UDP-Glucuronosyltransferases in responses to environmental and endogenous toxins

UDP-葡萄糖醛酸基转移酶对环境和内源毒素的反应

• 批准号: 8663275
• 负责人: Delores Juanita Grant
• 金额: $ 18.07万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-17 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8663275
• 关键词: 2q37; Address; African American; Alleles; Androgens; Animals; Catabolism; Caucasians; Caucasoid Race; Chromosomes; Chromosomes, Human, Pair 5; DNA; Drug Metabolic Detoxication; ES Cell Line; Environmental Estrogen; Environmental Pollutants; Enzymes; Event; Excision; Excretory function; Family; Family member; Future; Gene Expression Profile; Gene Family; Gene Structure; Generations; Genes; Genetic Variation; Glucuronic Acids; Glucuronosyltransferase; Haplotypes; Health; Human; Hydroxyl Radical; Individual; Isoenzymes; Knockout Mice; Liver; Mammary gland; Mediating; Metabolism; Modeling; Morphine; Mus; Nicotine; Organism; Orthologous Gene; Pathway interactions; Pattern; Play; Process; Prostate; Rodent; Role; Sequence Homology; Steroids; Structure; Substrate Specificity; Testing; Testis Brain; Therapeutic Agents; Tissues; Toxic Environmental Substances; Toxin; UGT1A1 gene; Vertebrates; Water; Xenobiotics; base; bisphenol A; drug clearance; embryonic stem cell; environmental agent; enzyme pathway; gene conservation; gene function; genetic manipulation; human DNA; human tissue; member; mouse model; public health relevance; response; restoration; steroid hormone; steroid metabolism; water solubility

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.

描述（由申请人提供）：UDP葡萄糖醛酸基转移酶同工酶（UGT）对于解毒和消除结构多样的亲脂性分子（包括正常细胞代谢产物、环境污染物和异生物质（包括治疗剂））至关重要。这些酶催化其底物与葡萄糖醛酸的结合，这一过程既使潜在有毒分子失活，又增加其水溶性和随后的排泄。尽管该途径对于防止内生素和环境毒素积累及其在治疗药物代谢中的作用非常重要，但有关各个 UGT 酶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。原因之一是人类和小鼠 UG2B 基因成员之间存在巨大差异。基于序列同源性，尚不可能定义七个人类 UGT2B 基因的小鼠直系同源物。这禁止使用无效小鼠系来推断特定人 UGT2B 基因在特定底物的葡萄糖醛酸化中的作用。在本申请中，我们提出了一种新策略，我们相信该策略将生成可用于确定 UGT2B 基因（特别是 UGT2B15 和 UGT217）功能的小鼠品系。我们期望这些细胞系将以人体组织研究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至关重要，而且在抵御环境毒素方面也至关重要。此外，我们将测试携带不同 UGT2B17/UGT2B15 单倍型的小鼠在这些反应中会有所不同的假设。