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
Different Therapeutic Aspects of Peroxisomes Proliferator-Activated ReceptorsAI Publications
Peroxisome proliferator-activated receptors (PPARs) was discovered in 1990 belong to the super family of steroid hormone receptors. Three subtypes of PPAR which have been identified so far- PPARα, PPARβ/δ, and PPARγ. Human peroxisome proliferator-activated receptors (hPPARs) were initially recognized as therapeutic targets for the development of drugs to treat metabolic disorders, such as diabetes and dyslipidemia but now they have been used in energy burning, dyslipidemia, diabetes, inflammation, Hepatic steatosis, liver cancer, diabetic neuropathy, atherosclerosis also. These are included in management of NIDDM, macrophage differentiation, adipose differentiation , anti-cancer, inhibition of TH2 cytokine production and rheumatoid arthritis. PPARβ/δ can use to treat Huntington’s disease, fertility, dyslipidemia. The functions of a third PPAR isoform and its potential as a therapeutic target are currently under investigation.
Metabolism of 5-FU, deoxyuridine, and dUTP in Brain Mitochondria:kathleenmccann
5-FU (5-flourouracil) is currently in clinical trials for treatment of gliomas.1 In neoplastic cells, this drug is metabolized by two pathways. 5-FU is converted to
5-dUMP by thymidine phosphorylase and thymidine kinase. 5-FdUMP then competitively inhibits the conversion of dUMP to TMP by thymidylate synthase. This increases dUTP and depletes the TTP needed for DNA synthesis and repair, leading to apoptosis. 5-FdUMP is further phosphorylated to 5-FdUTP and is incorporated into DNA. In the second pathway, 5-FU is phosphorylated by actions of uridine phosphorylase and uridine kinase to 5-FUMP and then further phosphorylated to 5-FUTP and incorporated into RNA. However, the metabolism of 5-FU is as yet undefined in brain. 5-FU neurotoxicity may present as leukoencephalopathy, cerebellar signs, or acute demyelination. The use of thymidine infusions to reverse symptoms strongly suggested that the neurotoxicity is caused by dNTP pool imbalance. It is necessary to understand the underlying mechanisms to minimize neurotoxicity and judiciously use therapeutic thymidine.
Deoxyuridine metabolism in the brain mitochondria is not fully understood. While a small amount is needed for RNA synthesis, incorporation of dUTP into mitochondrial DNA (mtDNA) can lead to mutagenesis and apoptosis, especially as base excision repair is known to be inefficient in brain mtDNA.
These investigations aim to establish the activity of the enzymes necessary for regulation of dUTP pools in brain mitochondria: dUTPase, thymidine phosphorylase, and thymidine synthase. We also investigate the metabolism of 5-flourouricil (5-FU), the metabolite of which, 5-FdUMP, functions as a dUMP analogue.
Different Therapeutic Aspects of Peroxisomes Proliferator-Activated ReceptorsAI Publications
Peroxisome proliferator-activated receptors (PPARs) was discovered in 1990 belong to the super family of steroid hormone receptors. Three subtypes of PPAR which have been identified so far- PPARα, PPARβ/δ, and PPARγ. Human peroxisome proliferator-activated receptors (hPPARs) were initially recognized as therapeutic targets for the development of drugs to treat metabolic disorders, such as diabetes and dyslipidemia but now they have been used in energy burning, dyslipidemia, diabetes, inflammation, Hepatic steatosis, liver cancer, diabetic neuropathy, atherosclerosis also. These are included in management of NIDDM, macrophage differentiation, adipose differentiation , anti-cancer, inhibition of TH2 cytokine production and rheumatoid arthritis. PPARβ/δ can use to treat Huntington’s disease, fertility, dyslipidemia. The functions of a third PPAR isoform and its potential as a therapeutic target are currently under investigation.
