Shephard/Phillips TMAU webinar 09/12

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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. 1. FMO3 bugs, genes and drugsElizabeth Shephard and Ian Phillips webinar, September 2012
    2. 2. FMO3 Flavin-containing monooxygenase 3• FMO3 – mutations can cause Trimethylaminuria, TMAU• FMO3 – is a drug metabolising enzyme
    3. 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. 4. FMO3 and trimethylaminuria Choline bacterial GUT action Trimethylamine (TMA) TMALIVER FMO3 XFMO3 trimethylaminuria TMA N-oxide
    5. 5. GENES FMO3 mutations causative of TMAuria or implicated in the disorder T201K M405IfsXR51G N114S A52T I199T R238P E314XE32K M82T P153L W388X G475D R308Q Q470X 532 M66I G148X R223QI37T M434I R500X V143E D198E E305X V58I K64KfsX2 C197fsX K394KfsX11 R492W R387L N61S
    6. 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. 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 reducedNature Genetics, 1997, 17(4): p. 491-4 Dolphin, Janmohamed, Smith, Shephard, Phillips
    8. 8. Diagnosis - Urine analysisMeasures the concentrations of TMA and TMA N-oxideResults 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%
    9. 9. Secondary TMAU• Acquired TMAU – viral hepatitis• Bacterial overgrowth in intestine• Disease states – Liver and kidney• Transient TMAU – Childhood – Menstruation – Precursor overload
    10. 10. Other factors that increase TMA in urine• Urinary tract infection• Bacterial vaginosis• Cervical cancer• Note for these conditionsTMA N-oxide:TMA + TMA N-oxide is normal
    11. 11. TMAU information links• GeneReview of Trimethylaminuria www.ncbi.nlm.nih.gov/books/NBK1103/• Clinical Utility Gene Card of Trimethylaminuriawww.eurogentest.orgClick on trimethylaminuria to download PDF
    12. 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. 13. Detoxification O O drug e.g. N-oxide S-oxideor other foreign FMO3 chemical and TMA Liver
    14. 14. Pharmacogenetics• How our genes influence the way we handle a drug • Absorption • Distribution • Clearance (e.g. FMO)
    15. 15. Why drug metabolism and clearance matters Plasma concentration Plasma concentrationMetabolism and drug concentrationdrops before next dose Limited or no metabolism drug concentration does NOT drop before next dose Potential for adverse effect
    16. 16. Examples of FMO3 drug substratesDrug Class of drugBupivacaine; Lidocaine AnaestheticsBenzydamine Anti-inflammatory (throat lozenges and sprays) *Chlorpromazine Anti-psychoticClozapine Anti-psychoticFluphenazine Anti-psychoticOlanzapine Anti-psychoticPerazine Anti-psychotic(S)-Nicotine Neuronal stimulantTamoxifen Anti-estrogen * Impaired metabolism in TMAU individuals
    17. 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. 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. 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. 20. Drug recycling (retro-reduction) CYP Imipramine DesipramineFMO Several enzymesImipramine N-oxide
    21. 21. Multi-pathway Drug metabolism 80% Pathway A Drug 20% Pathway B 10% Drug Pathway A (impaired) 90% Pathway B
    22. 22. FMO3 genotype and treatment of colon polyps with sulindac E158K E308G 532 Gut bacteria FMO3sulindac sulindac sulphide sulindac sulphoxideprodrug active drug inactive
    23. 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

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