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

Expert Opinion on Drug Metabolism & Toxicology
Elizabeth A Shephard, Ian R Phillips

Abstract

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. 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. 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. 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.

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Citations

Jun 29, 2014·Toxicological Sciences : an Official Journal of the Society of Toxicology·Swetha RudraiahJosé E Manautou
Jun 7, 2015·Biochemical Pharmacology·Sandra G Gonzalez MalagonElizabeth A Shephard
Dec 21, 2013·Toxicology and Applied Pharmacology·John D WatsonPaul C Boutros
Sep 30, 2016·Expert Opinion on Drug Metabolism & Toxicology·Ian R Phillips, Elizabeth A Shephard
Mar 12, 2020·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Sunil VeeravalliElizabeth A Shephard
Dec 25, 2019·Nature Structural & Molecular Biology·Callum R NicollAndrea Mattevi
Oct 25, 2020·Archives of Toxicology·Nuno G OliveiraRicardo Jorge Dinis-Oliveira

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