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Research ArticleToxicology

Differences in Early Acetaminophen Hepatotoxicity between Obese ob/ob and db/db Mice

Jacinthe Aubert, Karima Begriche, Matthieu Delannoy, Isabelle Morel, Julie Pajaud, Catherine Ribault, Sylvie Lepage, Mitchell R. McGill, Catherine Lucas-Clerc, Bruno Turlin, Marie-Anne Robin, Hartmut Jaeschke and Bernard Fromenty
Journal of Pharmacology and Experimental Therapeutics September 2012, 342 (3) 676-687; DOI: https://doi.org/10.1124/jpet.112.193813
Jacinthe Aubert
Institut National de la Santé et de la Recherche Médicale, U991(J.A., K.B., M.D., I.M., J.P., C.R., M.-A.R., B.F.) and Plate-forme d'Histopathologie H2P2 (B.T.), Université de Rennes 1, Rennes, France; Laboratoire de Toxicologie Biologique et Médico-Légale (I.M., S.L.), Laboratoire de Biochimie Générale, (C.L.-C.), and Département d'Anatomie et Cytologie Pathologiques (B.T.), Hôpital Pontchaillou, Rennes, France; and Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas (M.R.M., H.J.)
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Karima Begriche
Institut National de la Santé et de la Recherche Médicale, U991(J.A., K.B., M.D., I.M., J.P., C.R., M.-A.R., B.F.) and Plate-forme d'Histopathologie H2P2 (B.T.), Université de Rennes 1, Rennes, France; Laboratoire de Toxicologie Biologique et Médico-Légale (I.M., S.L.), Laboratoire de Biochimie Générale, (C.L.-C.), and Département d'Anatomie et Cytologie Pathologiques (B.T.), Hôpital Pontchaillou, Rennes, France; and Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas (M.R.M., H.J.)
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Matthieu Delannoy
Institut National de la Santé et de la Recherche Médicale, U991(J.A., K.B., M.D., I.M., J.P., C.R., M.-A.R., B.F.) and Plate-forme d'Histopathologie H2P2 (B.T.), Université de Rennes 1, Rennes, France; Laboratoire de Toxicologie Biologique et Médico-Légale (I.M., S.L.), Laboratoire de Biochimie Générale, (C.L.-C.), and Département d'Anatomie et Cytologie Pathologiques (B.T.), Hôpital Pontchaillou, Rennes, France; and Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas (M.R.M., H.J.)
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Isabelle Morel
Institut National de la Santé et de la Recherche Médicale, U991(J.A., K.B., M.D., I.M., J.P., C.R., M.-A.R., B.F.) and Plate-forme d'Histopathologie H2P2 (B.T.), Université de Rennes 1, Rennes, France; Laboratoire de Toxicologie Biologique et Médico-Légale (I.M., S.L.), Laboratoire de Biochimie Générale, (C.L.-C.), and Département d'Anatomie et Cytologie Pathologiques (B.T.), Hôpital Pontchaillou, Rennes, France; and Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas (M.R.M., H.J.)
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Julie Pajaud
Institut National de la Santé et de la Recherche Médicale, U991(J.A., K.B., M.D., I.M., J.P., C.R., M.-A.R., B.F.) and Plate-forme d'Histopathologie H2P2 (B.T.), Université de Rennes 1, Rennes, France; Laboratoire de Toxicologie Biologique et Médico-Légale (I.M., S.L.), Laboratoire de Biochimie Générale, (C.L.-C.), and Département d'Anatomie et Cytologie Pathologiques (B.T.), Hôpital Pontchaillou, Rennes, France; and Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas (M.R.M., H.J.)
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Catherine Ribault
Institut National de la Santé et de la Recherche Médicale, U991(J.A., K.B., M.D., I.M., J.P., C.R., M.-A.R., B.F.) and Plate-forme d'Histopathologie H2P2 (B.T.), Université de Rennes 1, Rennes, France; Laboratoire de Toxicologie Biologique et Médico-Légale (I.M., S.L.), Laboratoire de Biochimie Générale, (C.L.-C.), and Département d'Anatomie et Cytologie Pathologiques (B.T.), Hôpital Pontchaillou, Rennes, France; and Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas (M.R.M., H.J.)
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Sylvie Lepage
Institut National de la Santé et de la Recherche Médicale, U991(J.A., K.B., M.D., I.M., J.P., C.R., M.-A.R., B.F.) and Plate-forme d'Histopathologie H2P2 (B.T.), Université de Rennes 1, Rennes, France; Laboratoire de Toxicologie Biologique et Médico-Légale (I.M., S.L.), Laboratoire de Biochimie Générale, (C.L.-C.), and Département d'Anatomie et Cytologie Pathologiques (B.T.), Hôpital Pontchaillou, Rennes, France; and Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas (M.R.M., H.J.)
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Mitchell R. McGill
Institut National de la Santé et de la Recherche Médicale, U991(J.A., K.B., M.D., I.M., J.P., C.R., M.-A.R., B.F.) and Plate-forme d'Histopathologie H2P2 (B.T.), Université de Rennes 1, Rennes, France; Laboratoire de Toxicologie Biologique et Médico-Légale (I.M., S.L.), Laboratoire de Biochimie Générale, (C.L.-C.), and Département d'Anatomie et Cytologie Pathologiques (B.T.), Hôpital Pontchaillou, Rennes, France; and Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas (M.R.M., H.J.)
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Catherine Lucas-Clerc
Institut National de la Santé et de la Recherche Médicale, U991(J.A., K.B., M.D., I.M., J.P., C.R., M.-A.R., B.F.) and Plate-forme d'Histopathologie H2P2 (B.T.), Université de Rennes 1, Rennes, France; Laboratoire de Toxicologie Biologique et Médico-Légale (I.M., S.L.), Laboratoire de Biochimie Générale, (C.L.-C.), and Département d'Anatomie et Cytologie Pathologiques (B.T.), Hôpital Pontchaillou, Rennes, France; and Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas (M.R.M., H.J.)
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Bruno Turlin
Institut National de la Santé et de la Recherche Médicale, U991(J.A., K.B., M.D., I.M., J.P., C.R., M.-A.R., B.F.) and Plate-forme d'Histopathologie H2P2 (B.T.), Université de Rennes 1, Rennes, France; Laboratoire de Toxicologie Biologique et Médico-Légale (I.M., S.L.), Laboratoire de Biochimie Générale, (C.L.-C.), and Département d'Anatomie et Cytologie Pathologiques (B.T.), Hôpital Pontchaillou, Rennes, France; and Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas (M.R.M., H.J.)
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Marie-Anne Robin
Institut National de la Santé et de la Recherche Médicale, U991(J.A., K.B., M.D., I.M., J.P., C.R., M.-A.R., B.F.) and Plate-forme d'Histopathologie H2P2 (B.T.), Université de Rennes 1, Rennes, France; Laboratoire de Toxicologie Biologique et Médico-Légale (I.M., S.L.), Laboratoire de Biochimie Générale, (C.L.-C.), and Département d'Anatomie et Cytologie Pathologiques (B.T.), Hôpital Pontchaillou, Rennes, France; and Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas (M.R.M., H.J.)
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Hartmut Jaeschke
Institut National de la Santé et de la Recherche Médicale, U991(J.A., K.B., M.D., I.M., J.P., C.R., M.-A.R., B.F.) and Plate-forme d'Histopathologie H2P2 (B.T.), Université de Rennes 1, Rennes, France; Laboratoire de Toxicologie Biologique et Médico-Légale (I.M., S.L.), Laboratoire de Biochimie Générale, (C.L.-C.), and Département d'Anatomie et Cytologie Pathologiques (B.T.), Hôpital Pontchaillou, Rennes, France; and Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas (M.R.M., H.J.)
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Bernard Fromenty
Institut National de la Santé et de la Recherche Médicale, U991(J.A., K.B., M.D., I.M., J.P., C.R., M.-A.R., B.F.) and Plate-forme d'Histopathologie H2P2 (B.T.), Université de Rennes 1, Rennes, France; Laboratoire de Toxicologie Biologique et Médico-Légale (I.M., S.L.), Laboratoire de Biochimie Générale, (C.L.-C.), and Département d'Anatomie et Cytologie Pathologiques (B.T.), Hôpital Pontchaillou, Rennes, France; and Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas (M.R.M., H.J.)
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Abstract