Metabolism of 5-FU, deoxyuridine, and dUTP in Brain Mitochondria:kathleenmccann
5-FU (5-flourouracil) is currently in clinical trials for treatment of gliomas.1 In neoplastic cells, this drug is metabolized by two pathways. 5-FU is converted to
5-dUMP by thymidine phosphorylase and thymidine kinase. 5-FdUMP then competitively inhibits the conversion of dUMP to TMP by thymidylate synthase. This increases dUTP and depletes the TTP needed for DNA synthesis and repair, leading to apoptosis. 5-FdUMP is further phosphorylated to 5-FdUTP and is incorporated into DNA. In the second pathway, 5-FU is phosphorylated by actions of uridine phosphorylase and uridine kinase to 5-FUMP and then further phosphorylated to 5-FUTP and incorporated into RNA. However, the metabolism of 5-FU is as yet undefined in brain. 5-FU neurotoxicity may present as leukoencephalopathy, cerebellar signs, or acute demyelination. The use of thymidine infusions to reverse symptoms strongly suggested that the neurotoxicity is caused by dNTP pool imbalance. It is necessary to understand the underlying mechanisms to minimize neurotoxicity and judiciously use therapeutic thymidine.
Deoxyuridine metabolism in the brain mitochondria is not fully understood. While a small amount is needed for RNA synthesis, incorporation of dUTP into mitochondrial DNA (mtDNA) can lead to mutagenesis and apoptosis, especially as base excision repair is known to be inefficient in brain mtDNA.
These investigations aim to establish the activity of the enzymes necessary for regulation of dUTP pools in brain mitochondria: dUTPase, thymidine phosphorylase, and thymidine synthase. We also investigate the metabolism of 5-flourouricil (5-FU), the metabolite of which, 5-FdUMP, functions as a dUMP analogue.
Nucleic acid metabolism is an important topic in metabolism paper which will be useful for B.Sc., M.sc ., Biochemistry ,Biotechnology,Microbiology and Medical Students
Nucleic acid metabolism is an important topic in metabolism paper which will be useful for B.Sc., M.sc ., Biochemistry ,Biotechnology,Microbiology and Medical Students
pharmacokinetics- action of body on the drug. includes absorption, dissolution, metabolism and excretion of drug. In this presentation metabolism and excretion of the drug are covered . Includes conversion of lipophilic / non-water soluble compounds into easily removable compounds by the action of hepatic enzymes which can be microsomal or non-microsomal . Excretion is further removal or elimination of compounds or agents from the body. Drug elimination is the sum of the processes of removing an administered drug from the body. In the pharmacokinetic ADME scheme (absorption, distribution, metabolism, and excretion), it is frequently considered to encompass both metabolism and excretion. Hydrophobic drugs, to be excreted, must undergo metabolic modification making them more polar. Hydrophilic drugs, on the other hand, can undergo excretion directly, without the need for metabolic changes to their molecular structures. Introduction
Most drugs are xenobiotics, ie, chemical substances not naturally produced by the body. Xenobiotics undergo various body processes for detoxification, thus reducing their toxicity and allowing them to be readily available for excretion. These processes allow for the chemical modification of drugs into their metabolites and are known as drug metabolism or metabolic biotransformation.
These metabolites are the byproducts of drug metabolism and can be characterized by active, inactive, and toxic metabolites. Active metabolites are biochemically active compounds with therapeutic effects, whereas inactive metabolites are biochemically inactive compounds with neither a therapeutic nor toxic effect. Toxic metabolites are biochemically active compounds similar to active metabolites but have various harmful effects.
Drug metabolism occurs at a specific location in the body, resulting in a low concentration of active metabolites in the systemic circulation. This phenomenon is called first-pass metabolism because it limits drug bioavailability. First-pass metabolism primarily occurs in the liver; however, metabolizing enzymes can be found throughout the body.
Understanding these alterations in chemical activity is crucial in utilizing the optimal pharmacological intervention for any patient. This is a topic of interest to any provider who routinely treats patients with medications. The metabolism of pharmaceutical drugs is an important aspect of pharmacology and medicine. For example, the rate of metabolism determines the duration and intensity of a drug's pharmacologic action. Drug metabolism also affects multidrug resistance in infectious diseases and in chemotherapy for cancer, and the actions of some drugs as substrates or inhibitors of enzymes involved in xenobiotic metabolism are a common reason for hazardous drug interactions. These pathways are also important in environmental science, with the xenobiotic metabolism of microorganisms determining whether a pollutant will be broken down or not is covered.pharmacokinetic
drug metabolism, phase I metabolism, biotransformation, Xenobiotics- substances foreign to body
Non polar lipid soluble compounds are made polar lipid insoluble, so that they are easily excreted.
Advantages of metabolism
Termination of drug action
↓ toxicity
Reduced lipophilicity.
