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Idiosyncratic reactions: Individual factors leading to response (adverse reactions for instance) upon exposure to a xenobiotic Xenobiotic response Individual factors Pharmaco- or toxicological
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Xenobiotics = small M.W. foreign compounds - drugs, - atmospheric and alimentary compounds, - pollutants as well as natural products Exposure unavoidable
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Xenobiotic Metabolites A Metabolites B Elimination Influence of metabolism on xenobiotic response XME Target pharmaco toxico XME expression may vary according to - genetic - environmental factors
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Xenobiotic Metabolites Elimination Target: interactions with proteins (receptors enzymes…), ADN, lipids, small molecules Pharmacological or Toxicological response Defense system, immune system No response Exposure metabolism target Reaction (cell, organ, organism) Response
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Gene Medications Response linked to polymorphism Metabolism CYP2C9Tolbutamide, warfarin, phenytoin, Anticoagulant effect of warfarin nonsteroidal anti-inflammatories CYP2D6Beta blockers, antidepressants, antipsychotics,Tardive dyskinesia from antipsychotics codeine, debrisoquin, dextromethorphan,narcotic side effects, efficacy, and encainide, flecainide, guanoxan,requirement; beta-blocker effect methoxyamphetamine, N-propylajmaline, perhexiline, phenacetin, phenformin, propafenone, sparteinedependence; imipramine dose Dihydropyrimidine dehydrogenase FluorouracilFluorouracil neurotoxicity Thiopurine methyltransferaseMercaptopurine, thioguanine, azathioprineThiopurine toxicity and efficacy; risk of second cancers Transport mdr1digoxin, anti HIVplasma concentration, effect Target ACE Enalapril, lisinopril, captoprilRenoprotective effects, cardiac indices, blood pressure, immunoglobulin A nephropathy Potassium channels HERGQuinidine Drug-induced long QT syndrome CisaprideDrug-induced torsade de pointe KvLQTTerfenadine, disopyramide, meflaquineDrug-induced long QT syndrome hKCNE2ClarithromycinDrug-induced arrhythmia
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THIOPURINE METHYL-TRANSFERASE (TPMT) AZATHIOPRINE METABOLISM AZATHIOPRINE 6-MERCAPTOPURINE TPMTHGPRT, … XO 6-MMP 6-THIOGUANINE Ntides 6-TGN THIOURIC ACID ACTIVE TOXIC GSTs
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Xenobiotic Metabolites B Elimination Interaction with cell, receptor Target: interactions with proteins (receptors enzymes…), ADN, lipids, small molecules Pharmacological or Toxicological response Defense system, immune system No response Exposure metabolism target Reaction (cell, organ, organism) Response
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68% of the patients have an altered p53 in the tumor. 87% of non responders and 57% of the responders (p<0,003) have an alteration of p53. Response to chemotherapy in head and neck cancer
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Logistic regression Cabelguenne et coll. Response to chemotherapy in head and neck cancer
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Xenobiotic Metabolites B Elimination Interaction with cell, receptor Target: interactions with proteins (receptors enzymes…), ADN, lipids, small molecules Pharmacological or Toxicological response Defense system, immune system No response Exposure metabolism target Reaction (cell, organ, organism) Response
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Hepatitis Tienilic acidquinolones Dihydralazineanti-HIV carbamazepine anticonvulsants Diclofenac Halothane Iproniazid Agranulocytosis sulfamidesClozapine Blood dyscrasias Procainamideanti-HIV aminopyrine clozapine carbamazepine propylthiouracile hydralazine Systemic lupus erythromatosus hydralazine sulfamides Toxidermias sulfamidesquinolones anticonvulsantsNSAIDs penicillinsanti-HIV Examples of drugs inducing adverse immune reactions
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* These diseases are life-threatening * They cannot be predicted * which individuals? * which drugs? * Mechanisms? -----> prediction * metabolism * individual reaction
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Xenobiotic: X Reactive Metabolite: RM* P-RM* EMR* Neoantigen Presentation to the immune system Immune response depends on many factors variable 2 nd exposure control exposure Metabolism Toxic response
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N O NHSO 2 H 3 C NH 2 N O NHSO 2 H 3 C NHOH N O NHSO 2 H 3 C NO NAT2 UGT GSH from Park et al. 1998 Detoxication CYP 2C9
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Lyell syndrome, TEN: very severe toxidermia to sulfamides 13/14 NAT2 -
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Toxidermias in AIDS patients treated with sulfamides NGSTM1 - / NAT2 - (%) Patients with Tx 4146 (OR=2.5) Patients withoutTx 7925 Total13032 Wolkenstein et al. 2000
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Genotype/Phenotype discrepency in AIDS patients 64 Patients slowrapid phenotype559 Genotype3034 25 discrepencies genotype fast/phenotype slow checked by sequence Disease may modify the phenotype
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Response is also dependent on immune response * In the same study: CD8+ above median --> OR 5,7 p<0,0005), Wolkenstein et al. * HLA A30B13Cw6 more frequent than in control population ( Oszkaya-Bayazit, J. AM. Acad. Dermatol. 2001) Response is dependent on target cells GST P1 genotype: GST P1*B are protected against toxidermias (OR~9.5 p< 0,005 Wolkenstein et al.
