UDP-Glucuronosyltransferases in responses to environmental and endogenous toxins

描述(由申请人提供)：UDP葡萄糖醛酸基转移酶同功酶(UGT)对于解毒和消除结构多样的亲脂分子至关重要，包括正常细胞代谢的产物、环境污染物和包括治疗剂在内的外源生物。这些酶催化其底物与葡萄糖醛酸的结合，这一过程既能使潜在的有毒分子失去活性，又能增加其水溶性和随后的排泄。尽管这一途径在防止内生菌和环境毒素的积累以及它在治疗药物新陈代谢中的作用方面非常重要，但关于单个UGT酶的功能仍然存在许多问题，特别是在UG2B亚家族的七个成员的情况下。原因之一是人类和小鼠的UG2B基因成员之间存在着巨大的差异。基于序列同源性，还不可能确定七个人类UGT2B基因的小鼠同源。这就禁止了使用无效的小鼠品系来推断特定的人类UGT2B基因在特定底物的葡萄糖醛酸化反应中的作用。在这项申请中，我们提出了一种新的策略，我们相信这将产生有助于确定UGT2B基因功能的小鼠系，特别是UGT2B15和UGT217。我们预计这些细胞株将以人类组织研究预测的方式表达这些基因，这些基因不仅在类固醇新陈代谢中至关重要，而且在保护环境毒素方面也是至关重要的。此外，我们将检验这样一种假设，即携带不同UGT2B17/UGT2B15单倍型的小鼠在这些反应中会有所不同。

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.