Mammalian flavin-containing monooxygenase (FMO, EC 1.14.13.8) metabolizes a great number and variety of xenobiotics. Evidence is accumulating for the existence of multiple forms of this enzyme but relatively little is known of their regulation or role in xenobiotic metabolism. The major focus of this laboratory is on characterization of the properties and developmental regulation of lung FMO and assessing the role of this monooxygenase system in the metabolism of a number of xenobiotics for which lung is a portal of entry and/or the target organ for toxicity. The present study will examine the molecular mechanism(s) of the previously observed increase in maternal lung FMO during gestation and document the development of this monooxygenase system in fetal and neonatal rabbits. Developmental regulation of FMO and activity toward xenobiotics will also be measured in other tissues in which this """"""""lung"""""""" form of FMO is expressed (kidney, brain and bladder). Nicotine, cocaine, methamphetamine, thioureas and arylamines are all potential substrates for lung FMO and this study will determine the role of this monooxygenase system in metabolic activation or detoxication in non-pregnant and pregnant adult rabbits and in fetal and neonates, as well. Monkeys possess a form of lung FMO very similar to the rabbits, and the studies on xenobiotic metabolism will also be performed with Rhesus lung. Purification of monkey lung FMO will provide the first FMO from primates for study. The structural characteristics which confer the lung FMO with its unusually physio- chemical properties will be studied by analysis of expressed chimeric proteins constructed from rabbit liver and lung FMO cDNAs. Finally, the novel and unusual finding that rabbit lung FMO is associated with the major calcium-binding protein of microsomes, calreticulin, will be studied to determine if this provides an alternate explanation for the enhanced stability of lung FMO, or it could possibly be a mechanism of control.
