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Les Mutations Spontanées Du Gène Vkorc1 Chez L’Homme Et Le Rat : Réalité De La Résistance Ahmed Hodroge

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Les Mutations Spontanées Du Gène Vkorc1 Chez L’Homme Et Le Rat : Réalité De La Résistance Ahmed Hodroge Les mutations spontanées du gène Vkorc1 chez l’homme et le rat : réalité de la résistance Ahmed Hodroge To cite this version: Ahmed Hodroge. Les mutations spontanées du gène Vkorc1 chez l’homme et le rat : réalité de la résis- tance. Sciences agricoles. Université Claude Bernard - Lyon I, 2011. Français. NNT : 2011LYO10281. tel-00866731 HAL Id: tel-00866731 https://tel.archives-ouvertes.fr/tel-00866731 Submitted on 27 Sep 2013 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. N° d’ordre 281-2011 Année 2011 THESE DE L‘UNIVERSITE DE LYON Délivrée par L’UNIVERSITE CLAUDE BERNARD LYON 1 ECOLE DOCTORALE EDISS Pour l’obtention du DIPLOME DE DOCTORAT (arrêté du 7 août 2006) Soutenue publiquement le 13 décembre 2011 par Ahmed HODROGE TITRE : Les mutations spontanées du gène Vkorc1 chez l’homme et le rat. Réalité de la résistance. Directeur de thèse : Pr Etienne BENOIT & Dr Virginie LATTARD JURY : Mme Virginie LATTARD Chargée de Recherche CR1 CNRS- Nancy 1 Mme Sophie RAHUEL-CLERMONT Chargée de Recherche CR 1, CNRS-Nancy 1 Mme Helene GREIGE-GERGES Professeur, Faculté des Sciences-2- Liban M Etienne BENOIT Professeur, Campus Vétérinaire UCBL1 M François MION Professeur, faculté de Médecine UCBL1 M Yves MICHELIN Professeur, Campus agronomique-Clermont M François PENIN Ingénieur de Recherche CNRS UCBL1 1 Je tiens tout d’abord à remercier les membres de ce jury à Madame le Professeur Helene GREIGE-GERGES, qui m’a fait le plaisir et l’honneur d’être rapporteur de cette thèse et à qui j’exprime ma profonde gratitude. à Madame Sophie RAHUEL-CLERMONT, qui m’a fait l’honneur de s’intéresser à mon travail et qui a accepté d’être rapporteur de cette thèse. à Monsieur le professeur Yves MICHELIN, Directeur adjoint de l'UMR Métafort, qui m’a fait l’honneur et le plaisir d’accepter d’être rapporteur de ce travail. à Monsieur le professeur François MION, pour sa précieuse participation au jury et son soutien. Je le remercie très respectueusement. à Monsieur François PENIN, qui a accepté de participer au jugement de mon travail. à Monsieur le professeur Etienne BENOIT, et Madame Virginie LATTARD, pour leur encadrement, leur enseignement, leur confiance, leurs grandes qualités scientifiques et leur humour. Ce sont eux qui m’ont donné le goût de la recherche. Je leur dis Merci. Ce travail a été réalisé au sein de « USC 1233 Mycotoxines et toxicologie Comparée des xénobiotiques, à VetAgro Sup, campus vétérinaire de Lyon » Ce travail a bénéficié du soutien financier du Ministère de l’agriculture et de la pêche, de l’Institut Nationale de la Recherche Agronomique et de VetAgro Sup A mes parents Je tiens ensuite à remercier : Etienne BENOIT, qui m’a accueilli et encadré au sein de son laboratoire me permettant de réaliser ce travail, merci d’être toujours présent Virginie LATTARD, pour sont encadrement, sa confiance, qui m’a appris beaucoup, sans elle c’était loin d’être fini. Un petit coucou à Antoine et Chloé et à la famille BENOIT. Merci évidemment à toutes les personnes de l’école vétérinaire qui ont contribué de près ou de loin à la réalisation de cette thèse, que ce soit d’un point de vue technique ou par un simple soutien. A mes amis (par ordre alphabétique) : Abdé (bro), Adrien, Aurélia, Aymeric, Benjamin (Abdel bechir), Camille, Chloé, Gary, Jérôme (Maître), Olivier. Les amis du service de Biochimie, du service d’informatique et le laboratoire de Tox, d’Alim, du R.U, aux doctorants, pour nos discussions sérieuses et surtout moins sérieuses. A mes compatriotes libanais avec qui j’ai partagé quatre ans sur Lyon et particulièrement à Zeinab, Hussein, Mohamad…. A mon cousin et sa famille. Je souhaite enfin remercier tous mes proches (Hassan, Ali, Mona, Zahra, Abass, Aziza), en particulier toutes les personnes que j’aime et qui m’aiment. Table des matières 1 INTRODUCTION GENERALE.......................................................................................... 12 2 PARTIE BIBLIOGRAPHIQUE .......................................................................................... 14 2.1 La coagulation .................................................................................................................... 14 2.1.1 Hémostase primaire ....................................................................................................................... 14 2.1.2 La coagulation plasmatique ........................................................................................................... 16 2.1.3 La Fibrinolyse ou hémostase tertiaire............................................................................................ 19 2.2 Cycle de la vitamine K et coagulation .............................................................................. 21 2.2.1 Les vitamines K ............................................................................................................................. 21 2.2.2 Cycle de la vitamine K .................................................................................................................. 31 2.3 Les anticoagulants antivitaminique K .............................................................................. 46 2.3.1 Historique des antivitamines K ..................................................................................................... 46 2.3.2 Structure et propriétés physico-chimiques des AVKs ................................................................... 47 2.3.3 Mécanismes d’action des AVKs ................................................................................................... 50 2.3.4 Métabolisme des AVKs ................................................................................................................ 51 2.3.5 Utilisation pratique des AVKs en médecine humaine ................................................................... 54 2.4 La résistance aux anticoagulants ...................................................................................... 61 2.4.1 Définition de la résistance ............................................................................................................. 61 2.4.2 Historique de la résistance aux AVKs chez les rongeurs .............................................................. 61 2.4.3 Mécanisme de la résistance aux AVKs ......................................................................................... 64 2.4.4 Réalité de la résistance chez l’homme ........................................................................................... 71 3 OBJECTIFS DE MON TRAVAIL ...................................................................................... 79 4 STRATEGIE ..................................................................................................................... 82 5 MATERIELS ET METHODES .......................................................................................... 83 5.1 Matériels ............................................................................................................................. 83 5.1.1 Réactifs de biologie cellulaire ....................................................................................................... 83 5.1.2 Réactifs biochimiques ................................................................................................................... 83 5.1.3 Réactifs de biologie moléculaire ................................................................................................... 83 5.2 Méthodes expérimentales .................................................................................................. 84 5.2.1 Etude pharmacogénétique ............................................................................................................. 84 5.2.2 Etude biochimique......................................................................................................................... 87 6 RESULTATS .................................................................................................................... 94 6.1 Validation du modèle d’expression hétérologue de l’enzyme VKORC1 ...................... 94 3 6.1.1 Objectifs ........................................................................................................................................ 94 6.1.2 Méthodes ....................................................................................................................................... 95 6.1.3 Principaux résultats ....................................................................................................................... 95 6.2 Etude de l’implication des mutations de rVKORC1 dans la résistance aux AVKs ..... 97 6.2.1 Objectifs ........................................................................................................................................ 97 6.2.2 Méthodes ....................................................................................................................................... 97 6.2.3 Principaux résultats ......................................................................................................................
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