title: New insights into the intracellular distribution pattern of cationic amphiphilic drugs.
abstract: Cationic amphiphilic drugs (CADs) comprise a wide variety of different substance classes such as antidepressants, antipsychotics, and antiarrhythmics. It is well recognized that CADs accumulate in certain intracellular compartments leading to specific morphological changes of cells. So far, no adequate technique exists allowing for ultrastructural analysis of CAD in intact cells. Azidobupramine, a recently described multifunctional antidepressant analogue, allows for the first time to perform high-resolution studies of CADs on distribution pattern and morphological changes in intact cells. We showed here that the intracellular distribution pattern of azidobupramine strongly depends on drug concentration and exposure time. The mitochondrial compartment (mDsRed) and the late endo-lysosomal compartment (CD63-GFP) were the preferred localization sites at low to intermediate concentrations (i.e. 1 μM, 5 μM). In contrast, the autophagosomal compartment (LC3-GFP) can only be reached at high concentrations (10 μM) and long exposure times (72 hrs). At the morphological level, LC3-clustering became only prominent at high concentrations (10 μM), while changes in CD63 pattern already occurred at intermediate concentrations (5 μM). To our knowledge, this is the first study that establishes a link between intracellular CAD distribution pattern and morphological changes. Therewith, our results allow for gaining deeper understanding of intracellular effects of CADs.
authors.affiliation: Max Planck Institute of Psychiatry, Clinical Department, Munich, Germany.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Vater
authors.affiliation: Department Physikalische Chemie I, Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Leonhard
authors.initials: L
authors.lastname: Möckl
authors.affiliation: Max Planck Institute of Psychiatry, Department of Translational Research in Psychiatry, Munich, Germany.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Gormanns
authors.affiliation: Lead Discovery Center, Dortmund, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Schultz Fademrecht
authors.affiliation: Max Planck Institute of Psychiatry, Department of Translational Research in Psychiatry, Munich, Germany.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Mallmann
authors.affiliation: Max Planck Institute of Psychiatry, Clinical Department, Munich, Germany.|Nencki Institute of Experimental Biology, Warsaw, Poland.
authors.forename: Karolina
authors.initials: K
authors.lastname: Ziegart-Sadowska
authors.affiliation: Max Planck Institute of Psychiatry, Clinical Department, Munich, Germany.
authors.forename: Monika
authors.initials: M
authors.lastname: Zaba
authors.affiliation: Max Planck Institute of Psychiatry, Department of Translational Research in Psychiatry, Munich, Germany.
authors.forename: Marie L
authors.initials: ML
authors.lastname: Frevert
authors.affiliation: Department Physikalische Chemie I, Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Bräuchle
authors.affiliation: Max Planck Institute of Psychiatry, Clinical Department, Munich, Germany.|HMNC GmbH, Munich, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Holsboer
authors.affiliation: Max Planck Institute of Psychiatry, Department of Translational Research in Psychiatry, Munich, Germany.
authors.forename: Theo
authors.initials: T
authors.lastname: Rein
authors.affiliation: Max Planck Institute of Psychiatry, Clinical Department, Munich, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Schmidt
authors.affiliation: Max Planck Institute of Psychiatry, Clinical Department, Munich, Germany.|HMNC GmbH, Munich, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Kirmeier
mesh_terms: D000929:Antidepressive Agents, Tricyclic / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D000071182:Autophagosomes / Q000378:metabolism; D002412:Cations / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D006367:HeLa Cells; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D042541:Intracellular Space / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D004364:Pharmaceutical Preparations / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000929:Antidepressive Agents, Tricyclic; D002412:Cations; D004364:Pharmaceutical Preparations