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Drug Metabolism

PostPosted: Thu Dec 08, 2011 1:16 pm
by dotty111
I have been diagnosed with secondary TMAU via urine test, but my DNA genotyping, purchased from 23andMe, shows I have some of the genetic variations that predispose me to TMAU. In this situation, would I have secondary TMAU or mild Primary TMAU?

I experience intermittent TMAU, generally dependent on the food I eat, but this is not my main area of interest...
I experience severe, debilitating reactions to most medications that I am prescribed, this is a huge problem at the moment because I have uncontrolled high blood pressure.
I also find that supplementation of Progesterone, as part of my HRT regime, significantly affects the way I metabolise some drugs, and possibly affects metabolisation of oestrogen too.
Both my mother and my grandmother also experienced severe side effects to medication, so I presume this to be a congenital condition.
I am trying to find in-depth information about this subject but I've found that TMAU is the main focus of discussion regarding problems with the FMO3 gene.

I am trying to find a Consultant or Researcher who can help me re: drug intolerances (and inappropriate tolerances too!) and with metabolisation of environmental chemicals. I am in London and attend various clinics at Guy's/St.Thomas' and Chelsea & Westminster. Referral via GP or one of my Consultants can be obtained easily, but nobody seems to quite know who to refer me to...

I would be grateful for any possible help!

Re: Drug Metabolism

PostPosted: Fri Dec 09, 2011 11:53 am
by PoetFire
Hi Dotty

Yes I think your reactions to medicines could be due to sub-normal FMO3 function. Even if you are just a 'carrier', it may be enough to cause problems with big loads because of 'no reserve capacity'. FMO3, as well as dealing with 'external' compounds (and internal) is also a 'drug metabolizing' enzyme that activates or detoxifies drugs. It probably deals with 1,000s of compounds (that are a certain structure and contain a sulfur, nitrogen or phosphorous molecule)

It could be one of the other drug metabolizing enzymes too, such as the CYP450 family which complement FMO3 in oxidizing things. Maybe you have a weakness in that system and/or FMO3.

There was some talk that FMO3 might be associated with high blood pressure in some because an amine that controls HBP is a good FMO3 substrate. A later paper said no but it wouldn't surprise me. Not always. My own BP is fine.

Personally I suspect anyone with a 'smell problem that is regarded as TMAU2 probably has a weakness in their FMO3 system, but they are told not to DNA test so nobody knows yet. They may only be 'carriers' (in theory) but in real life they probably have 'no reserve capacity' at least, or even can sometimes dip into TMAU1 zone.

The only NHS Dr I can think will be of any help to you is Dr Robin Lachmann at UCL although that might not meet your expectations. Everyone is pretty conservative about what FMO3 is to blame for at the moment.

Genetics is not as black and white as I expected. If you have a collection of small faults it can be enough to dip you into TMAU1 zone sometimes in my opinion. It's a % game, depending on the loads at anytime too.

Re: Drug Metabolism

PostPosted: Fri Dec 09, 2011 11:57 am
by PoetFire
My apologies. I didn't realise this was the questions for Dr Dolphin thread.

Re: Drug Metabolism

PostPosted: Fri Dec 09, 2011 12:49 pm
by dotty111
PoetFire,

Thanks for your input.

I'm homozygous for a couple of the variations, so I guess that makes me more than a carrier?

The annoying thing was to not get the DNA results from 23andMe validated by a DNA test from the NHS - everything still just centers around the TMAU diagnosis, it doesn't go further than that. I understand the extreme social problems that having TMAU can bring, but, as mine is intermittent, it's essentially dealable with - I just need to keep the stress levels down and watch what I eat.
I see TMAU as a symptom of malfunctioning FMO3, not as a standalone problem in itself. Having said that, have I just disassociated myself from the rest of this forum, eek?!

I've been reading some of John R Cashman's recent research and the results are both alarming and interesting re: FMO3. Specific genotype variations seem to predict specific side effects of some drugs (in human models), and there also seems to be links between FMO3 problems and developing some illnesses (in mouse models).
My situation, apart from the drug/medication problems, is that I have a long-standing illness that defies diagnosis... I'm hoping that some genetic problem may be underlying this, as my father suffered similar symptoms before he died.

Being a mere Joe Bloggs, trying to get information that may help my situation is very difficult, apart from the problems of terminology, I trained as an artist not a biologist!

