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.
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