Genetic predisposition to drug hepatotoxicity: Role in hepatitis caused by amineptine, a tricyclic antidepressant

Authors

  • Dominique Larrey,

    Corresponding author
    1. Unité de Recherches de Physiopathologie Hépatique (INSERM U24) and Service d'Hépatologie, Hǒpital Beaujon, Clichy
    2. Centre de Pharmacovigilance, Hǒpital Fernand Widal, and Laboratoire de Chimie, Ecole Normale Supérieure, Paris, France
    • INSERM U24, Hǒpital Beaujon, 92118 Clichy, France
    Search for more papers by this author
  • Alain Berson,

    1. Unité de Recherches de Physiopathologie Hépatique (INSERM U24) and Service d'Hépatologie, Hǒpital Beaujon, Clichy
    2. Centre de Pharmacovigilance, Hǒpital Fernand Widal, and Laboratoire de Chimie, Ecole Normale Supérieure, Paris, France
    Search for more papers by this author
  • François Habersetzer,

    1. Unité de Recherches de Physiopathologie Hépatique (INSERM U24) and Service d'Hépatologie, Hǒpital Beaujon, Clichy
    2. Centre de Pharmacovigilance, Hǒpital Fernand Widal, and Laboratoire de Chimie, Ecole Normale Supérieure, Paris, France
    Search for more papers by this author
  • Marina Tinel,

    1. Unité de Recherches de Physiopathologie Hépatique (INSERM U24) and Service d'Hépatologie, Hǒpital Beaujon, Clichy
    2. Centre de Pharmacovigilance, Hǒpital Fernand Widal, and Laboratoire de Chimie, Ecole Normale Supérieure, Paris, France
    Search for more papers by this author
  • Anne Castot,

    1. Unité de Recherches de Physiopathologie Hépatique (INSERM U24) and Service d'Hépatologie, Hǒpital Beaujon, Clichy
    2. Centre de Pharmacovigilance, Hǒpital Fernand Widal, and Laboratoire de Chimie, Ecole Normale Supérieure, Paris, France
    Search for more papers by this author
  • Gérard Babany,

    1. Unité de Recherches de Physiopathologie Hépatique (INSERM U24) and Service d'Hépatologie, Hǒpital Beaujon, Clichy
    2. Centre de Pharmacovigilance, Hǒpital Fernand Widal, and Laboratoire de Chimie, Ecole Normale Supérieure, Paris, France
    Search for more papers by this author
  • Philippe Lettéron,

    1. Unité de Recherches de Physiopathologie Hépatique (INSERM U24) and Service d'Hépatologie, Hǒpital Beaujon, Clichy
    2. Centre de Pharmacovigilance, Hǒpital Fernand Widal, and Laboratoire de Chimie, Ecole Normale Supérieure, Paris, France
    Search for more papers by this author
  • Eric Freneaux,

    1. Unité de Recherches de Physiopathologie Hépatique (INSERM U24) and Service d'Hépatologie, Hǒpital Beaujon, Clichy
    2. Centre de Pharmacovigilance, Hǒpital Fernand Widal, and Laboratoire de Chimie, Ecole Normale Supérieure, Paris, France
    Search for more papers by this author
  • Jacqueline Loeper,

    1. Unité de Recherches de Physiopathologie Hépatique (INSERM U24) and Service d'Hépatologie, Hǒpital Beaujon, Clichy
    2. Centre de Pharmacovigilance, Hǒpital Fernand Widal, and Laboratoire de Chimie, Ecole Normale Supérieure, Paris, France
    Search for more papers by this author
  • Patrick Dansette,

    1. Unité de Recherches de Physiopathologie Hépatique (INSERM U24) and Service d'Hépatologie, Hǒpital Beaujon, Clichy
    2. Centre de Pharmacovigilance, Hǒpital Fernand Widal, and Laboratoire de Chimie, Ecole Normale Supérieure, Paris, France
    Search for more papers by this author
  • Dominique Pessayre

    1. Unité de Recherches de Physiopathologie Hépatique (INSERM U24) and Service d'Hépatologie, Hǒpital Beaujon, Clichy
    2. Centre de Pharmacovigilance, Hǒpital Fernand Widal, and Laboratoire de Chimie, Ecole Normale Supérieure, Paris, France
    Search for more papers by this author

Abstract

Amineptine-induced immunoallergic hepatitis is unpredictable. It may be related to its oxidation into a reactive metabolite acting as hapten. We have looked for a possible genetic predisposition involving drug oxidation capacity and/or cell defense mechanisms in nine patients with previous amineptine hepatitis. Drug oxidation capacity was assessed using dextromethorphan, a test compound recently proposed as a substitute for debrisoquine. The eight patients tested had the extensive metabolizer phenotype. The susceptibility to amineptine metabolites was studied by an in vitro test assessing the destruction of the patients' lymphocytes by reactive metabolites generated from amineptine by a standardized oxidation microsomal system. Lymphocyte death increased with the dose of amineptine (1 to 2.5 mM); it was increased by preincubation with trichloropropene oxide, but was absent when amineptine was omitted or when the oxidation system was not operating. Mean lymphocyte death was twice higher in the nine patients with amineptine hepatitis than in 17 healthy controls. In contrast, when the test was performed with acetaminophen (3 to 10 mM), lymphocyte death was similar in controls and in patients. Basal epoxide hydrolase activity toward benzo[a]pyrene-4,5-oxide and glutathi-one concentration was similar in lymphocytes from controls and patients. Family studies showed an increased susceptibility to amineptine metabolites in lymphocytes from several first-degree relatives of two patients. These results show that amineptine hepatitis occurs in patients with extensive dextromethorphan oxidation capacity but with an increased susceptibility to amineptine reactive metabolites, probably related to a genetic deficiency in a cell defense mechanism.

Ancillary