Renal / biliary excretion ↑
↑ water solubility
↑ polarity
↑ excretion
Loss of phsiological activity
Active drug → more active drug
Non Active drug → active drug
Active drug → inactive drug
BIOTRANSFORMATION REACTIONS - 2 TYPES
Phase I / Non synthetic / Functionalization
A functional group is generated
Metabolite – active or inactive
Phase II / Synthetic / Conjugation
Metabolite is usually inactive
BIOTRANSFORMATION REACTIONS - 2 TYPES
Phase I / Non synthetic / Functionalization
A functional group is generated
Metabolite – active or inactive
Phase II / Synthetic / Conjugation
Metabolite is usually inactive
Depending upon nature and localisation of enzymes which catalyse reaction –
Microsomal enzymes
Non- Microsomal enzymes
Oxidation of alcohol
ethanol→ acetaldehyde → acetic acid →TCA cycle → CO₂
Eg.
chloral hydrate → trichloroacetic acid
mefenamic acid → hydroxy methyl derivative
ALIPHATIC HYDROXYLATION
Hydroxyl group added to drug
RCH2CH3 O RCHOHCH3
Salicylic acid to Gentisic acid
Ibuprofen
Tolbutamide, Chlorpropamide,
Knee anatomy and clinical tests 2024.pdfvimalpl1234
This includes all relevant anatomy and clinical tests compiled from standard textbooks, Campbell,netter etc..It is comprehensive and best suited for orthopaedicians and orthopaedic residents.
The Gram stain is a fundamental technique in microbiology used to classify bacteria based on their cell wall structure. It provides a quick and simple method to distinguish between Gram-positive and Gram-negative bacteria, which have different susceptibilities to antibiotics
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Lung Cancer: Artificial Intelligence, Synergetics, Complex System Analysis, S...Oleg Kshivets
RESULTS: Overall life span (LS) was 2252.1±1742.5 days and cumulative 5-year survival (5YS) reached 73.2%, 10 years – 64.8%, 20 years – 42.5%. 513 LCP lived more than 5 years (LS=3124.6±1525.6 days), 148 LCP – more than 10 years (LS=5054.4±1504.1 days).199 LCP died because of LC (LS=562.7±374.5 days). 5YS of LCP after bi/lobectomies was significantly superior in comparison with LCP after pneumonectomies (78.1% vs.63.7%, P=0.00001 by log-rank test). AT significantly improved 5YS (66.3% vs. 34.8%) (P=0.00000 by log-rank test) only for LCP with N1-2. Cox modeling displayed that 5YS of LCP significantly depended on: phase transition (PT) early-invasive LC in terms of synergetics, PT N0—N12, cell ratio factors (ratio between cancer cells- CC and blood cells subpopulations), G1-3, histology, glucose, AT, blood cell circuit, prothrombin index, heparin tolerance, recalcification time (P=0.000-0.038). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and PT early-invasive LC (rank=1), PT N0—N12 (rank=2), thrombocytes/CC (3), erythrocytes/CC (4), eosinophils/CC (5), healthy cells/CC (6), lymphocytes/CC (7), segmented neutrophils/CC (8), stick neutrophils/CC (9), monocytes/CC (10); leucocytes/CC (11). Correct prediction of 5YS was 100% by neural networks computing (area under ROC curve=1.0; error=0.0).
CONCLUSIONS: 5YS of LCP after radical procedures significantly depended on: 1) PT early-invasive cancer; 2) PT N0--N12; 3) cell ratio factors; 4) blood cell circuit; 5) biochemical factors; 6) hemostasis system; 7) AT; 8) LC characteristics; 9) LC cell dynamics; 10) surgery type: lobectomy/pneumonectomy; 11) anthropometric data. Optimal diagnosis and treatment strategies for LC are: 1) screening and early detection of LC; 2) availability of experienced thoracic surgeons because of complexity of radical procedures; 3) aggressive en block surgery and adequate lymph node dissection for completeness; 4) precise prediction; 5) adjuvant chemoimmunoradiotherapy for LCP with unfavorable prognosis.
Flu Vaccine Alert in Bangalore Karnatakaaddon Scans
As flu season approaches, health officials in Bangalore, Karnataka, are urging residents to get their flu vaccinations. The seasonal flu, while common, can lead to severe health complications, particularly for vulnerable populations such as young children, the elderly, and those with underlying health conditions.
