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Saturday, August 27, 2011

New FMO3 paper : Cancer drug found to use FMO3 as a pathway

Flavin monooxygenases, FMO1 and FMO3, not cytochrome P450 isoenzymes, contribute to metabolism of anti-tumour triazoloacridinone, C-1305, in liver microsomes and HepG2 cells

Fedejko-Kap B, Niemira M, Radominska-Pandya A, Mazerska Z.
Source : Department of Pharmaceutical Technology and Biochemistry, Chemical Faculty, Gdańsk University of Technology , Gdańsk , Poland



With the enzyme 'flavin containing mono-oxygenase isoform 3' (FMO3) being involved with (mostly) oxidizing many compounds of a certain structure with a sulfur, nitrogen (amine), and phosphorous molecule, with many being odorous, and being recognised as being at fault for causing trimethylaminuria; FMO3 is always of interest to the blog.

This paper is not of any direct relevance to people with FMO3 deficiency or FMO3 substrate overload or TMAU, but indirectly it is useful in that the pharmaceutical industry are always interested in how the body metabolizes their drugs and concerned about lawsuits due to unforeseen bad reactions which are often due to some issue with the xenobiotic metabolizing enzymes (known in the industry as the 'drug metabolizing enzymes'). Often when drugs are withdrawn from sale it is because of an unforeseen interaction with the DME's, one of which is FMO3. For some reason FMO3 has been a neglected DME, with most interest being in the CYP family of enzymes, and there has not been much interest in FMO3 from the main part of our medical research industry; the drug manufacturers. Probably because there is no obvious life threatening or visual disorder associated with FMO3 deficiency or overload other than TMAU (which in most cases seems very transient). At the moment if someone has 0% function of the FMO3 enzyme, it is thought they would have no problem other than (in the medical system's view) the 'trivial' problem of TMAU. However, it seems the FMO3 enzyme deals with 1,000's of substrates in everyday metabolism, including with things from our environment (including from diet and the gut flora) as well as 'internally' (like neurotransmitters, hormones etc). So although lack of FMO3 may not show any obvious health problem that could interest the medical system, it does seem that it is important for fully metabolizing 1,000s of substrates in our body.

The pharmaceutical industry, as well as wishing to make their drugs work as best they can, are also extemely concerned about bad reactions that could lead to lawsuits. So any drug that is proven to use the FMO3 enzyme for metobolism could lead to interest in FMO3 research overall, and this would be good for anyone with an FMO3 issue. In this case it seems to be a drug that is used for cancer. The researchers have shown that FMO3 seems to activate the drug for it to have its effect. It seems to also inhibit two of the main enzymes from the CYP family, which for some reason they are seeing as a good thing in this case.

The post author has no formal qualification in the subject, therefore we asked an expert if they would like to make any comment on the post. Dr John Cashman, a long-time researcher in the FMO family of enzymes kindly made the following comments :

DR. JOHN CASHMAN: Yes, I suspect there are 1000 FMO substrates ... or more. Just needs to be looked at. (Re drug metabolism and FMO) While a number of important drugs have been characterized as human FMO substrates, I suspect only about 5% of the commercially used drugs have been reported as FMO substrates. Most drugs (70% or so) are metabolized by CYP. After that, about 20% is glucuronidated or otherwise conjugated. The reason for this is that historically, the way metabolism studies were done favored CYP and actually decreased FMO functional activity. So the upshot is less evidence for FMO-related pathways and more evidence for CYP pathways.

Another reason FMO is off the radar screen is that FMO has not been associated with a wide variety of adverse drug-drug interactions as has CYP. So CYP gets all the focus because of these adverse reactions. Of course this is a good thing for FMO and I have written in the literature re the advantages of FMO in the metabolism of a drug.



links of interest :
2011 : FAD-dependent enzymes involved in the metabolic oxidation of xenobiotics
A physiological role for flavin containing monooxygenase (FMO3) in humans?
A common FMO3 polymorphism may amplify the effect of nicotine exposure in sudden infant death syndrome
Role of flavin-containing monooxygenase in drug development
Flavin-containing monooxygenases: mutations, disease and drug response
Flavin-containing monooxygenase 3 and human disease
Flavin-containing monooxygenase genetic polymorphism: impact on chemical metabolism and drug development
Mammalian flavin-containing monooxygenases: structure/function, genetic polymorphisms and role in drug metabolism

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