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Toxicity of sulfamides linked to -Metabolism ± (NAT2/GST…) - Organism response + (GSTP1…) - Immune response ++ (CD8, HLA…) - multistep - each factor has influence
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Xenobiotic: X Reactive Metabolite: RM* P-RM*EMR*Neoantigen Presentation to the immune system Immune response depends on many factors variable 2 nd exposure control exposure Metabolism Toxic response
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Autoantibodies against xenobiotic metabolizing enzymes diseasexenobioticautoantibodies hepatitistienilic acidCYP2C9, LKM2 dihydralazineCYP1A2, LM anticonvulsantsCYP? halothaneCYP2E1 iproniazideMAO B ?CYP2D6, LKM1 ?UGT, LKM3 ?GST agranulocytosisclozapineMPO Addison or PGS? CYP 17, 21, Scc CYP 1A2 CYP 2A6
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DRUG Immune response autoantibodies Reactive metabolite: R* R*-P neoantigen R*-E Enzyme: E P 1 2 3 4 4 4
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CYP 2C9 Neoantigen: AT-CYP 2C9 tiénilic acid Hépatitis anti LKM2 Immune response autoantibodies 1 2 4 3 H2OH2O S C O Cl OCH 2 COOH Cl Ar S C O S C O O S C O HO
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Covalent Binding with human liver microsomes and yeasts expressing a single human P450 Tienilic acid pmol/min/nmolP450 Human liver microsomes 98 control yeasts0 1A177 1A241 2C88-10 2C9340-380 2C1845-42 2C1941 2D66 3A40-0
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SPECIFICITY of the COVALENT BINDING of TIENILIC ACID on HUMAN LIVER MICROSOMES. 50403020100 0 1000 2000 P 450 2C cpm/band protein migration protein migration # bands with NADPH without NADPH
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R* enzyme xenobiotic enzyme xenobioticR* enzyme R* enzyme + Covalent binding
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Links between the formation of a protein-adduct and an abnormal immune reponse
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In most cases a reactive metabolite was produced; it was able bind to protein(s) (covalent binding). Tienilic acid Halothane CHFC Dihydralazine Diclofenac Carbamazepine Sulfamide procainamide Clozapine Phenytoin Iproniazide......
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Hypothesis: the quantity of reactive metabolite is important - high production of reactive metabolite - concentration of RM on one target - dose adverse drug reaction - RM * adverse drug reaction
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Hypothesis: the quantity of reactive metabolite is important - high production of reactive metabolite - concentration of RM on one target - dose adverse drug reaction - RM * adverse drug reaction
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Captoril: lower doses -------> lower incidence Halothane: high variability in the covalent binding Isoflurane and enflurane: lower covalent binding lower incidence hepatitis CHFC: ???? clozapine / olenzapine: highest covalent binding = highest incidence agranulocytosis anticonvulsants, sulfamides: higher sensitivity in patients with higher production of RM*
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Xenobiotic: X Reactive Metabolite: RM* P-RM*EMR*Neoantigen Presentation to the immune system Immune response depends on many factors variable 2 nd exposure control exposure Metabolism Toxic response
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Animals models - difficult: many factors to control - metabolism - generation of hapten - variable immune response * genetic *non genetic
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* Lewis, Th1: Dihydralazine p.o. : liver disease, inflammation, no autoantibodies Dihydralazine, hapten s.c.: liver disease, inflammation no autoantibodies * BN (HgCl2), Th2: Dihydralazine, hapten s.c.: no liver disease, no inflammation autoantibodies Tienilic acid, hapten s.c.: no liver disease, no inflammation no autoantibodies
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Animal model Conclusions * No complete disease was observed * Partial response Th1: inflammation, liver disease Th2: autoantibodies * Autoantibodies: not pathogenic * Control of immune system * unknown factors such as infection
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Xenobiotic: X Reactive Metabolite: RM* P-RM*EMR*Neoantigen Presentation to the immune system Immune response depends on many factors variable 2 nd exposure control exposure Metabolism Toxic response
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Xenobiotic Protein: P* Molecular mimicry: P Reactive metabolite M* Enzyme: P NEOANTIGEN P* or P-M* Immune response: presentation, processing, HLA B cells, autoantibodies, epitopes T cells, Th1/Th2 Tolerance Rare diseases not very well understood not predictable (xenobiotic, individuals) Auto-Ab Ab Auto-Ab Scheme 2
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Anti-HIV treatments lead to: - high prevalence of adverse reactions (Fellay et al. Lancer 2001) - hyperlipidémia (SREBP1c, ABC Cassette) - numerous drug interactions (metabolism) - variation in response (metabolism and transport) Abacavir (Mellal et al. Lancet 2002) - 4 to 9% ADR - linked to HLA57
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Xenobiotic Metabolites B Elimination Interaction with cell, receptor Target: interactions with proteins (receptors enzymes…), ADN, lipids, small molecules Pharmacological or Toxicological response Defense system, immune system No response Exposure metabolism target Reaction (cell, organ, organism) Response Conclusions
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Becquemont, Pharmacogenomics 2010 HLA-B*5701 HLA-B*5801 HLA-B*1502 HLA-A*3101 HLA-B*3802 HLA-B*7301 HLA-DRB5*0201 HLA-B*1502 HLA-DRB1*1501 Abacavir hypersensitivity Flucloxacillin DILI cholestasis Allopurinol SJS Carbamazepine SJS (Asian) Phenytoin SJS (Asian) Carbamazepine SJS (european) Sulfomethoxazole SJS oxicams SJS Clozapine neutropenia Co-amoxiclav SJS
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D D-->R*-->R*P= Apoptosis Necrosis APC no signal 2 APC signal 2 danger signal Tolerance Helper T cell Helper T cell B and T cell mediated toxicity Mphages NK cells cells
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Autoreactive B-cell T-cell Autoantibodies production
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