UDP GLUCURONOSYLTRANSFERASES, DETOXIFICATION OF NNK

描述：(申请者描述)UGT扮演着极其重要的角色 作为细胞中的遗传保护酶，通过防止 能与细胞大分子反应的致癌化合物和 将外源物质氧化成活性致癌电性物质。为 例如，几种主要的烟草前致癌物质，如 多环芳烃(PAHs)，如苯并苯(BaP)和 烟草特有的亚硝胺(TSNAs)类4-(甲基亚硝基)-1- (3-吡啶)-1-丁酮(NNK)，通过UDP-葡萄糖醛酸基转移酶解毒 (UGT)通过增加这些化合物的亲水性来诱导葡萄糖醛酸化反应 助剂，使其更易溶于水，更容易排泄，更少 激活。本提案的主要目标是审查戒毒 UGT作为烟草诱导的差异敏感性的一种机制 癌症，特别是主要NNK的葡萄糖醛酸化作用 代谢物4-(methyinitrosamino)-1-(3-pyridyl)-1-butanone(NNL)。NNK和 NNAL被认为是诱导肺和 其他呼吸道癌症。个体间的巨大变异性 糖醛酸化形式的NNAL(NNAL-Gluc)与游离NNAL的比率表明 个体对NNK的葡萄糖醛酸化能力可能有很大差异 代谢产物和解毒NNK。这与最近的研究一致。 这表明肺癌风险的种族差异可能在一定程度上是 用个体受试者对NNK解毒能力的差异来解释 通过NNAL葡萄糖醛酸化反应。在我们的初步研究中，我们已确认 至少一种具有NNAL-葡萄糖醛酸化活性的人UGT(UGT1*9)和 证明该活性可被苯巴比妥酚和酚类化合物诱导 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 烟草致癌物活化或激活相关酶的宿主表达 停用，我们假设一个人有能力 葡萄糖醛酸脂NNAL将与个体患肺和 可能是其他呼吸道癌症。这项提议的目的是 将是，(I)充分表征人类的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(S) (Ii)阐明并从功能上评估潜在的重要基因 人类糖基化终产物转移酶基因的多态可能反映个体？S 将NNAL转换为NNAL-Gluc的能力，以衡量某人的能力 使NNK解毒，以及(Iii)检查这些多态基因类型的重要性 病例：肺癌易感性的对照研究。这些研究应该 使我们能够阐明潜在的重要遗传生物标记物 反思一个人？S患烟草相关癌症的风险。

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's 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.