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Wednesday, July 29, 2009

FMO3 paper July 2009 : Expression and characterization of functional dog flavin-containing monooxygenase 3

At the moment, FMO3 enzyme is a main suspect in most cases of 'genetic metabolic' body odor, although trimethylaminuria is the only documented form of metabolic body odor associated with this enzyme. So any research into FMO3 is of interest. especially since it is probably the most neglected and least-researched of the xenobiotic metabolizing enzymes, despite being very abundant in the liver and one of the most used, dealing with 1,000s of substrates.

Being one of the drug-metabolizing enzymes, it makes it the more surprising that little is known about FMO3, since it means those with suboptimal FMO3 function may be expected to react badly to drugs that use FMO3 for activation/detoxication.

Presumably this is why some Pfizer researchers have published this paper, being interested in the 'pharmacokinetics' of FMO3. They were investigating whether beagle FMO3 function closely co-related with human FMO3 function, since normally animals are tested upon, before human trials of new drugs. It looks as if dog FMO3 has substantial differences to human FMO3.

Pubmed abstract: http://www.ncbi.nlm.nih.gov/pubmed/19635782

Full article: http://dmd.aspetjournals.org/cgi/reprint/dmd.109.027714v1

Below are some quotes that may be of interest to metabolic body odor sufferers:

The flavin-containing monooxygenases (FMOs) are a family of enzymes capable of catalyzing the oxidation of various drugs, xenobiotics and endogenous substrates containing a soft nucleophile, usually nitrogen or sulfur (Cashman, 2000; Krueger and Williams, 2005). In humans, FMO-dependent drug metabolism can have important clinical implications (Cashman, 2000). Like cytochrome P450s, the FMOs are microsomal enzymes that require NADPH and O2, and FMOs have shown overlapping substrate specificity with P450s. FMOs also typically convert their xenobiotic substrates into more polar products that are less pharmacologically-active and more easily excreted, thereby enhancing their elimination from the body (Cashman, 1995). The mammalian FMO gene family includes five different isoforms (FMO1 through FMO5) (Lawton et al., 1994). In humans, as well as in a variety of preclinical species, tissue distribution patterns of FMO isoforms have been described (Cashman and Zhang, 2006; Phillips and Shephard, 2008). FMO3 is the most abundantly expressed isoform in adult human liver, existing at levels similar to the major human liver P450 isoform, CYP3A4 (Haining et al., 1997). FMO3 has been observed to contribute to the metabolic clearance of a variety of drugs, e.g. cimetidine, nicotine, and tamoxifen, as
well as the diet-derived substrate trimethylamine (Cashman et al., 1992; Cashman et al., 1993; Mani et al., 1993). It has been demonstrated that FMO3 is essential for the N-oxygenation and metabolic clearance of trimethylamine (Dolphin et al., 1997; Lang et al., 1998). This led to the discovery that human FMO3 is also a highly polymorphic gene (Koukouritaki et al., 2005). Specifically, a total of 29 allelic variants of FMO3 have each been observed to be associated with the human condition known as trimethylaminuria or “fish odor syndrome” (Phillips and Shephard, 2008).

Preclinical species, e.g. mouse, rat, dog, monkey, serve as a valuable tool for the drug discovery and drug development process. Data obtained from in vivo metabolism and toxicology studies in these models are essential for scaling and prediction of pharmacokinetic and pharmacodynamic behavior of drug candidates to be potentially administered to humans. Importantly, the accuracy of such predictions greatly depends on similarity of metabolic processes between species. This makes it particularly important to have a complete characterization of the metabolic pathways of a candidate compound in a given species prior to determination of safe doses for humans. The dog is the most widely used nonrodent species in preclinical drug safety studies (Gad and Gad, 2003). We suggest that to gain a definitive understanding of the relevance of drug metabolism in dogs to that in humans, a characterization of species differences in FMOs is necessary

In summary, our study has demonstrated that dFMO3 is expressed at appreciable levels in beagle dog liver as well as in lung. Given that FMO3 is the major form expressed in human liver, expressed dog FMO3 could be an important preclinical tool when it comes to comparing pathways of hepatic drug metabolism. Our data demonstrates that dFMO3 is capable of catalyzing the N- and S-oxidation of prototypical FMO substrates. Importantly, given that the kinetic data for dFMO3 displayed some significant differences when compared with hFMO3, additional characterization of the enzyme will be necessary in order to properly interpret data from preclinical experiments where FMO3 appears to have a role. While there is considerable information on species differences in tissue distribution and expression profiles of FMOs, there is relatively little information describing metabolism of specific FMO substrates (or substrates with specific structural features) across all species. Conversely, studies that compare not just enzyme activity but also the effect of structural properties on kinetic parameters may provide greater insight and appreciation for the catalytic function of the dog FMO3 isoform and other FMO3 orthologs.

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