Dr. Vidisha Kumari, a leading epidemiologist in Bangalore, emphasizes the importance of getting vaccinated. "The flu vaccine is our best defense against the influenza virus. It not only protects individuals but also helps prevent the spread of the virus in our communities," he says.
This year, the flu season is expected to coincide with a potential increase in other respiratory illnesses. The Karnataka Health Department has launched an awareness campaign highlighting the significance of flu vaccinations. They have set up multiple vaccination centers across Bangalore, making it convenient for residents to receive their shots.
To encourage widespread vaccination, the government is also collaborating with local schools, workplaces, and community centers to facilitate vaccination drives. Special attention is being given to ensuring that the vaccine is accessible to all, including marginalized communities who may have limited access to healthcare.
Residents are reminded that the flu vaccine is safe and effective. Common side effects are mild and may include soreness at the injection site, mild fever, or muscle aches. These side effects are generally short-lived and far less severe than the flu itself.
Healthcare providers are also stressing the importance of continuing COVID-19 precautions. Wearing masks, practicing good hand hygiene, and maintaining social distancing are still crucial, especially in crowded places.
Protect yourself and your loved ones by getting vaccinated. Together, we can help keep Bangalore healthy and safe this flu season. For more information on vaccination centers and schedules, residents can visit the Karnataka Health Department’s official website or follow their social media pages.
Stay informed, stay safe, and get your flu shot today!
Explore natural remedies for syphilis treatment in Singapore. Discover alternative therapies, herbal remedies, and lifestyle changes that may complement conventional treatments. Learn about holistic approaches to managing syphilis symptoms and supporting overall health.
Title: Sense of Smell
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the primary categories of smells and the concept of odor blindness.
Explain the structure and location of the olfactory membrane and mucosa, including the types and roles of cells involved in olfaction.
Describe the pathway and mechanisms of olfactory signal transmission from the olfactory receptors to the brain.
Illustrate the biochemical cascade triggered by odorant binding to olfactory receptors, including the role of G-proteins and second messengers in generating an action potential.
Identify different types of olfactory disorders such as anosmia, hyposmia, hyperosmia, and dysosmia, including their potential causes.
Key Topics:
Olfactory Genes:
3% of the human genome accounts for olfactory genes.
400 genes for odorant receptors.
Olfactory Membrane:
Located in the superior part of the nasal cavity.
Medially: Folds downward along the superior septum.
Laterally: Folds over the superior turbinate and upper surface of the middle turbinate.
Total surface area: 5-10 square centimeters.
Olfactory Mucosa:
Olfactory Cells: Bipolar nerve cells derived from the CNS (100 million), with 4-25 olfactory cilia per cell.
Sustentacular Cells: Produce mucus and maintain ionic and molecular environment.
Basal Cells: Replace worn-out olfactory cells with an average lifespan of 1-2 months.
Bowman’s Gland: Secretes mucus.
Stimulation of Olfactory Cells:
Odorant dissolves in mucus and attaches to receptors on olfactory cilia.
Involves a cascade effect through G-proteins and second messengers, leading to depolarization and action potential generation in the olfactory nerve.
Quality of a Good Odorant:
Small (3-20 Carbon atoms), volatile, water-soluble, and lipid-soluble.
Facilitated by odorant-binding proteins in mucus.
Membrane Potential and Action Potential:
Resting membrane potential: -55mV.
Action potential frequency in the olfactory nerve increases with odorant strength.
Adaptation Towards the Sense of Smell:
Rapid adaptation within the first second, with further slow adaptation.
Psychological adaptation greater than receptor adaptation, involving feedback inhibition from the central nervous system.
Primary Sensations of Smell:
Camphoraceous, Musky, Floral, Pepperminty, Ethereal, Pungent, Putrid.
Odor Detection Threshold:
Examples: Hydrogen sulfide (0.0005 ppm), Methyl-mercaptan (0.002 ppm).
Some toxic substances are odorless at lethal concentrations.
Characteristics of Smell:
Odor blindness for single substances due to lack of appropriate receptor protein.
Behavioral and emotional influences of smell.
Transmission of Olfactory Signals:
From olfactory cells to glomeruli in the olfactory bulb, involving lateral inhibition.
Primitive, less old, and new olfactory systems with different path
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