Webinar presentations : FMO3 : bugs, genes and drugs.
Speakers : Professors Elizabeth Shepahrd & Ian Phillips, speaking to the TMAU community of rareconnect.org. Slideshow by Professor Shephard
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Shephard/Phillips TMAU webinar 09/12
1. FMO3
bugs, genes and drugs
Elizabeth Shephard and Ian Phillips
webinar, September 2012
2. FMO3
Flavin-containing monooxygenase 3
• FMO3 – mutations can cause Trimethylaminuria, TMAU
• FMO3 – is a drug metabolising enzyme
3. BUGS
Gut microbiome
• Human body made up of ~1013 cells
• Our intestines contain ~1014 bacterial cells
• Gut microbiome is our second genome
• Now recognised as a key factor in health and
disease
4. FMO3 and trimethylaminuria
Choline
bacterial
GUT action
Trimethylamine
(TMA)
TMA
LIVER FMO3 XFMO3
trimethylaminuria
TMA N-oxide
6. Amino acids – different ways we name them
Full name 3 letter code 1 letter code
alanine ala A
glycine gly G
glutamic acid glu E
leucine leu L
lysine lys K
proline pro P
X = STOP
7. Primary TMAU –genetic basis
Enzyme activity trimethylamine trimethylamine N-oxide
P153
L153
Time (min.)
P (proline) at position 153 – normal enzyme activity
L (leucine) at position 153 – enzyme activity severely reduced
Nature Genetics, 1997, 17(4): p. 491-4 Dolphin, Janmohamed, Smith, Shephard, Phillips
8. Diagnosis - Urine analysis
Measures the concentrations of TMA and TMA N-oxide
Results are usually given as a percentage
TMA N-oxide
X 100
TMA + TMA N-oxide
Unaffected = 90 to 100%
Mild/moderate’ = 40 to 90 %
Severe = less than 40%
10. Other factors that increase TMA in urine
• Urinary tract infection
• Bacterial vaginosis
• Cervical cancer
• Note for these conditions
TMA N-oxide:TMA + TMA N-oxide is normal
11. TMAU information links
• GeneReview of Trimethylaminuria
www.ncbi.nlm.nih.gov/books/NBK1103/
• Clinical Utility Gene Card of Trimethylaminuria
www.eurogentest.org
Click on trimethylaminuria to download PDF
12. DRUGS
FM03 – is a drug metabolising enzyme
• Drugs (and other chemicals foreign to the body) have to
be removed.
• Evolved a defence mechanism to clear foreign chemicals
from the body – called detoxification.
• Foreign chemicals are changed (metabolised) and then
leave the body through the urine, bile and/or feces.
• Therapeutic drugs are foreign chemicals (as are e.g.
cosmetics and many dietary components).
13. Detoxification
O O
drug e.g. N-oxide
S-oxide
or other foreign FMO3
chemical
and
TMA
Liver
14. Pharmacogenetics
• How our genes influence the way we handle a
drug
• Absorption
• Distribution
• Clearance (e.g. FMO)
15. Why drug metabolism and clearance matters
Plasma concentration Plasma concentration
Metabolism and drug concentration
drops before next dose
Limited or no metabolism
drug concentration does NOT
drop before next dose
Potential for adverse effect
16. Examples of FMO3 drug substrates
Drug Class of drug
Bupivacaine; Lidocaine Anaesthetics
Benzydamine Anti-inflammatory (throat
lozenges and sprays) *
Chlorpromazine Anti-psychotic
Clozapine Anti-psychotic
Fluphenazine Anti-psychotic
Olanzapine Anti-psychotic
Perazine Anti-psychotic
(S)-Nicotine Neuronal stimulant
Tamoxifen Anti-estrogen
* Impaired metabolism in TMAU individuals
17. Cytochome P450 monooxygenases
CYPs
• We have a lot of different CYP genes
CYP1 family e.g. CYP1A1, CYP1A2, CYP1B1
CYP2 family e.g. CYP2C19, CYP2D6
CYP3 family e.g. CYP3A4
Many prescription drugs are metabolised by
CYP2C19, CYP2D6 and/or CYP3A4
18. Drugs are often metabolised by
more than one CYP and/or FMO
• Each enzyme might produce a different drug
metabolite
OR
• Several enzymes might produce the same metabolite
19. Multi-pathway drug metabolism
FMOs and CYPs
Response to the anti-depressant imipramine
CYP1A2
imipramine CYP2D6 desipramine
+ metabolites
FMO1 CYP3A4
imipramine N-oxide
20. Drug recycling
(retro-reduction)
CYP
Imipramine Desipramine
FMO Several enzymes
Imipramine N-oxide
22. FMO3 genotype and
treatment of colon polyps with sulindac
E158K E308G
532
Gut bacteria FMO3
sulindac sulindac sulphide sulindac sulphoxide
prodrug active drug inactive
23. Examples of ‘non-drug’ FMO3 substrates
Chemical Type or Origin
4-chlorophenyl methyl Environmental sulfides
sulphide ; Diphenyl sulphide
Aldicarb; Phorate ; Fenthion pesticides
(Phenylselenomethyl)- Fuel additive
trimethylsilane
Farnesylcysteine modified amino acid
Seleno-l-methionine Methionine analogue
Numerous metabolites ? Gut bacteria