Clinical investigations suggest that hepatotoxicity after acetaminophen (APAP) overdose could be more severe in the context of obesity and nonalcoholic fatty liver disease. The pre-existence of fat accumulation and CYP2E1 induction could be major mechanisms accounting for such hepatic susceptibility. To explore this issue, experiments were performed in obese diabetic ob/ob and db/db mice. Preliminary investigations performed in male and female wild-type, ob/ob, and db/db mice showed a selective increase in hepatic CYP2E1 activity in female db/db mice. However, liver triglycerides in these animals were significantly lower compared with ob/ob mice. Next, APAP (500 mg/kg) was administered in female wild-type, ob/ob, and db/db mice, and investigations were carried out 0.5, 2, 4, and 8 h after APAP intoxication. Liver injury 8 h after APAP intoxication was higher in db/db mice, as assessed by plasma transaminases, liver histology, and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay. In db/db mice, however, the extent of hepatic glutathione depletion, levels of APAP-protein adducts, c-Jun N-terminal kinase activation, changes in gene expression, and mitochondrial DNA levels were not greater compared with the other genotypes. Furthermore, in the db/db genotype plasma lactate and β-hydroxybutyrate were not specifically altered, whereas the plasma levels of APAP-glucuronide were intermediary between wild-type and ob/ob mice. Thus, early APAP-induced hepatotoxicity was greater in db/db than ob/ob mice, despite less severe fatty liver and similar basal levels of transaminases. Hepatic CYP2E1 induction could have an important pathogenic role when APAP-induced liver injury occurs in the context of obesity and related metabolic disorders.

