UDP GLUCURONOSYLTRANSFERASES, DETOXIFICATION OF NNK

描述：（申请人的描述）UGT发挥着极其重要的作用， 作为细胞中的基因保护酶， 致癌化合物，可与细胞大分子反应， 将外源性物质氧化成活性致癌亲电体。为 例如，几种主要的烟草前致癌物，如烟草前致癌物的代谢物， 多环芳烃（PAHS），如苯并芘（BaP）， 烟草特有的亚硝胺（TSNAs），如4-（甲基亚硝胺）-1- （3-吡啶基）-1-丁酮（NNK）通过UDP-葡萄糖醛酸基转移酶解毒 （UGT）诱导的葡萄糖醛酸化，通过增加这些 试剂，使它们更易溶于水，更容易排泄， 活跃本建议的主要目的是研究戒毒问题 通过UGT作为对烟草诱导的差异敏感性的机制 癌症，特别关注主要NNK的葡萄糖醛酸化 代谢产物4-（甲基亚硝氨基）-1-（3-吡啶基）-1-丁酮（NNL）。NNK和 NNAL被认为是诱导肺和 其他呼吸消化道癌症。个体间差异较大， 葡萄糖醛酸化形式的NNAL（NNAL-gluc）：游离NNAL的比例表明， 不同的人对NNK葡萄糖醛酸化的能力可能有很大差异 代谢物和解毒NNK。这与最近的研究一致 这表明肺癌风险的种族差异可能部分是 解释为个体受试者解毒NNK的能力差异 通过NNAL葡萄糖醛酸化。在我们的初步研究中， 至少一种具有NNAL-葡萄糖醛酸化活性的人UGT（UGT 1 *9），和 证明这种活性是诱导苯巴比妥和酚 老鼠体内的抗氧化剂由于代谢活化和 致癌物如NNK的解毒可能受到以下平衡的影响： 参与烟草致癌物激活的酶的宿主表达， 失活，我们假设一个人的能力， 葡萄糖醛酸盐NNAL将与个体肺和 潜在的其他呼吸消化道癌症。本提案的目的 将是，（I）充分表征人体中的NNAL葡萄糖醛酸化途径 通过测定负责葡萄糖醛酸化的主要UGT同工酶 NNAL的，（ii）阐明和功能评估潜在的重要遗传 在人类UGT基因的多态性，这可能反映了一个人的 将NNAL转化为NNAL-gluc的能力，作为一个人 解毒NNK，和（iii）检查这些多态基因型的重要性 肺癌易感性对照研究这些研究应 使我们能够阐明潜在的重要遗传生物标志物， 反思一个人？与烟草有关的癌症的风险。

DESCRIPTION: (Applicant's Description) UGTs play an extremely important role as genoprotective enzymes in the cell by preventing the accumulation of carcin-ogenic compounds which could react with cellular macromolecules and the oxidation of xenobiotics into active carcinogenic electrophiles. For example, several major tobacco procarcinogens, such as metabolites of the polycyclic aromatic hydrocarbons (PAHS) like benzoapyrene (BaP) and tobacco-specific nitrosamines (TSNAs) like 4-(methylnitrosamino)-1- (3-pyridyl)-1-butanone (NNK), are detoxified via UDP-glucuronosyltransferase (UGT)-induced glucuronidation by increasing the hydrophilicity of these agents, rendering them more water soluble, more easily excreted and less active. The major goal of the present proposal is to examine detoxification by UGTs as a mechanism for differential susceptibility to tobacco-induced cancers, specifically focusing on the glucuronidation of the major NNK metabolite, 4-(methyinitrosamino)-1-(3-pyridyl)-1-butanone (NNL). NNK and NNAL are considered to be major contributors to the induction of lung and other aerodigestive tract cancers. Large inter-individual variability in the ratio of the glucuronidated form of NNAL (NNAL-gluc):free NNAL suggests that individuals may differ greatly in their ability to glucuronidate NNK metabolites and to detoxify NNK. This is consistent with recent studies suggesting that racial differences in lung cancer risk may, in part, be explained by differences in the ability of individual subjects to detoxify NNK via NNAL glucuronidation. In our preliminary studies, we have identified at least one human UGT (UGT1*9) which possesses NNAL-glucuronidating 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 or deactivation, we have hypothesized that an individual's ability to glucuronidate NNAL will be correlated and that individual's risk for lung and potentially other aerodigestive tract cancers. The objective of this proposal will be to, (I) fully characterize the NNAL glucuronidation pathway in humans by determining the major UGT isoenzyme(s) responsible for the glucuronidation of NNAL, (ii) elucidate and functionally assess potentially important genetic polymorphism's in the human UGT gene which may reflect on an individual's capacity to convert NNAL to NNAL-gluc as a measure of one' ability to detoxify NNK, and (iii) examine the importance of these polymorphic genotypes in a case:control study of lung cancer susceptibility. These studies should enable us to elucidate potentially important genetic biomarkers which may reflect upon an individual?s risk for tobacco-related cancers.