UDP-Glucuronosyltransferases in responses to environmental and endogenous toxins

描述（由申请方提供）：UDP葡萄糖醛酸基转移酶同工酶（UGT）对于结构多样的亲脂性分子（包括正常细胞代谢产物、环境污染物和外源性物质（包括治疗剂））的解毒和消除至关重要。这些酶催化其底物与葡萄糖醛酸的结合，这是一个既使潜在毒性分子失活又增加其水溶性和随后排泄的过程。尽管该途径在防止内毒素和环境毒素积累方面的重要性及其在治疗剂代谢中的作用，但关于单个UGT酶的功能的许多问题仍然存在，特别是在UG2B亚家族的七个成员的情况下。其中一个原因是人类和小鼠UG2B基因成员之间存在巨大差异。基于序列同源性，尚不可能确定7个人UGT2B基因的小鼠直系同源物。这禁止使用无效小鼠系外推特定人UGT2B基因在特定底物葡萄糖醛酸化中的作用。在本申请中，我们提出了一种新的策略，我们相信该策略将产生可用于确定UGT 2B基因，特别是UGT 2B15和UGT 217的功能的小鼠品系。我们期望这些细胞系将以人类组织研究所预测的方式表达这些基因，并且这些基因不仅在类固醇代谢中，而且在保护免受环境毒素影响方面都是至关重要的。此外，我们将检验携带不同UGT2B17/UGT2B15单倍型的小鼠在这些反应中存在差异的假设。

DESCRIPTION (provided by applicant): The UDP glucuronosyltransferase isoenzymes (UGT) are critical for the detoxification and elimination of structurally diverse lipophilic molecules including products of normal cellular metabolism, environmental pollutants, and xenobiotics including therapeutic agents. These enzymes catalyze the conjugation of their substrates with glucuronic acid, a process that acts to both inactive the potentially toxic molecule and also to increase its water solubility and subsequent excretion. Despite the importance of this pathway in protection against accumulation of endobiotics and environmental toxins and its role in metabolism of therapeutic agents, many questions regarding the function of individual UGT enzymes remain, particularly in the case of the seven members of the UG2B subfamily. One of the reasons for this is that there are enormous differences between members of the human and mouse UG2B genes. Based on sequence homology it has not been possible to define the mouse ortholog of the seven human UGT2B genes. This has prohibited the use of null mouse lines in extrapolating the role of particular human UGT2B genes in the glucuronidation of specific substrates. In this application we propose a new strategy that we believe will generate mouse lines useful for determining the function of the UGT2B genes, and in particular of UGT2B15 and UGT217. We expect that these lines will express these genes in a manner predicted by studies of human tissues and that these genes will be critical, not only in steroid metabolism, but also in protection against environmental toxins. Furthermore, we will test the hypothesis that mice carrying different UGT2B17/UGT2B15 haplotypes will differ in these responses.