Mammalian flavin-containing monooxygenase (FMO) metabolizes a great number of therapeutic and illegal drugs and plant alkaloids including tamoxifen, codeine and nicotine. Unlike the cytochrome P450 (CYP) monooxygenases, FMO usually produces inactive, non-toxic metabolites. The FMO superfamily has 5 families, each with a single member. FMO2, the major form in lung, is developmentally regulated, appearing during late gestation in fetal lung and reaching adult levels soon after birth, suggesting a critical function in protection of the fetus and neonate against foreign chemicals. This study explores the structural basis for the properties of FMOs in general, and FMO1 and FMO2 in particular utilizing chimeras and site-directed mutagenesis. Expression of Rhesus and human FMO2 cDNA will make possible, for the first time, study of the properties of the primate orthologs. Humans appear unique in transcription of a non-functional mRNA. Collaborative studies with the University of London will investigate an apparent polymorphism, evident in individuals of African descent, heterozygous for a full-length mutant. In vitro studies of FMO regulation will be performed utilizing high-precision lung slices. FMOs are present in high concentration in nasal tissue. The contribution of nasal FMO (relative to CYP) in the metabolism of nicotine will be determined, as will the potential for modulation of nasal FMO activity in vitro and in vivo. Indole-3-carbinol (I3C), a major component of cruciferous vegetables currently being examined in human clinical trials, represses FMO activity and FMO1 protein levels in liver and intestine, while inducing a number of CYPs, providing a model for the contribution of FMO in drug metabolism in vivo. Results from these studies will further the understanding of the importance of this enzyme in human health.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL038650-12
Application #
6030567
Study Section
Special Emphasis Panel (ZRG4-ALTX-1 (01))
Project Start
1987-04-01
Project End
2001-06-30
Budget Start
1999-07-01
Budget End
2001-06-30
Support Year
12
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Oregon State University
Department
Type
Organized Research Units
DUNS #
053599908
City
Corvallis
State
OR
Country
United States
Zip Code
97339
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Henderson, Marilyn C; Siddens, Lisbeth K; Krueger, Sharon K et al. (2014) Flavin-containing monooxygenase S-oxygenation of a series of thioureas and thiones. Toxicol Appl Pharmacol 278:91-9
Palmer, Amy L; Leykam, Virginia L; Larkin, Andrew et al. (2012) Metabolism and Pharmacokinetics of the Anti-Tuberculosis Drug Ethionamide in a Flavin-Containing Monooxygenase Null Mouse. Pharmaceuticals (Basel) 5:1147-1159
Celius, Trine; Pansoy, Andrea; Matthews, Jason et al. (2010) Flavin-containing monooxygenase-3: induction by 3-methylcholanthrene and complex regulation by xenobiotic chemicals in hepatoma cells and mouse liver. Toxicol Appl Pharmacol 247:60-9
Krueger, Sharon K; Henderson, Marilyn C; Siddens, Lisbeth K et al. (2009) Characterization of sulfoxygenation and structural implications of human flavin-containing monooxygenase isoform 2 (FMO2.1) variants S195L and N413K. Drug Metab Dispos 37:1785-91
Siddens, Lisbeth K; Henderson, Marilyn C; Vandyke, Jonathan E et al. (2008) Characterization of mouse flavin-containing monooxygenase transcript levels in lung and liver, and activity of expressed isoforms. Biochem Pharmacol 75:570-9
Henderson, Marilyn C; Siddens, Lisbeth K; Morre, Jeffrey T et al. (2008) Metabolism of the anti-tuberculosis drug ethionamide by mouse and human FMO1, FMO2 and FMO3 and mouse and human lung microsomes. Toxicol Appl Pharmacol 233:420-7
Krueger, Sharon K; Siddens, Lisbeth K; Henderson, Marilyn C et al. (2005) Haplotype and functional analysis of four flavin-containing monooxygenase isoform 2 (FMO2) polymorphisms in Hispanics. Pharmacogenet Genomics 15:245-56
Krueger, Sharon K; Williams, David E (2005) Mammalian flavin-containing monooxygenases: structure/function, genetic polymorphisms and role in drug metabolism. Pharmacol Ther 106:357-87