Mammalian flavin-containing monooxygenase (EC 1-14.13.8) oxygenates a large number and variety of nitrogen- and sulfur-containing xenobiotics. This enzyme plays a major role in the metabolic disposition of many drugs, alkaloids and industrial chemicals. The properties of purified mammalian flavin-containing monooxygenase have been limited to the study of the liver enzyme with the vast amount of work being done with the pig enzyme. The isolation of the rabbit lung enzyme by this laboratory was the first report of purification to homogeneity from an extrahepatic tissue. Unlike the other microsomal system, cytochrome P-450, flavin-containing monooxygenase is not inducible by exposure to xenobiotics but does appear to be hormonally and developmentally regulated. It has also been thought to exist as a single form in a particular species. The physiological function of flavin-containing monooxygenase is uncertain, but may be involved in the synthesis of disulfied bonds in polypeptides. We have purified this enzyme from rabbit lung microsomes and found the lung enzyme to be distinct from the liver enzyme with respect to immunochemical and catalytic properties. Furthermore, the lung enzyme is induced several-fold during pregnancy. In order to unequivocally characterize rabbit lung flavin-containing monooxygenase as a novel form (distinct gene product) of this enzyme, I propose to: 1) isolate the enzyme from rabbit lung and liver; 2) compare the physical properties and substrate specificities of these enzymes; and 3) perform immunochemical analysis with polyclonal antibodies. Antibodies to the rabbit lung enzyme will also be utilized in immunohistochemical localization studies, immunoquantitation during development and pregnancy, in immunoisolation of cell-free translation products from mRNA and, finally, in the production of cDNA. The physiological function of this enzyme in the formation of disulfide bonds in polypeptides will be examined and the role of this enzyme in the metabolism of known lung toxicants such as yield-naphthylthiourea, N-methylthiobenzamide, nicotine and 2-aminofluorene will be studied. These physiological and toxicological studies will be related to changes occurring during development and pregnancy. Finally, the enhanced stability of this enzyme may allow for the utilization of flavin-analogues and 31pNMR for studying the interaction of the flavin moiety with various amino acid residues and the unique reaction mechanism of this flavoprotein. These studies are designed to elucidate the mechanism of induction during pregnancy and to provide insights into the hormonal and developmental control of this enzyme.
| Siddens, Lisbeth K; Krueger, Sharon K; Henderson, Marilyn C et al. (2014) Mammalian flavin-containing monooxygenase (FMO) as a source of hydrogen peroxide. Biochem Pharmacol 89:141-7 |
| 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 |
| 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 |
