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Tuesday, January 25, 2011

New FMO research paper from Phillips & Shephard

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
Of the few researchers into the Flavin containing mono-oxygenase family of enzymes, 2 of the most prominent over the years have been Professors Elizabeth Shephard of University College, and Ian Phillips of Queen Mary University, both in London.

Today they release a new paper on the FMO family of enzymes, this time using knockout mice to remove the FMO family from the mice and see how they react to drugs known to use FMO enzymes to metabolize the drugs.

Only the abstract is available for free, so little can be drawn from the abstract itself. Some may recall that one of Dr Christodolou's proposals for a TMAU research project was in part to develop FMO knockout mice. Unfortunately that research never proceeded due to lack of funding

Any research about the FMO family of enzymes is likely to be of interest to someone with genetic TMAU, since TMAU is at this point regarded as strictly being due to deficiency in FMO3, but perhaps other FMO's may be found to play a role in the future. Currently there are 6 forms of FMO known (FMO 1-6).

The potential of knockout mouse lines in defining the role of flavin-containing monooxygenases in drug metabolism.
Shephard EA, Phillips IR.

University College London, Institute of Structural and Molecular Biology, Gower Street, London WC1E 6BT, UK. e.shephard@ucl.ac.uk

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.

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