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.
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