Footnotes

  • This work was supported by the Institut Nationale de la Santé et de la Recherche Médicale. J.A. and K.B. were recipients of grants from the President of Université de Rennes 1 and the Région Bretagne, respectively.

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    http://dx.doi.org/10.1124/jpet.112.193813.

  • ABBREVIATIONS:

    APAP
    acetaminophen
    ACO
    acyl-coenzyme A oxidase
    ALT
    alanine aminotransferase
    ANOVA
    analysis of variance
    AST
    aspartate aminotransferase
    γGCS
    γ-glutamylcysteine synthetase
    GSH
    glutathione
    GST
    glutathione transferase
    GSTK
    GST κ
    GSTP1
    GST π-1
    HES
    hematoxylin, eosin, and safran
    HO-1
    heme oxygenase-1
    HSC70
    heat shock cognate protein 70
    HSD
    Honestly Significant Difference
    Hsp70
    heat shock protein 70
    IGFBP-1
    insulin-like growth factor binding protein-1
    JNK
    c-Jun N-terminal kinase
    P-JNK
    phosphorylated JNK
    l-CPT1
    l-carnitine palmitoyltransferase 1
    mtDNA
    mitochondrial DNA
    NAFLD
    nonalcoholic fatty liver disease
    NAPQI
    N-acetyl-p-benzoquinone imine
    NASH
    nonalcoholic steatohepatitis
    Nrf2
    NF-E2-related factor-2
    PCR
    polymerase chain reaction
    RT-qPCR
    real-time quantitative PCR
    PDK4
    pyruvate dehydrogenase kinase 4
    PPARα
    peroxisome proliferator-activated receptor-α
    Trib3
    Tribbles homolog 3
    TUNEL
    terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling
    wt
    wild-type.

  • Received February 28, 2012.
  • Accepted May 29, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 342 (3)
Journal of Pharmacology and Experimental Therapeutics
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1 Sep 2012
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Research ArticleToxicology

Acetaminophen-Induced Liver Injury in Obese Mice

Jacinthe Aubert, Karima Begriche, Matthieu Delannoy, Isabelle Morel, Julie Pajaud, Catherine Ribault, Sylvie Lepage, Mitchell R. McGill, Catherine Lucas-Clerc, Bruno Turlin, Marie-Anne Robin, Hartmut Jaeschke and Bernard Fromenty
Journal of Pharmacology and Experimental Therapeutics September 1, 2012, 342 (3) 676-687; DOI: https://doi.org/10.1124/jpet.112.193813

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Research ArticleToxicology

Acetaminophen-Induced Liver Injury in Obese Mice

Jacinthe Aubert, Karima Begriche, Matthieu Delannoy, Isabelle Morel, Julie Pajaud, Catherine Ribault, Sylvie Lepage, Mitchell R. McGill, Catherine Lucas-Clerc, Bruno Turlin, Marie-Anne Robin, Hartmut Jaeschke and Bernard Fromenty
Journal of Pharmacology and Experimental Therapeutics September 1, 2012, 342 (3) 676-687; DOI: https://doi.org/10.1124/jpet.112.193813
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