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Assessment of the genotoxic and carcinogenic potentials of 3-aminothiophene derivatives using in vitro and in silico methodologies

Authors

  • Alban Lepailleur,

    Corresponding author
    1. Normandie Univ, France
    2. UNICAEN, CERMN (Centre d'Etudes et de Recherche sur le Médicament de Normandie, FR CNRS INC3M - SF ICORE, Université de Caen Basse - Normandie, U.F.R. des Sciences Pharmaceutiques), Caen, France
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  • Ronan Bureau,

    1. Normandie Univ, France
    2. UNICAEN, CERMN (Centre d'Etudes et de Recherche sur le Médicament de Normandie, FR CNRS INC3M - SF ICORE, Université de Caen Basse - Normandie, U.F.R. des Sciences Pharmaceutiques), Caen, France
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  • Marie-Pierre Halm-Lemeille,

    1. Normandie Univ, France
    2. UNICAEN, CERMN (Centre d'Etudes et de Recherche sur le Médicament de Normandie, FR CNRS INC3M - SF ICORE, Université de Caen Basse - Normandie, U.F.R. des Sciences Pharmaceutiques), Caen, France
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  • Michel Bouquet,

    1. PCAS, Longjumeau, France
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  • Régis Pecquet,

    1. PCAS, Longjumeau, France
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  • Christine Paris-Soubayrol,

    1. PCAS, Longjumeau, France
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  • Jérémie Le. Goff,

    1. Normandie Univ, France
    2. UNICAEN, ABTE (Aliments Bioprocédés Toxicologie Environnements, EA 4651, Université de Caen - Basse Normandie, Centre François Baclesse, Caen, France
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  • Véronique André,

    1. Normandie Univ, France
    2. UNICAEN, ABTE (Aliments Bioprocédés Toxicologie Environnements, EA 4651, Université de Caen - Basse Normandie, Centre François Baclesse, Caen, France
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  • Yannick Lecluse,

    1. Normandie Univ, France
    2. UNICAEN, Cancers et Préventions (UMR 1086, Université de Caen - Basse Normandie, Centre François Baclesse), Caen, France
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  • Pierre Lebailly,

    1. Normandie Univ, France
    2. UNICAEN, Cancers et Préventions (UMR 1086, Université de Caen - Basse Normandie, Centre François Baclesse), Caen, France
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  • Marie-Aline Maire,

    1. UMR CNRS 7360, LIEC (Laboratoire Interdisciplinaire des Environnements Continentaux) Université de Lorraine. UFR Sci. F.A., Metz, France
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  • Paule Vasseur

    1. UMR CNRS 7360, LIEC (Laboratoire Interdisciplinaire des Environnements Continentaux) Université de Lorraine. UFR Sci. F.A., Metz, France
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ABSTRACT

Thiophene derivatives, a class of compounds widely used in products such as pharmaceuticals, agrochemicals or dyestuffs, represent chemicals of concern. Indeed, the thiophene ring is often considered as a structural moiety that may be involved in toxic effects in humans. We primarily focus on the genotoxic/mutagenic and carcinogenic potentials of the methyl 3-amino-4-methylthiophene-2-carboxylate (1), a precursor of the articaine local anesthetic (4) which falls within the scope of the European REACH (Registration, Evaluation, Authorisation and restriction of CHemicals) legislation. To discern some structure–toxicity relationships, we also studied two related compounds, namely the 3-amino 4-methylthiophene (2) and the 2-acetyl 4-chlorothiophene (3). Techniques employed to assess mutagenic and DNA-damaging effects involved the Salmonella mutagenicity assay (or Ames test) and the single-cell gel electrophoresis assay (or Comet assay). In the range of tested doses, none of these derivatives led to a positive response in the Ames tests and DNA damage was only observed in the Comet assay after high concentration exposure of 2. The study of their carcinogenic potential using the in vitro SHE (Syrian Hamster Embryo) cell transformation assay (CTA) highlighted the activity of compound 2. A combination of experimental data with in silico predictions of the reactivity of thiophene derivatives towards cytochrome P450 (CYP450), enabled us to hypothesize possible pathways leading to these toxicological profiles. Copyright © 2013 John Wiley & Sons, Ltd.

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