title: Acute toxicity of 8 antidepressants: what are their modes of action?
abstract: Currently, the hazard posed by pharmaceutical residues is a major concern of ecotoxicology. Most of the antidepressants belong to a family named the Cationic Amphipathic Drugs known to have specific interactions with cell membranes. The present study assessed the impact of eight antidepressants belonging to selective serotonin reuptake inhibitors or serotonin norepinephrine reuptake inhibitors by the combination of multi-approaches (in vivo, in vitro, in silico) and gives some insights on the mode of action for these molecules. Antidepressants were from the most to the least toxic compound for Daphnia magna: Sertraline (EC50=1.15 mg L(-1))>Clomipramine (2.74 mg L(-1))>Amitriptyline (4.82 mg L(-1))>Fluoxetine (5.91 mg L(-1))>Paroxetine (6.24 mg L(-1))>Mianserine (7.81 mg L(-1))>Citalopram (30.14 mg L(-1)) and Venlafaxine (141.28 mg L(-1)). These acute toxicities were found correlated to Log Kow coefficients (R=0.93, p<0.001) and to cytotoxicity assessed on abalone hemocytes through the neutral red uptake assay (R=0.96, p<0.001). If narcosis as mode of action is typically expected during acute ecotoxicity bioassays, we showed by molecular modeling that particular interactions can exist between antidepressants and phosphatidylcholine, a major component of cell membranes, leading to a more specific mode of action corresponding to a potential acidic hydrolysis of ester functions.
authors.affiliation: UMR BOREA (Biologie des ORganismes et Ecosystèmes Aquatiques), CNRS-7208/MNHN/UPMC/IRD-207/UCBN, Esplanade de la Paix, 14032 Caen Cedex, France; CERMN, UFR des Sciences Pharmaceutiques, UPRES EA4258 - FR CNRS INC3M - SF 4206 ICORE, Université de Caen Basse-Normandie, Bd Becquerel, 14032 Caen Cedex, France. Electronic address: laetitia-minguez@hotmail.fr.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Minguez
authors.affiliation: UMR BOREA (Biologie des ORganismes et Ecosystèmes Aquatiques), CNRS-7208/MNHN/UPMC/IRD-207/UCBN, Esplanade de la Paix, 14032 Caen Cedex, France; CERMN, UFR des Sciences Pharmaceutiques, UPRES EA4258 - FR CNRS INC3M - SF 4206 ICORE, Université de Caen Basse-Normandie, Bd Becquerel, 14032 Caen Cedex, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Farcy
authors.affiliation: CERMN, UFR des Sciences Pharmaceutiques, UPRES EA4258 - FR CNRS INC3M - SF 4206 ICORE, Université de Caen Basse-Normandie, Bd Becquerel, 14032 Caen Cedex, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Ballandonne
authors.affiliation: CERMN, UFR des Sciences Pharmaceutiques, UPRES EA4258 - FR CNRS INC3M - SF 4206 ICORE, Université de Caen Basse-Normandie, Bd Becquerel, 14032 Caen Cedex, France.
authors.forename: Alban
authors.initials: A
authors.lastname: Lepailleur
authors.affiliation: UMR BOREA (Biologie des ORganismes et Ecosystèmes Aquatiques), CNRS-7208/MNHN/UPMC/IRD-207/UCBN, Esplanade de la Paix, 14032 Caen Cedex, France.
authors.forename: Antoine
authors.initials: A
authors.lastname: Serpentini
authors.affiliation: UMR BOREA (Biologie des ORganismes et Ecosystèmes Aquatiques), CNRS-7208/MNHN/UPMC/IRD-207/UCBN, Esplanade de la Paix, 14032 Caen Cedex, France.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Lebel
authors.affiliation: CERMN, UFR des Sciences Pharmaceutiques, UPRES EA4258 - FR CNRS INC3M - SF 4206 ICORE, Université de Caen Basse-Normandie, Bd Becquerel, 14032 Caen Cedex, France.
authors.forename: Ronan
authors.initials: R
authors.lastname: Bureau
authors.affiliation: CERMN, UFR des Sciences Pharmaceutiques, UPRES EA4258 - FR CNRS INC3M - SF 4206 ICORE, Université de Caen Basse-Normandie, Bd Becquerel, 14032 Caen Cedex, France.
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Halm-Lemeille
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000633:toxicity*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003621:Daphnia / Q000187:drug effects* / Q000378:metabolism; D004785:Environmental Pollutants / Q000633:toxicity*; D049851:Gastropoda / Q000166:cytology / Q000187:drug effects*; D006434:Hemocytes / Q000166:cytology / Q000187:drug effects; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D008958:Models, Molecular; D010713:Phosphatidylcholines / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000633:toxicity*
chemical_list: D000928:Antidepressive Agents; D004785:Environmental Pollutants; D010713:Phosphatidylcholines; D017367:Selective Serotonin Reuptake Inhibitors
keywords: Daphnia magna; Haliotis tuberculata; Lysosomotropism; Multi-approach; Narcosis; Pharmaceutical