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FMO3 bugs, genes and drugs Elizabeth Shephard and Ian Phillips webinar, September 2012 FMO3 Flavin-containing monooxygenase 3 • FMO3 – mutations can cause Trimethylaminuria, TMAU • FMO3 – is a drug metabolising enzyme 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 FMO3 and trimethylaminuria Choline bacterial action GUT Trimethylamine (TMA) TMA LIVER FMO3 TMA N-oxide XFMO3 trimethylaminuria GENES FMO3 mutations causative of TMAuria or implicated in the disorder R51G N114S A52T P153L E32K M82T M66I I37T V58I K64KfsX2 N61S G148X V143E T201K I199T R238P R223Q D198E C197fsX M405IfsX E314X R308Q E305X W388X G475D 532 Q470X M434I R500X K394KfsX11 R492W R387L 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 Primary TMAU –genetic basis trimethylamine N-oxide Enzyme activity trimethylamine 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 Diagnosis - Urine analysis Measures the concentrations of TMA and TMA N-oxide Results are usually given as a percentage TMA N-oxide TMA + TMA N-oxide X Unaffected = 90 to 100% Mild/moderate’ = 40 to 90 % Severe = less than 40% 100 Secondary TMAU • Acquired TMAU – viral hepatitis • Bacterial overgrowth in intestine • Disease states – Liver and kidney • Transient TMAU – Childhood – Menstruation – Precursor overload 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 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 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). Detoxification O O drug FMO3 or other foreign chemical and TMA Liver e.g. N-oxide S-oxide Pharmacogenetics • How our genes influence the way we handle a drug • Absorption • Distribution • Clearance (e.g. FMO) Metabolism and drug concentration drops before next dose Plasma concentration Plasma concentration Why drug metabolism and clearance matters Limited or no metabolism drug concentration does NOT drop before next dose Potential for adverse effect 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 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 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 Multi-pathway drug metabolism FMOs and CYPs Response to the anti-depressant imipramine CYP1A2 imipramine CYP2D6 desipramine + metabolites FMO1 imipramine N-oxide CYP3A4 Drug recycling (retro-reduction) Imipramine FMO CYP Several enzymes Imipramine N-oxide Desipramine Multi-pathway Drug metabolism Drug 80% Pathway A 20% Pathway B Drug 10% 90% Pathway B Pathway A (impaired) FMO3 genotype and treatment of colon polyps with sulindac E158K E308G 532 Gut bacteria sulindac sulindac sulphide prodrug active drug FMO3 sulindac sulphoxide inactive Examples of ‘non-drug’ FMO3 substrates Chemical Type or Origin 4-chlorophenyl methyl sulphide ; Diphenyl sulphide Environmental sulfides Aldicarb; Phorate ; Fenthion pesticides (Phenylselenomethyl)trimethylsilane Fuel additive Farnesylcysteine modified amino acid Seleno-l-methionine Methionine analogue Numerous metabolites ? Gut bacteria