REGULATION OF FLAVIN MONOOXYGENASE GENE EXPRESSION

哺乳动物中含有黄素的单加氧酶(FMO)在多种外源物质的代谢过程中起着重要作用，包括许多治疗药物以及几种环境毒物和前体。目前有证据表明，有五个不同的哺乳动物FMO基因，其基因产物显示重叠，但不是相同的底物专一性。FMO表现出明显的组织和物种特异性表达模式。此外，在人类中也有广泛的个体间表达差异的报道。鉴于环境对FMO表达没有显著影响，个体间差异将在很大程度上受到遗传因素的控制。很明显，FMO组织特异性表达将有助于许多外来化合物的器官选择性，因为活性中间体的不同解毒或活性较低的化合物的生物激活。此外，人类FMO基因的多态，以及发育过程中表达的质和量的变化，将对表达的个体间差异产生重大影响，从而有助于治疗和环境毒物的特异性反应。这项建议的总体目标是了解FMO组织和时间特异性表达的分子机制，以及阐明导致其表达的个体间差异的多态。这一目标将通过解决以下特定目标来实现：(1)分离、表征和比较FM01、FMO2和FM03基因的调节区；(2)确定FMO在发育过程中表达变化的机制；(3)鉴定、表征和确定人类FMO多态的功能意义；以及(4)确定推测的人类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增进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。这将对今后药物和治疗方案的合理设计以及为高危个人或人群制定预防/干预战略至关重要。

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.