The potential of knockout mouse lines in defining the role of flavin-containing monooxygenases in drug metabolism

Abstract

Importance of the field: 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.

Areas covered in the review: 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.

What the reader will gain: 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.

Take home message: 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.

Keywords::

• clozapine
• drug metabolism
• FMO
• imipramine
• knockout mouse
• retro-reduction
• src kinase inhibitor
• tamoxifen

Notes

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