Re: Drug Metabolism

PostPosted: Fri Dec 09, 2011 1:38 pm
by PoetFire
Hi Dotty

Do you mind saying what variants you had diagnosed with 23andme ? I have also done that test. Unfortunately it was not as thorough as hoped. They only test 13 codons out of the 532 codons for FMO3, most being common variants which often are mostly regarded as 'less' of a problem than 'mutants', which can greatly affect function. You can send me a PM instead if you would rather say that way (if at all). 23andme was very limited but better than nothing.

You haven't disassociated yourself from me because I think I have 'FMO3 body odor' rather than just a problem with trimethylamine. TMA is special because it has no alternative pathway for detox. The theory is that all the others have alternative pathways but IMHO they build up in such large amounts that the whole system ends up log-jammed. With most substrates constantly sourced from the gut

I don't know about the others too, but I always feel lousy, which would be my main concern if it wasn't for the stress of smelling. I'm sure it will be 'FMO3 toxicity'.

Unfortunately FMO3 is currently regarded as the most 'trivial' of the drug metabolizing enzymes, and almost no research is going into it. Quite often they only find connections with these enzymes by accident, even the important ones. The 'fish odour' was only picked up because a mother said her child could smell fishy and they guessed it was TMA and only tested for that.

Re: Drug Metabolism

PostPosted: Wed Dec 14, 2011 1:25 pm
by kittycat
Thanks for this interesting thread people...You won't alienate anyone with your opinions Dotty, I think we all read the forums for the debates...In fact I decided to take B2 again after reading your post (and the recent ones on proboards)Tho I've read some alarming stories recently about overuse of supplements...and there's been a few cases of people using Fixodent(?) and the added zinc in it has depleted their bodies of copper, and damaged their bones..kcx

Re: Drug Metabolism

PostPosted: Wed Dec 14, 2011 1:59 pm
by smelly
dotty111,

dont ever feel bad for speaking outside of the 'tmau box' :) I think we all are probably aware that the odour we experience is only part of a range of things that are going wrong inside us, but the tmau diagnosis is all we have to go on. I dont really understand the bigger medical discussion but I love that others do and are asking the right questions. Its the only way to make any progress on this, so keep asking those questions please! :lol:

Re: Drug Metabolism

PostPosted: Fri Mar 16, 2012 10:21 pm
by FADworker
Hi Dotty

Without knowing what changes to the FMO3 gene sequence were found its difficult to say how they would affect your overall FMO enzyme activity although it sounds as though you have a couple of "reduced-function' variations that would generally decrease your total FMO activity resulting in the intermittent TMAU you experience. Other factors can/may alter FMO3 activity, eg. the activity may be depressed if you have a viral infection and it is known to be affected by a womans monthly cycle. So, as Poefire says, its esy to get tipped over into a situation where you have insufficient activity resulting in odour especially if you eat something high in a TMA precursor. Of course, nobody would ever know this if humans hadn't - for some unknown evolutionary reason - appeared to have retained an extraordinary good sense of smell for TMA and, at the same time, unfortunately generally find it unpleasant.

TMAU1 is really reserved for individuals who inherit two 'loss-of-function' FMO3 gene copies resulting in no FMO3 activity at all. As Poetfire says TMA is slightly unusual in that it is cleared from the body essentially via just one major metabolic pathway - oxidation to TMAO - and this oxidation reaction is mediated solely by FMO3. Most 'foreign compounds' (think drugs, pesticides, environmental pollutants and, of course, all the chemicals in the food we eat - not just the chemicals put there by modern farming but the 1000's of natural components as well) that we are exposed to are cleared via several different pathways each of which may have one or more 'drug-metabolizing' enzymes (DMEs for short) to catalyze the reaction. In other words there's a significant amount of redundancy built in.

I think any knock-on effects on drug metabolism would be marginal - yes, FMO3 does indeed metabolize a wide range of these foreign comounds but, as I've said above, there will usually be more than one metabolic pathway available and so a decrease in one enzyme - FMO3 - would be compensated for. There are other 'mutations' in other DME genes and its quite possible that you might have inherited some of these - some are relatively 'common' in comparison to those that affect FMO3 - but there is no simple NHS test available that would check all of these.

Hope that helps.