究中的基因分型。这些 研究可能提供潜在的重要遗传生物标志物，这些标志物可能反映 根据个人的口腔和潜在的其他与烟草有关的风险 癌症。

DESCRIPTION (Adapted from the applicant's abstract): UDP glucuronosyltransferases (UGTs) may play important roles in cells as genoprotective enzymes by preventing the accumulation of carcinogenic compounds which could react with cellular macromolecules causing the oxidation of xenobiotics into active carcinogenic electrophiles. Several major tobacco procarcinogens, such as metabolites of the polycyclic aromatic hydrocarbons (PAHs) such as benzo[a]pyrene (BaP) and tobacco-specific nitrosamines (TSNAs) like 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone (NNK), are detoxified via UGT-induced glucuronidation by increasing the hydrophilicity of these agents, thus rendering them more water-soluble, more easily excreted, and less bioactive. The major goal of the proposed work is to examine detoxification by UGTs as a mechanism for differential susceptibility to oral cancer, specifically focusing on the glucuronidation of the major NNK metabolite, 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanol (NNAL). NNK and NNAL are considered to be major contributors to the induction of cancers of the oral cavity and lung. Large inter-individual variability in the ratio of the glucuronidated form of NNAL (NNAL-Gluc):free NNAL suggests that individuals differ greatly in their ability to glucuronidate NNK metabolites and to detoxify NNK. This is consistent with recent studies which suggest that racial differences in morbidity and mortality of lung and potentially oral cancer may, in part, be explained by differences in the ability of individual subjects to detoxify NNK via NNAL glucuronidation. Preliminary studies have identified at least two human UGTs (1A9 and 2B7) which possess NNAL-glucoronidating activity and demonstrate that this activity is inducible by phenobarbitol and phenolic antioxidants in rats. As the balance between metabolic activation and detoxification of carcinogens such as NNK may be influenced by the balance of host expression of enzymes involved in tobacco carcinogen activation, the hypothesis was created that an individual's ability to glucuronidate NNAL is correlated with that individual's risk for oral cancer as well as for other aerodigestive tract cancers. Therefore, the objective of this proposed work is to (1) fully characterize the NNAL glucuronidation pathway in humans, (2) to elucidate, functionally assess, and determine the prevalence of potentially important genetic polymorphisms in the human UGT gene which may reflect an individual's capacity to convert NNAL to NNAL-gluc as a measure of one's ability to detoxify NNK, and (3) to examine the importance of these polymorphic genotypes in a case-control study of susceptibility to oral cancer. These studies may provide potentially important genetic biomarkers which may reflect upon an individual's risk for oral and potentially other tobacco-related cancers.