REGULATION OF FLAVIN-MONOOXYGENASE GENE EXPRESSION

描述(改编自调查者摘要)： 黄素单加氧酶(FMO)具有广泛的底物专一性 对于软亲核试剂，包括氮、硫和 含磷的外源生物。这种酶似乎最活跃在 几种这类化合物的解毒作用，尽管FMO也参与 几种前致癌物和原毒素的代谢激活。因此， 这种酶在化学的早期事件中起着重要的作用。 致癌和毒性。分子克隆研究现已确定 FMO基因家族的5个截然不同的成员拥有52%至57%的序列 身份。不同的FMO同工酶表现出显著的差异 组织特异性表达。这些差异将有助于实现目标 多种有毒外源物质差异解毒的器官特异性 或者是生物激活。然而，目前还没有关于这种分子的研究。 控制这些酶的表达的机制(S)。的假说 这一建议是对FMO的组织特异性表达进行调控 通过特定转录因子与调控因子的不同结合 序列。进一步假设，整个分子机制 调节这些基因在物种之间是保守的，尽管它的 应用于不同的基因将表现出物种特异性。最后， 假设异种生物代谢的个体间差异 部分原因是人类一种或多种FMO酶的多态。这些 假设将通过完成以下具体目标来检验：(1) 扩大对主要病原菌的分离和鉴定的初步研究 兔和人的FMO基因；(2)确定和表征组织和 识别和表征FMO的细胞特异性调控机制 顺式和跨式调节元件；以及(3)识别、表征和 确定FMO多态在人群中的意义。 这些研究的完成将大大加深对 控制这一重要酶系统表达的机制和 它对几种人类疾病的影响。

DESCRIPTION (Adapted from the Investigator's Abstract): The flavin-containing monoxygenases (FMO) exhibit a broad substrate specificity for soft nucleophiles, including nitrogen-, sulfur-, and phosphorous-containing xenobiotics. The enzyme appears most active in the detoxication of several such compounds, although the FMO also participate in the metabolic activation of several procarcinogens and protoxins. As such, this enzyme plays an important role in the early events of chemical carcinogenesis and toxicity. Molecular cloning studies have now identified 5 distinct members of the FMO gene family sharing 52 to 57 percent sequence identity. The different FMO isozymes exhibit dramatic differences in their tissue-specific expression. These differences will contribute to the target organ specificity of many toxic xenobiotics due to differential detoxication or bioactivation. However, no studies have appeared regarding the molecular mechanism(s) controlling the expression of these enzymes. The hypothesis of this proposal is that the tissue-specific expression of the FMO is regulated by the differential binding of specific transcription factors to regulatory sequences. It is further hypothesized that the overall molecular mechanism regulating these genes will be conserved between species, although its application to different genes will exhibit species-specificity. Finally, it is hypothesized that interindividual differences in xenobiotic metabolism is due in part to polymorphisms in one or more the human FMO enzymes. These hypotheses will be tested by completion of the following specific aims: (1) Extend initial studies on the isolation and characterization of the major rabbit and human FMO genes; (2) Determine and characterize tissue- and cell-specific regulatory mechanisms by identifying and characterizing FMO cis- and trans-regulatory elements; and (3) Identify, characterize, and determine the significance of FMO polymorphisms in the human population. Completion of these studies will add greatly to the understanding of the mechanisms controlling the expression of this important enzyme system and its impact on several human pathologies.