REGULATION OF FLAVIN MONOOXYGENASE GENE EXPRESSION

哺乳动物含黄素单加氧酶（FMO）在许多异种生物的代谢处置中起着重要作用，包括许多治疗药物，以及一些环境毒物和毒物。目前存在的证据表明，五种不同的哺乳动物FMO基因的基因产物表现出重叠，但不相同的底物特异性。FMO表现出明显的组织和物种特异性表达模式。此外，在人类中也报道了广泛的个体间表达差异。由于环境对FMO的表达没有明显的影响，个体间变异将主要由遗传因素控制。很明显，由于活性中间体的不同解毒作用或活性较低的化合物的生物活化作用，FMO的组织特异性表达将有助于许多外来化合物的器官选择性。此外，人类FMO的多态性，以及发育过程中表达的定性和定量变化，将对个体间表达变化产生重大影响，从而促进治疗和环境毒性特异性反应。本提案的总体目标是了解FMO组织特异性和时间特异性表达的分子机制，并阐明导致其表达个体间差异的多态性。这一目标将通过解决以下具体目标来实现：(1)分离、表征和比较FM01、FMO2和FM03基因的调控区域；(2)确定发育过程中FMO表达变化的机制；(3)鉴定、表征并确定人类FMO多态性的功能意义；(4)确定推定的人FM06基因的组织特异性表达模式和催化活性。这些研究的完成将对提高我们对该基因家族的认识及其对药物代谢和环境毒理学的贡献做出重大贡献。这对于未来药物和治疗方案的基本原理设计以及为处于危险中的个人或人群制定预防/干预策略至关重要。

The mammalian flavin-containing monooxygenases (FMO) play an important role in the metabolic disposition of numerous xenobiotics, including many therapeutics, as well as several environmental toxicants and protoxicants. Evidence currently exists for five distinct mammalian FMO genes whose gene products exhibit overlapping, but not identical substrate specificity. The FMO exhibit marked tissue- and species-specific expression patterns. In addition, wide interindividual variation in expression has been reported in the human. Given the absence of significant environmental influence on FMO expression, interindividual variation will be controlled largely be genetic factors. It is clear FMO tissue-specific expression will contribute to the organ selectivity of many foreign compounds due to differential detoxication of reactive intermediates or bioactivation of less reactive compounds. Further, polymorphisms in the human FMO, as well as qualitative and quantitative changes in expression during development, will have a significant impact on interindividual variation in expression, thus contributing to therapeutic and environmental toxicant idiosyncratic responses. The overall objective of this proposal is to understand the molecular mechanisms underlying the tissue- and temporal-specific expression of the FMO, as well as elucidate polymorphisms that contribute to interindividual variation in their expression. This objective will be accomplished by addressing the following specific aims: (1)Isolate, characterize and compare the regulatory regions of the FM01, FMO2, and FM03 genes; (2) Determine the mechanism whereby FMO expression changes during development; (3) Identify, characterize and determine the functional significance of human FMO polymorphisms; and (4) Determine the tissue-specific expression pattern and catalytic activity of a putative human FM06 gene. Completion of these studies will make a significant contribution in advancing our knowledge of this gene family and their contribution to drug metabolism and environmental toxicology. It will be critical for the future rationale design of drugs and therapeutic regimens, as well as for the development of prevention/intervention strategies for at risk individuals or populations.