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Blog Archive

Wednesday, October 8, 2008

Pubmed paper: FMO (flavin-containing monooxygenase enzyme) induced in mice by aryl hydrocarbon.

Pubmed paper September 2008
ARYL HYDROCARBON RECEPTOR (AHR)-DEPENDENT INDUCTION OF FLAVIN-CONTAINING MONOOXYGENASE mRNAs IN MOUSE LIVER.
www.ncbi.nlm.nih.gov/pubmed/18765683

This is a paper published recently by researchers at the University of Toronto, where mice were shown to have FMO3 induced by a xenobiotic (aryl hydrocarbon). It's unclear if this has any significance to poor FMO3 function in humans, but does seem to put a few small dents in what students are taught at medical school, that FMO3 enzyme is neither inducible nor inhibitable (although this was already disproven when indoles were shown to inhibit the enzyme in 1999). They were testing the detox enzymes with aryl hydrocarbon in 2006 and discovered FMO was inducible, so it looks like they concentrated on FMO in particular this time.

Probably most/all FMO/TMAU experts will regard FMO as uninducible.

The lead researcher was asked about the finding in an email, and replied that he doesn't think it has any promise to helping TMAU currently. He is about to retire and his lab does not research metabolism directly, so it looks like that line of research from that group may have run it's course. How much impact this has on understanding FMO is unkown.

The full paper is available free in PDF format on this site: Drug Metabolism and Disposition

It is not known whether TCDD can induce hepatic FMO3 in humans. We aligned the mouse AHR-associated region with human and rat genomes by a BLAT analysis (Kent, 2002); see Suppl Fig. 5). The mouse AHR-associated region showed minimal overlap with genomic sequences in human (26 of 78 base-pairs aligning) or in rat (20 of 78 base-pairs aligning). Further, the aligned regions are on separate chromosomes from the FMO3 gene in each species. Taken together these results suggest that the AHR-binding-element is part of a mouse-specific regulatory module and, at present, it cannot be inferred from promoter analysis in silico whether human FMO3 is likely to be inducible by AHR agonists.

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