The potential of knockout mouse lines in defining the role of flavin-containing monooxygenases in drug metabolism.
BACKGROUND
Flavin-containing monooxygenases (FMOs) metabolize a number of therapeutic drugs. However, their role in drug metabolism has been overlooked compared with that of the cytochromes P450 (CYPs). Genetic variants of FMOs are expected to influence drug response and/or contribute to adverse drug reactions.


METHODS
We review tissue-specific expression of FMOs and genetic variation that may influence drug metabolism. We discuss how the use of mouse lines in which Fmo genes have been deleted can demonstrate the role an FMO plays in the metabolism of a drug, particularly if the drug is subject to metabolism by other enzymes, for example, CYPs, or undergoes retro-reduction. We cite seminal papers and review articles to give the reader an appreciation of the FMO field.


RESULTS
Insights into the problems associated with determining the contribution of an FMO to the metabolism of a drug and how an Fmo-knockout mouse line has revealed the role of FMO1 in the metabolism of imipramine in vivo.


CONCLUSIONS
The use of an Fmo-knockout mouse line demonstrates a more important role for FMOs in multi-pathway drug metabolism than has previously been appreciated.
Shephard
Elizabeth A
EA
University College London, Institute of Structural and Molecular Biology, Gower Street, London WC1E 6BT, UK. e.shephard@ucl.ac.uk
Phillips
Ian R
IR
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D064420:Drug-Related Side Effects and Adverse Reactions; D014644:Genetic Variation; D006801:Humans; D007099:Imipramine / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010105:Oxygenases / Q000235:genetics / Q000378:metabolism*; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide
D004364:Pharmaceutical Preparations; D003577:Cytochrome P-450 Enzyme System; D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming); D007099:Imipramine