The implications of polymorphisms in mammalian flavin-containing monooxygenases in drug discovery and development.
Use of the human flavin-containing monooxygenases (FMOs) in drug design and discovery could represent a paradigm shift in drug development and basic research. Although FMOs have been previously viewed as minor contributors to drug metabolism, the advantages associated with using FMOs to diversify the metabolism of a drug are now being recognized. Because FMOs typically oxygenate a wide variety of nucleophilic compounds to polar, benign metabolites, and because drugs do not induce expression of FMOs or inhibit their activity, potential drug-drug interactions are minimized. Interindividual variation for this class of enzyme is largely dependent on genetic variation. Examples of FMO allelic variation and splicing variants suggest that these genetic mutations could contribute to the interindividual and interethnic variability of FMO-mediated metabolism.
Cashman
John R
JR
Human BioMolecular Research Institute, 5310 Eastgate Mall, San Diego, CA 92121, USA. JCashman@HBRI.org
D000818:Animals; D001711:Biotransformation / Q000235:genetics; D015195:Drug Design; D004341:Drug Evaluation / Q000379:methods; D006801:Humans; D010105:Oxygenases / Q000235:genetics* / Q000378:metabolism*; D011110:Polymorphism, Genetic
D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming)