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1. Roadmap to DILI research in Europe. A proposal from COST action ProEuroDILINet

Author

Lucena, M.I., Villanueva-Paz, M., Alvarez-Alvarez, I., Aithal, G.P., Björnsson, E.S., Cakan-Akdogan, G., Cubero, F.J., Esteves, F., Falcon-Perez, J.M., Fromenty, B., Garcia-Ruiz, C., Grove, J.I., Konu, O., Kranendonk, M., Kullak-Ublick, G.A., Miranda, J.P., Remesal-Doblado, A., Sancho-Bru, P., Nelson, L., Andrade, R.J., Daly, A.K., and Fernandez-Checa, J.C.

Published
2024
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4. Roadmap to DILI research in Europe. A proposal from COST action ProEuroDILINet

Author

Instituto de Salud Carlos III, Agencia Estatal de Investigación (España), Ministerio de Ciencia, Innovación y Universidades (España), European Commission, Fundação para a Ciência e a Tecnologia (Portugal), Lucena, M. Isabel, Villanueva-Paz, M., Álvarez-Álvarez, I., Aithal, G. P., Björnsson, E. S., Cakan-Akdogan, G., Cubero, Francisco Javier, Esteves, F., Falcón-Pérez, Juan M., Fromenty, B., Garcia-Ruiz, Carmen, Grove, J. I., Konu, O., Kranendonk, M., Kullak-Ublick, G. A., Miranda, Joana, Remesal-Doblado, A., Sancho-Bru, P., Nelson, L., Andrade, Raúl J., Daly, A. K., Fernández-Checa, José C., Instituto de Salud Carlos III, Agencia Estatal de Investigación (España), Ministerio de Ciencia, Innovación y Universidades (España), European Commission, Fundação para a Ciência e a Tecnologia (Portugal), Lucena, M. Isabel, Villanueva-Paz, M., Álvarez-Álvarez, I., Aithal, G. P., Björnsson, E. S., Cakan-Akdogan, G., Cubero, Francisco Javier, Esteves, F., Falcón-Pérez, Juan M., Fromenty, B., Garcia-Ruiz, Carmen, Grove, J. I., Konu, O., Kranendonk, M., Kullak-Ublick, G. A., Miranda, Joana, Remesal-Doblado, A., Sancho-Bru, P., Nelson, L., Andrade, Raúl J., Daly, A. K., and Fernández-Checa, José C.

Abstract

In the current article the aims for a constructive way forward in Drug-Induced Liver Injury (DILI) are to highlight the most important priorities in research and clinical science, therefore supporting a more informed, focused, and better funded future for European DILI research. This Roadmap aims to identify key challenges, define a shared vision across all stakeholders for the opportunities to overcome these challenges and propose a high-quality research program to achieve progress on the prediction, prevention, diagnosis and management of this condition and impact on healthcare practice in the field of DILI. This will involve 1. Creation of a database encompassing optimised case report form for prospectively identified DILI cases with well-characterised controls with competing diagnoses, biological samples, and imaging data; 2. Establishing of preclinical models to improve the assessment and prediction of hepatotoxicity in humans to guide future drug safety testing; 3. Emphasis on implementation science and 4. Enhanced collaboration between drug-developers, clinicians and regulatory scientists. This proposed operational framework will advance DILI research and may bring together basic, applied, translational and clinical research in DILI.

Published
2024

8. Roadmap to DILI research in Europe. A proposal from COST action ProEuroDILINet

Author

Lucena, M I, Villanueva-Paz, M, Alvarez-Alvarez, I, Aithal, G P, Björnsson, E S, Cakan-Akdogan, G, Cubero, F J, Esteves, F, Falcon-Perez, J M, Fromenty, B, Garcia-Ruiz, C, Grove, J I, Konu, O, Kranendonk, M, Kullak-Ublick, G A, Miranda, J P, Remesal-Doblado, A, Sancho-Bru, P, Nelson, L, Andrade, R J, Daly, A K, Fernandez-Checa, J C, Lucena, M I, Villanueva-Paz, M, Alvarez-Alvarez, I, Aithal, G P, Björnsson, E S, Cakan-Akdogan, G, Cubero, F J, Esteves, F, Falcon-Perez, J M, Fromenty, B, Garcia-Ruiz, C, Grove, J I, Konu, O, Kranendonk, M, Kullak-Ublick, G A, Miranda, J P, Remesal-Doblado, A, Sancho-Bru, P, Nelson, L, Andrade, R J, Daly, A K, and Fernandez-Checa, J C

Abstract

In the current article the aims for a constructive way forward in Drug-Induced Liver Injury (DILI) are to highlight the most important priorities in research and clinical science, therefore supporting a more informed, focused, and better funded future for European DILI research. This Roadmap aims to identify key challenges, define a shared vision across all stakeholders for the opportunities to overcome these challenges and propose a high-quality research program to achieve progress on the prediction, prevention, diagnosis and management of this condition and impact on healthcare practice in the field of DILI. This will involve 1. Creation of a database encompassing optimised case report form for prospectively identified DILI cases with well-characterised controls with competing diagnoses, biological samples, and imaging data; 2. Establishing of preclinical models to improve the assessment and prediction of hepatotoxicity in humans to guide future drug safety testing; 3. Emphasis on implementation science and 4. Enhanced collaboration between drug-developers, clinicians and regulatory scientists. This proposed operational framework will advance DILI research and may bring together basic, applied, translational and clinical research in DILI.

Published
2023

11. NAFLD et dysfonction mitochondriale

Author

Roden, Dan, Fromenty, B., Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], Nutrition, Métabolismes et Cancer (NuMeCan), and Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)

Subjects
Oxidative stress, NAFLD, Obesity, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Mitochondria
Abstract

National audience; Numerous investigations have shown the presence of mitochondrial dysfunction in nonalcoholic fatty liver disease (NAFLD). While mitochondrial oxidation pathways are increased during simple steatosis, these adaptations wane during nonalcoholic steatohepatitis (NASH). The degradation of mitochondrial functions then continues during cirrhosis. These mitochondrial dysfunctions seem to be, at least in part, the consequence of inflammation. Patients with NAFLD should be discouraged from consuming alcohol, a molecule with many deleterious effects on mitochondria.; De nombreuses investigations ont mis en évidence la présence de dysfonctions mitochondriales au cours de la stéatose hépatique non alcoolique (NAFLD). Tandis que les oxydations mitochondriales sont plutôt augmentées au cours de la simple stéatose, ces adaptations métaboliques disparaissent lors de la stéatohépatite non alcoolique (NASH). La dégradation des fonctions mitochondriales se poursuit ensuite pendant la cirrhose. Ces dysfonctions mitochondriales semblent être, au moins en partie, la conséquence de l’inflammation. Les patients souffrant de NAFLD devraient être dissuadés de consommer de l’alcool, une molécule présentant de nombreux effets délétères sur les mitochondries.

Published
2023
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16. Hepatotoxicity of multikinase inhibitors Toxicité hépatique des inhibiteurs multikinases

Author

Danielou, M., Houron, C., Mir, O., Fromenty, B., Perlemuter, G., Voican, C.S., AP-HP. Université Paris Saclay, Cytokines, chimiokines et immunopathologie, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Gustave Roussy (IGR), Centre Hospitalier Universitaire [Rennes], Nutrition, Métabolismes et Cancer (NuMeCan), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), CHU Pontchaillou [Rennes], Département de médecine oncologique [Gustave Roussy], and Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)

Subjects
Drug-induced liver injury, [SDV]Life Sciences [q-bio], Hepatotoxicity, Multikinase inhibitors
Abstract

National audience; Les inhibiteurs multikinases (MKI) sont des molécules ciblées qui ont révolutionné la prise en charge des cancers. Cependant, il existe peu de données concernant le risque de toxicité hépatique de ces traitements et la gestion pratique de ces événements. Des perturbations asymptomatiques du bilan hépatique sont fréquemment observées dans les essais cliniques évaluant les MKI, mais les événements hépatotoxiques graves restent rares. Dans la majorité des cas, la période de latence varie d’une semaine à deux mois. La toxicité hépatique liée aux MKI est souvent de type hépatocellulaire et moins fréquemment mixte. Une amélioration du bilan hépatique est observée dans trois quarts des cas après l’arrêt du traitement par MKI, mais des cas d’hépatite médicamenteuse avec évolution fatale ont été rapportés. Le recours aux corticoïdes (20 à 40 mg/jour) a été nécessaire pour des cas d’hépatite liée à l’imatinib, au pazopanib et à l’association vémurafénib-ipilimumab. Puisqu’il n’existe actuellement aucune stratégie préventive, la détection précoce de l’hépatotoxicité aux MKI reste cruciale afin d’éviter les formes sévères. Pour cela, une surveillance de la fonction hépatique durant le traitement pourrait être utile. En l’absence de marqueur spécifique, il est important d’éliminer les autres causes d’atteinte hépatique pour éviter un arrêt non nécessaire de ces molécules.

Published
2021
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26. L’analyse du sérum par spectroscopie moyen infrarouge permet d’obtenir une signature du statut métabolique du foie chez la souris

Author

Le Corvec, M., primary, Allain, C., additional, Lardjane, S., additional, Cavey, T., additional, Turlin, B., additional, Fautrel, A., additional, Begriche, K., additional, Monbet, V., additional, Fromenty, B., additional, Leroyer, P., additional, Guggenbuhl, P., additional, Ropert, M., additional, Sire, O., additional, and Loréal, O., additional

Published
2016
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28. Predictive toxicology: the paths of the future

Author

Detilleux, Ph, Vallier, L, Legallais, C, Leclerc, E, Prot J, M, Choucha, L, Baudoin, R, Dufresne, M, Gautier, A, Carpentier, B, Mansuy, D, Pery, Alexandre R.R., Brochot, C, Manivet, Ph, Rabilloud, Thierry, Spire, C, Coumoul, Xavier, Junot, Ch, Laprevote, O, Le Pape, A, Tourneur, E, Ben Mkaddem, S, Chassin, C, Aloulou, M, Goujon J, M, Hertif, A, Ouali, N, Vimont, S, Monteiro, R, Rondeau, E, Elbim, C, Werts, C, Vandewalle, A, Pedruzzi, E, Coant, N, Bens, M, Cluzeaud, F, Ogier-Denis, E, Pongnimitprasert, N, Babin-Chevaye, C, Fay, M, Bernard, M, Dupuy, C, Ei Benna, J, Gougerot-Pocidale M, A, Braut-Boucher, F, Pinton, Philippe, Lucioli, Joelma, Tsybulskyy, D, Joly, Baptiste, Laffitte, J, Bourges-Abella, N, Oswald, Isabelle P., Kolf-Clauw, Martine, Pierre, St, Bats A, S, Chevalier, Aline, Bui L, Ch, Ambolet-Camoit, A, Garlatti, M, Aggerbeck, M, Barouki, R, Al Khansa, I, Blanck, O, Guillouzo, A, Bars, R, Rouas, C, Bensoussan, H, Suhard, D, Tessier, C, Grandcolas, L, Pallardy, M, Gueguen, Y, Sparfel, L, Pinel-Marie M, L, Boize, M, Koscielny, S, Desmots, S, Fardel, O, Alvergnas, M, Rouleau, A, Lucchi, G, Mantion, G, Heyd, B, Richert, L, Ducoroy, P, Martin, H, Val, St, Martinon, L, Cachier, H, Yahyaoui, A, Marfaing, H, Baeza-Squiban, A, Martin-Chouly, Corinne, Bonvallet, M, Morzadec, C, Vernhet, L, Baverel, G, El Hage, M, Nazaret, R, Conjard-Duplany, A, Ferrier, B, Martin, G, Legendre, A, Lecomte, Anthony, Froment, P, Habert, R, Lemazurier, E, Robinel, F, Dupont, O, Sanfins, E, Dairou, J, Chaffotte A, F, Busi, F, Rodrigues Lima, F, Dupret J, M, Mayati, A, Le Ferrec, Eric, Levoin, N, Paris, H, Uriac, Ph, N'Diaye, M, Lagadic-Gossmann, D, Assemat, E, Boublil, L, Borot M, C, Marano, F, Martiny V, Y, Moroy, G, Badel, A, Miteva M, A, Hussain, S, Ferecatu, I, Borot, C, Andreau, K, Boland, S, Leroux, M, Zucchini-Pascal, Nathalie, Peyre, L, Rahmani, Roger, Buron, N, Porcedou, M, Fromenty, B, Borgne-Sanchez, A, Rogue, A, Claude, N, Le Guével, Rémy, Institut National de l'Environnement Industriel et des Risques (INERIS), Laboratoire pharmaceutique Biologie Servier, Biologie Servier, Pharmacologie, toxicologie et signalisation cellulaire (U747), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Faculté de Médecine Xavier Bichat, Centre de recherche biomédicale Bichat-Beaujon (CRB3), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de recherche Pharmacologie-Toxicologie (UPT), Institut National de la Recherche Agronomique (INRA), Toxicité environnementale, cibles thérapeutiques, signalisation cellulaire (T3S - UMR_S 1124), Cytokines, chimiokines et immunopathologie, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Fonctions et dysfonctions épithéliales - UFC (EA 4267) (FDE), Université de Franche-Comté (UFC), Plate-forme Protéomique CLIPP - Clinical and Innovation Proteomic Platform [Dijon] (CLIPP), Franche-Comté Électronique Mécanique, Thermique et Optique - Sciences et Technologies (UMR 6174) (FEMTO-ST), Université de Franche-Comté (UFC)-Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure de Mécanique et des Microtechniques (ENSMM)-Université de Technologie de Belfort-Montbeliard (UTBM)-Université de Franche-Comté (UFC)-Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure de Mécanique et des Microtechniques (ENSMM)-Université de Technologie de Belfort-Montbeliard (UTBM)-Institut de Chimie Moléculaire de l'Université de Bourgogne [Dijon] (ICMUB), Université de Bourgogne (UB)-Centre National de la Recherche Scientifique (CNRS)-Université de Bourgogne (UB)-Centre National de la Recherche Scientifique (CNRS), Laboratoire des Sciences du Climat et de l'Environnement [Gif-sur-Yvette] (LSCE), Université Paris-Saclay-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Centre National de la Recherche Scientifique (CNRS), Cellules Souches et Radiations (SCSR (U967 / UMR-E_008)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris-Sud - Paris 11 (UP11), Laboratoire Bioprojet, Institut des Sciences Chimiques de Rennes (ISCR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes-Centre National de la Recherche Scientifique (CNRS), Unité de Biologie Fonctionnelle et Adaptative (BFA (UMR_8251 / U1133)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Mitologics SAS, Hôpital Robert Debré, Biomécanique et Bioingénierie (BMBI), Université de Technologie de Compiègne (UTC)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de radiotoxicologie expérimentale (IRSN/DRPH/SRBE/LRTOX), Service de RadioBiologie et d'Epidémiologie (IRSN/DRPH/SRBE), Institut de Radioprotection et de Sûreté Nucléaire (IRSN)-Institut de Radioprotection et de Sûreté Nucléaire (IRSN), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Université de Technologie de Belfort-Montbeliard (UTBM)-Ecole Nationale Supérieure de Mécanique et des Microtechniques (ENSMM)-Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université de Technologie de Belfort-Montbeliard (UTBM)-Ecole Nationale Supérieure de Mécanique et des Microtechniques (ENSMM)-Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Institut de Chimie Moléculaire de l'Université de Bourgogne [Dijon] (ICMUB), Université de Bourgogne (UB)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Bourgogne (UB)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut national des sciences de l'Univers (INSU - CNRS)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Stabilité génétique, Cellules Souches et Radiations (SCSR (U_967)), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Sud - Paris 11 (UP11), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université d'Angers (UA), Université de Technologie de Belfort-Montbeliard (UTBM)-Ecole Nationale Supérieure de Mécanique et des Microtechniques (ENSMM)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre National de la Recherche Scientifique (CNRS)-Université de Technologie de Belfort-Montbeliard (UTBM)-Ecole Nationale Supérieure de Mécanique et des Microtechniques (ENSMM)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie Moléculaire de l'Université de Bourgogne [Dijon] (ICMUB), Institut national des sciences de l'Univers (INSU - CNRS)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA), Université Paris-Sud - Paris 11 (UP11)-Université Paris Diderot - Paris 7 (UPD7)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure de Chimie de Rennes-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES), Institut National de l'Environnement Industriel et des Risques ( INERIS ), Physiologie Cellulaire des Regulations Hormonales, Nutritionnelles et Pharmacologiques, Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre de recherche biomédicale Bichat-Beaujon ( CRB3 ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Unité de recherche Pharmacologie-Toxicologie ( UPT ), Institut National de la Recherche Agronomique ( INRA ), Toxicologie, Pharmacologie et Signalisation Cellulaire ( U1124 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Centre National de la Recherche Scientifique ( CNRS ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service de biostatistique et d'épidémiologie ( SBE ), Institut Gustave Roussy ( IGR ) -Institut Gustave Roussy ( IGR ), Institut de recherche, santé, environnement et travail ( Irset ), Université d'Angers ( UA ) -Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -École des Hautes Études en Santé Publique [EHESP] ( EHESP ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ) -Université des Antilles ( UA ), Fonctions et dysfonctions épithéliales - UFC (EA 4267) ( FDE ), Université de Franche-Comté ( UFC ), Plate-forme Protéomique CLIPP - Clinical and Innovation Proteomic Platform [Dijon] ( CLIPP ), Franche-Comté Électronique Mécanique, Thermique et Optique - Sciences et Technologies (UMR 6174) ( FEMTO-ST ), Université de Franche-Comté ( UFC ) -Centre National de la Recherche Scientifique ( CNRS ) -Ecole Nationale Supérieure de Mécanique et des Microtechniques ( ENSMM ) -Université de Technologie de Belfort-Montbeliard ( UTBM ) -Université de Franche-Comté ( UFC ) -Centre National de la Recherche Scientifique ( CNRS ) -Ecole Nationale Supérieure de Mécanique et des Microtechniques ( ENSMM ) -Université de Technologie de Belfort-Montbeliard ( UTBM ) -Institut de Chimie Moléculaire de l'Université de Bourgogne [Dijon] ( ICMUB ), Université de Bourgogne ( UB ) -Centre National de la Recherche Scientifique ( CNRS ) -Université de Bourgogne ( UB ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire des Sciences du Climat et de l'Environnement [Gif-sur-Yvette] ( LSCE ), Université Paris-Saclay-Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ) -Centre National de la Recherche Scientifique ( CNRS ), Cellules Souches et Radiations ( SCSR - U 967 ), Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut des Sciences Chimiques de Rennes ( ISCR ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Ecole Nationale Supérieure de Chimie de Rennes-Institut National des Sciences Appliquées ( INSA ) -Centre National de la Recherche Scientifique ( CNRS ), Biologie Fonctionnelle et Adaptative ( BFA ), and Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS )

Subjects
[ SDV ] Life Sciences [q-bio], [SDV.TOX]Life Sciences [q-bio]/Toxicology, [SDV]Life Sciences [q-bio], ComputingMilieux_MISCELLANEOUS
Abstract

National audience

Published
2010

29. Toxicologie predictive: les voies du futur

Author

Ph Detilleux, Vallier, L., Legallais, C., Leclerc, E., M Prot J, Choucha, L., Baudoin, R., Dufresne, M., Gautier, A., Carpentier, B., Mansuy, D., Pery, Alexandre R. R., Brochot, C., Ph Manivet, Thierry Rabilloud, Spire, C., Xavier Coumoul, Ch Junot, Laprevote, O., Le Pape, A., Ronan Le Guével, Tourneur, E., Ben Mkaddem, S., Chassin, C., Aloulou, M., M Goujon J, Hertif, A., Ouali, N., Vimont, S., Monteiro, R., Rondeau, E., Elbim, C., Werts, C., Vandewalle, A., Pedruzzi, E., Coant, N., Bens, M., Cluzeaud, F., Ogier-Denis, E., Pongnimitprasert, N., Babin-Chevaye, C., Fay, M., Bernard Fromenty, Dupuy, C., Ei Benna, J., A Gougerot-Pocidale M, Braut-Boucher, F., Ph Pinton, Lucioli, J., Tsybulskyy, D., Baptiste Joly, Laffitte, J., Bourges-Abella, N., P Oswald I, Kolf-Clauw, M., St Pierre, S Bats A, Aline Chevalier, Ch Bui L, Ambolet-Camoit, A., Garlatti, M., Aggerbeck, M., Barouki, R., Al Khansa, I., Blanck, O., Guillouzo, A., Bars, R., Rouas, C., Bensoussan, H., Suhard, D., Tessier, C., Grandcolas, L., Pallardy, M., Gueguen, Y., Sparfel, L., L Pinel-Marie M, Boize, M., Koscielny, S., Desmots, S., Fardel, O., Alvergnas, M., Rouleau, A., Lucchi, G., Mantion, G., Heyd, B., Richert, L., Ducoroy, P., Martin, H., St Val, Martinon, L., Cachier, H., Yahyaoui, A., Marfaing, H., Baeza-Squiban, A., Corinne Martin-Chouly, Bonvallet, M., Morzadec, C., Vernhet, L., Baverel, G., El Hage, M., Nazaret, R., Conjard-Duplany, A., Ferrier, B., Martin, G., Legendre, A., Lecomte, A., Froment, P., Habert, R., Lemazurier, E., Robinel, F., Dupont, O., Sanfins, E., Dairou, J., F Chaffotte A, Busi, F., Rodrigues Lima, F., M Dupret J, Mayati, A., Eric Le Ferrec, Levoin, N., Paris, H., Ph Uriac, Diaye, M. N., Lagadic-Gossmann, D., Assemat, E., Boublil, L., C Borot M, Marano, F., Y Martiny V, Moroy, G., Badel, A., A Miteva M, Hussain, S., Ferecatu, I., Borot, C., Andreau, K., Boland, S., Leroux, M., Zucchini-Pascal, N., Peyre, L., Rahmani, R., Buron, N., Porcedou, M., Fromenty, B., Borgne-Sanchez, A., Rogue, A., Claude, N., and Jonchère, Laurent

Subjects
[SDV] Life Sciences [q-bio], [SDV.TOX] Life Sciences [q-bio]/Toxicology
Published
2010

30. High hepatic glutathione stores alleviate Fas-induced apoptosis in mice

Author

Fau, Daniel, S Berson A Haouzi D Vadrot N Fau D Grodet A Lettéron P Feldmann G El-Benna J Fromenty B Robin Ma Pessayre D., Cazanave, Franche-Comté Électronique Mécanique, Thermique et Optique - Sciences et Technologies (UMR 6174) (FEMTO-ST), Université de Technologie de Belfort-Montbeliard (UTBM)-Ecole Nationale Supérieure de Mécanique et des Microtechniques (ENSMM)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche biomédicale Bichat-Beaujon (CRB3), and Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
[SDV.TOX]Life Sciences [q-bio]/Toxicology
Abstract

International audience; BACKGROUND/AIMS: The agonistic Jo2 anti-Fas antibody reproduces human fulminant hepatitis in mice. We tested the hypothesis that enhancing hepatic glutathione (GSH) stores may prevent Jo2-induced apoptosis. METHODS: We fed mice with a normal diet or a sulfur amino acid-enriched (SAA(+)) diet increasing hepatic GSH by 63%, and challenged these mice with Jo2. RESULTS: The SAA(+) diet markedly attenuated the Jo2-mediated decrease in hepatic GSH and the increase in the oxidized glutathione (GSSG)/GSH ratio in cytosol and mitochondria. The SAA(+) diet prevented protein kinase Czeta (PKCzeta) and p47(phox) phosphorylations, Yes activation, Fas-tyrosine phosphorylation, Bid truncation, Bax, and cytochrome c translocations, the mitochondrial membrane potential collapse, caspase activation, DNA fragmentation, hepatocyte apoptosis, and mouse lethality after Jo2 administration. The protective effect of the SAA(+) diet was abolished by a small dose of phorone decreasing hepatic GSH back to the levels observed in mice fed the normal diet. Conversely, administration of GSH monoethyl ester after Jo2 administration prevented hepatic GSH depletion and attenuated toxicity in mice fed with the normal diet. CONCLUSIONS: The SAA(+) diet preserves GSSG/GSH ratios, and prevents PKCzeta and p47(phox) phosphorylations, Yes activation, Fas-tyrosine phosphorylation, mitochondrial permeabilization, and hepatic apoptosis after Fas stimulation. GSH monoethyl ester is also protective, suggesting possible clinical applications.

Published
2007

35. Acute ethanol administration oxidatively damages and depletes mitochondrial dna in mouse liver, brain, heart, and skeletal muscles: protective effects of antioxidants

Author

Abdellah Mansouri, Demeilliers, C., Amsellem, S., Pessayre, D., Fromenty, B., Institut National de la Santé et de la Recherche Médicale (INSERM), Université d'Oran, Department Electronic, Nutrition, Métabolismes et Cancer (NuMeCan), Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)

Subjects
Fomepizole, Male, Mice, Inbred ICR, Ethanol, Ubiquinone, Brain, Central Nervous System Depressants, Mitochondria, Liver, Oxidants, DNA, Mitochondrial, Antioxidants, Mitochondria, Heart, Mitochondria, Mitochondria, Muscle, Blotting, Southern, Mice, [SDV.TOX]Life Sciences [q-bio]/Toxicology, Animals, Pyrazoles, Vitamin E, Melatonin, Thymidine
Abstract

International audience; Ethanol metabolism causes oxidative stress and lipid peroxidation not only in liver but also in extra-hepatic tissues. Ethanol administration has been shown to cause oxidative degradation and depletion of hepatic mitochondrial DNA (mtDNA) in rodents, but its in vivo effects on the mtDNA of extra-hepatic tissues have not been assessed. We studied the effects of an acute intragastric ethanol administration (5 g/kg) on brain, heart, skeletal muscle, and liver mtDNA in mice. Ethanol administration caused mtDNA depletion and replacement of its supercoiled form by linearized forms in all tissues examined. Maximal mtDNA depletion was about similar (ca. 50%) in all organs studied. It occurred 2 h after ethanol administration in heart, skeletal muscle, and liver but after 10 h in brain. This mtDNA depletion was followed by increased mtDNA synthesis. A secondary, transient increase in mtDNA levels occurred 24 h after ethanol administration in all organs. In hepatic or extra-hepatic tissues, mtDNA degradation and depletion were prevented by 4-methylpyrazole, an inhibitor of ethanol metabolism, and attenuated by vitamin E, melatonin, or coenzyme Q, three antioxidants. In conclusion, our study shows for the first time that ethanol metabolism also causes oxidative degradation of the mitochondrial genome in brain, heart, and skeletal muscles. These effects could contribute to the development of (cardio)myopathy and brain injury in some alcoholic patients. Antioxidants prevent these effects in mice and could be useful in persevering drinkers.

Published
2001

36. Effect of stavudine on mitochondrial genome and fatty acid oxidation in lean and obese mice

Author

Gaou, I, Malliti, M, Guimont, MC, Lettéron, P., Demeilliers, C, Peytavin, G., Degott, C, Pessayre, D, Fromenty, B., Centre de recherche biomédicale Bichat-Beaujon (CRB3), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Pharmacie de l'Hôpital Bichat, Institut National de la Santé et de la Recherche Médicale (INSERM), Nutrition, Métabolismes et Cancer (NuMeCan), Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)

Subjects
Mice, Inbred ICR, Genome, Anti-HIV Agents, Reverse Transcriptase Polymerase Chain Reaction, Citric Acid Cycle, Fatty Acids, Immunoblotting, Nucleic Acid Hybridization, DNA, Lipid Metabolism, DNA, Mitochondrial, Thiobarbituric Acid Reactive Substances, Mitochondria, Mice, Stavudine, Oxygen Consumption, [SDV.TOX]Life Sciences [q-bio]/Toxicology, Animals, Obesity, Reactive Oxygen Species, Oxidation-Reduction
Abstract

International audience; Like other antihuman immunodeficiency virus dideoxynucleosides, stavudine may occasionally induce lactic acidosis and perhaps lipodystrophy in metabolically or genetically susceptible patients. We studied the effects of stavudine on mitochondrial DNA (mtDNA), fatty acid oxidation, and blood metabolites in lean and genetically obese (ob/ob) mice. In lean mice, mtDNA was depleted in liver and skeletal muscle, but not heart and brain, after 6 weeks of stavudine treatment (500 mg/kg/day). With 100 mg/kg/day, mtDNA transiently decreased in liver, but was unchanged at 6 weeks in all organs, including white adipose tissue (WAT). Despite unchanged mtDNA levels, lack of significant oxidative mtDNA lesions (as assessed by long polymerase chain reaction experiments), and normal blood lactate/pyruvate ratios, lean mice treated with stavudine for 6 weeks had increased fasting blood ketone bodies, due to both increased hepatic fatty acid beta-oxidation and decreased peripheral ketolysis. In obese mice, basal WAT mtDNA was low and was further decreased by stavudine. In conclusion, stavudine can decrease hepatic and muscle mtDNA in lean mice and can also cause ketoacidosis during fasting without altering mtDNA. Stavudine depletes WAT mtDNA only in obese mice. Fasting and ketoacidosis could trigger decompensation in patients with incipient lactic acidosis, whereas WAT mtDNA depletion could cause lipodystrophy in genetically susceptible patients.

Published
2001

41. Inhibition by nilutamide of the mitochondrial respiratory chain and ATP formation. Possible contribution to the adverse effects of this antiandrogen

Author

Berson A, Schmets L, Fisch C, Fau D, Wolf C, Fromenty B, Deschamps D, and Pessayre D

Subjects
Male, Cell Membrane Permeability, Cell Survival, Electron Spin Resonance Spectroscopy, Imidazoles, Palmitic Acid, Androgen Antagonists, Digitonin, Mitochondria, Liver, Intracellular Membranes, Palmitic Acids, Carbon Dioxide, Imidazolidines, Membrane Potentials, Rats, Rats, Sprague-Dawley, Adenosine Triphosphate, Oxygen Consumption, Liver, Animals, Carbon Radioisotopes, Oxidation-Reduction
Abstract

The effects of nilutamide on the mitochondrial respiratory chain were investigated in rats. In isolated mitochondria, nilutamide (100 microM) inhibited respiration that was supported by substrates feeding electrons into complex I of the respiratory chain but did not inhibit respiration that was supported by substrates donating electrons to complexes II, III or IV. Inhibition of complex I occurred without any lag time. In submitochondrial particles, nilutamide (100 microM) decreased both oxygen consumption mediated by NADH and the oxidation of NADH; addition of superoxide dismutase and catalase did not alleviate inhibition. There was no electron spin resonance evidence for detectable mitochondrial formation of the nilutamide nitro anion free radical by submitochondrial particles or for the formation of iron-nitrosyl complexes with mitochondrial Fe-S clusters in isolated hepatocytes. Severe inhibition of complex I by nilutamide (500 microM) led to upstream inhibition of fatty acid beta-oxidation. Nilutamide (100 microM) decreased the mitochondrial membrane potential and ATP formation in mitochondria energized by malate plus glutamate. In hepatocytes incubated without glucose, nilutamide (500 microM) led to an early (2 hr) drop in cellular ATP and early (4 hr) toxicity. With 5 mM glucose, however, ATP was not decreased and toxicity was mild at these early times. It was concluded that nilutamide itself inhibited the mitochondrial respiratory chain at the level of complex I and decreased ATP in hepatocytes incubated without glucose, which resulted in early toxicity. In the presence of glucose, ATP was not depleted at early times and delayed toxicity was probably the result of an oxidative stress (as previously reported).

Published
1994

42. Toxicity of the antiandrogen flutamide in isolated rat hepatocytes

Author

Fau D, Eugene D, Berson A, Letteron P, Fromenty B, Fisch C, and Pessayre D

Subjects
Male, Rats, Sprague-Dawley, Adenosine Triphosphate, Oxygen Consumption, Dose-Response Relationship, Drug, Liver, Animals, Female, Glutathione, Biotransformation, Cells, Cultured, Flutamide, Rats
Abstract

The hepatotoxicity of flutamide, an antiandrogen that produces hepatitis in some human recipients, was studied in isolated rat hepatocytes. Flutamide (1 mM) led to the covalent binding of reactive electrophilic metabolites to male rat hepatocyte proteins. It decreased the reduced glutathione (GSH)/glutathione disulfide ratio and total protein thiols. This was associated with an early increase in phosphorylase a activity (a Ca(++)-dependent enzyme) and a decrease in cytoskeleton-associated protein thiols, the formation of plasma membrane blebs, the release of lactate dehydrogenase (LDH) and a loss of cell viability. Both covalent binding and LDH release were decreased by piperonyl butoxide (an inhibitor of cytochrome P450) and increased by dexamethasone pretreatment (which induces cytochrome P450 3A). The toxicity was increased by beta-naphthoflavone (which induces cytochrome P450 1A). Hepatocytes from female rats (which lack cytochrome P450 3A2) exhibited lower covalent binding and lower LDH release. The addition of cystine (a GSH precursor) increased hepatocellular GSH and decreased LDH release in male hepatocytes. The administration of a diet deficient in sulfur-containing amino acids had the opposite effects; it produced toxicity with 100 microM flutamide. Flutamide (50 microM) markedly inhibited respiration (mainly at the level of complex I) in isolated male rat liver mitochondria and flutamide (1 mM) decreased ATP levels in isolated male rat hepatocytes. It was concluded that flutamide is toxic to rat hepatocytes as a result of the cytochrome P450 (3A and also 1A)-mediated formation of electrophilic metabolites, whose damaging effects are further aggravated by the inhibitory effect of flutamide on mitochondrial respiration and ATP formation.

Published
1994

47. Generation of free radicals during the reductive metabolism of the nitroaromatic compound, nilutamide

Author

Berson A, Wolf C, Berger V, Fau D, Chachaty C, Fromenty B, and Pessayre D

Subjects
Male, Free Radicals, Glutathione Disulfide, Electron Spin Resonance Spectroscopy, Imidazoles, Androgen Antagonists, Rats, Inbred Strains, Imidazolidines, Glutathione, Rats, Oxygen Consumption, Microsomes, Liver, Animals, Oxidation-Reduction, Cells, Cultured
Abstract

