Flavin-containing monooxygenase (FMO) oxygenates drugs and xenobiotics. FMO metabolites typically have reduced toxicity and/or therapeutic efficacy, but some substrates (e.g. thioureas) are bioactivated. FMO2 is the major isoform in lung of most mammals, including non-human primates. In humans, FMO2 exhibits a genetic polymorphism; all Caucasians and Asians genotyped to date possess two non-functional (FMO2*2A) alleles, whereas 27% of African-Americans and 5% of Hispanics possess at least one allele (FMO2*1) coding for full-length functional enzyme. The long-term goal of this project is to determine the significance of FMO2 expression in human lung with respect to drug metabolism and toxicity following exposure to xenobiotics that serve as substrates. The hypothesis under test is that pulmonary FMO2 plays an important role in the metabolism of many drugs and xenobiotics for which lung is a major route of exposure and/or the target organ; individuals expressing functional FMO2 will exhibit markedly different therapeutic responses to drug substrates and sensitivity following environmental exposures to xenobiotic substrates. The following specific aims are proposed to test this hypothesis. (1) Utilize expressed FMO2 and human lung cells overexpressing FMO2, in the presence and absence of CYPs expressed in lung, to assess the role of FMO2 in metabolism and toxicity of drugs and xenobiotics. (2) Employ a conditional knockout mouse model to assess the role of FMO2 in drug metabolism and toxicity in vivo. (3) Utilize lung tissue from African-Americans to correlate genotype to metabolic activation or detoxication of drugs and xenobiotics. These highly integrated studies seek to ascertain the role of FMO2 in pulmonary drug metabolism and toxicity and improve the health of an under-represented minority group expressing this enzyme. [unreadable] [unreadable] [unreadable] [unreadable]