Incubation of the antiandrogen nilutamide with rat liver microsomes and NADPH, under anaerobic conditions, led to the formation of the nitro anion free radical, as indicated by electron spin resonance spectroscopy. The steady-state concentration of the nitro anion free radical was not decreased by SKF 525-A, carbon monoxide or metyrapone (3 inhibitors of cytochrome P-450) but was decreased by NADP+ or p-chloromercuribenzoate (2 inhibitors of NADPH-cytochrome P-450 reductase). Under aerobic conditions, the nitro anion free radical was reoxidized by oxygen, and the electron spin resonance signal was not detected. This redox cycle was associated with NADPH oxidation, consumption of oxygen, and formation of superoxide anion, hydrogen peroxide and glutathione disulfide. Under anaerobic conditions, nilutamide was further reduced to chemically reactive metabolites. Anaerobic incubation of [3H]nilutamide (0.1 mM) with rat liver microsomes and a NADPH-generating system resulted in the in vitro covalent binding of [3H]nilutamide metabolites to microsomal proteins; covalent binding required NADPH; it was decreased in the presence of NADPH-cytochrome P-450 reductase inhibitors (methylene blue, 2'-adenosine monophosphate) or in the presence of the nucleophile glutathione, but was unaffected by cytochrome P-450 inhibitors (SKF 525-A, CO). Covalent binding was decreased markedly under aerobic conditions. We conclude that nilutamide is reduced by microsomal NADPH-cytochrome P-450 reductase into a nitro anion free radical. In the presence of oxygen, this nitro anion free radical undergoes redox cycling with oxygen, and forms reactive oxygen species. In anaerobiosis, it is reduced further to covalent binding species.

Published
1991

48. Amiodarone inhibits the mitochondrial beta-oxidation of fatty acids and produces microvesicular steatosis of the liver in mice

Author

Fromenty B, Fisch C, Labbe G, Degott C, Deschamps D, Berson A, Letteron P, and Pessayre D

Subjects
Male, Dose-Response Relationship, Drug, Fatty Acids, Amiodarone, Mitochondria, Liver, Ketone Bodies, Carbon Dioxide, Lipid Metabolism, Mice, Liver, Animals, Carbon Radioisotopes, Fat Necrosis, Oxidation-Reduction
Abstract

Amiodarone has been shown to produce microvesicular steatosis of the liver in some recipients. We have determined the effects of amiodarone on the mitochondrial oxidation of fatty acids in mice. In vitro, the formation of 14C-acid-soluble beta-oxidation products from [U-14C]palmitic acid by mouse liver mitochondria was decreased by 92% in the presence of 125 microM amiodarone and by 94% in the presence of 125 microM N-desethylamiodarone. Inhibition due to 100 or 150 microM amiodarone persisted in the presence of 5 mM acetoacetate, whereas acetoacetate totally relieved inhibition due to 15 microM rotenone. In vivo, exhalation of [14C]CO2 from [U-14C]palmitic acid was decreased by 31, 40, 58 and 78%, respectively, in mice receiving 19, 25, 50 and 100 mg.kg-1 of amiodarone hydrochloride 1 hr before the administration of [U-14C]palmitic acid. One hour after 100 mg.kg-1, the exhalation of [14C]CO2 from [1-14C]palmitic acid, [1-14C]octanoic acid or [1-14C]butyric acid was decreased by 78, 72 and 53%, respectively. Exhalation of [14C]CO2 from [1-14C]palmitic acid was normal between 6 and 9 hr after administration of 100 mg.kg-1 of amiodarone hydrochloride, but was still inhibited by 71 and 37%, 24 and 48 hr after 600 mg.kg-1. Twenty four hours after the latter dose of amiodarone, hepatic triglycerides were increased by 150%, and there was microvesicular steatosis of the liver. We conclude that amiodarone inhibits the mitochondrial beta-oxidation of fatty acids and produces microvesicular steatosis of the liver in mice.

Published
1990

49. Stereoselective and nonstereoselective effects of ibuprofen enantiomers on mitochondrial beta-oxidation of fatty acids

Author

Freneaux E, Fromenty B, Berson A, Labbe G, Degott C, Letteron P, Larrey D, and Pessayre D

Subjects
Male, Mice, Inbred ICR, Fatty Acids, Ibuprofen, Mitochondria, Liver, Rats, Inbred Strains, Stereoisomerism, Ketone Bodies, Carbon Dioxide, In Vitro Techniques, Lipid Metabolism, Rats, Mice, Animals, Carbon Radioisotopes, Oxidation-Reduction
Abstract

The effects of the R-(-) and S-(+)ibuprofen enantiomers were first studied in vitro with mouse liver mitochondria incubated in the presence of various concentrations of exogenous coenzyme A. In the presence of a low concentration of coenzyme A (2.5 microM), the R-(-)enantiomer (which forms an acylcoenzyme A) inhibited stereoselectively the beta oxidation of [1-14C]palmitic acid but not that of [1-14C]palmitoyl-L-carnitine (which can directly enter the mitochondria). In the presence, however, of a concentration of coenzyme A (50 microM) reproducing that present in liver cell cytosol, both enantiomers (2 mM) slightly inhibited the beta oxidation of [1-14C]palmitic acid and markedly inhibited the beta oxidation of [1-14C]octanoic acid and [1-14C]butyric acid. In vivo, both enantiomers (1 mmol.kg-1) similarly inhibited the formation of [14C]CO2 from [1-14C]fatty acids. Both enantiomers similarly decreased plasma ketone bodies. Both similarly increased hepatic triglycerides, and both produced mild microvesicular steatosis of the liver. We conclude that both ibuprofen enantiomers inhibit beta oxidation of fatty acids in vitro and in vivo. In addition, the R-(-)enantiomer may stereoselectively sequester coenzyme A; at low concentrations of coenzyme A in vitro, this may stereoselectively inhibit the mitochondrial uptake and beta oxidation of long chain fatty acids.

Published
1990

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