title: First-Generation Antipsychotic Haloperidol Alters the Functionality of the Late Endosomal/Lysosomal Compartment in Vitro.
abstract: First- and second-generation antipsychotics (FGAs and SGAs, respectively), have the ability to inhibit cholesterol biosynthesis and also to interrupt the intracellular cholesterol trafficking, interfering with low-density lipoprotein (LDL)-derived cholesterol egress from late endosomes/lysosomes. In the present work, we examined the effects of FGA haloperidol on the functionality of late endosomes/lysosomes in vitro. In HepG2 hepatocarcinoma cells incubated in the presence of 1,1'-dioctadecyl-3,3,3,3'-tetramethylindocarbocyanineperchlorate (DiI)-LDL, treatment with haloperidol caused the enlargement of organelles positive for late endosome markers lysosome-associated membrane protein 2 (LAMP-2) and LBPA (lysobisphosphatidic acid), which also showed increased content of both free-cholesterol and DiI derived from LDL. This indicates the accumulation of LDL-lipids in the late endosomal/lysosomal compartment caused by haloperidol. In contrast, LDL traffic through early endosomes and the Golgi apparatus appeared to be unaffected by the antipsychotic as the distribution of both early endosome antigen 1 (EEA1) and coatomer subunit β (β-COP) were not perturbed. Notably, treatment with haloperidol significantly increased the lysosomal pH and decreased the activities of lysosomal protease and β-d-galactosidase in a dose-dependent manner. We conclude that the alkalinization of the lysosomes' internal milieu induced by haloperidol affects lysosomal functionality.
authors.affiliation: Servicio de Bioquímica-Investigación, Hospital Universitario Ramón y Cajal, IRyCIS, 28034 Madrid, Spain. alberto_canfran@hotmail.com.
authors.forename: Alberto
authors.initials: A
authors.lastname: Canfrán-Duque
authors.affiliation: Unidad de Neurología Experimental, Hospital Universitario Ramón y Cajal, IRyCIS, 28034 Madrid, Spain. luis.c.barrio@hrc.es.
authors.forename: Luis C
authors.initials: LC
authors.lastname: Barrio
authors.affiliation: Servicio de Bioquímica-Investigación, Hospital Universitario Ramón y Cajal, IRyCIS, 28034 Madrid, Spain. milalermafernandez@yahoo.es.
authors.forename: Milagros
authors.initials: M
authors.lastname: Lerma
authors.affiliation: Servicio de Bioquímica-Investigación, Hospital Universitario Ramón y Cajal, IRyCIS, 28034 Madrid, Spain. gema.delapena@hrc.es.
authors.forename: Gema
authors.initials: G
authors.lastname: de la Peña
authors.affiliation: Servicio de Bioquímica-Clínica, Hospital Universitario Ramón y Cajal, IRyCIS, 28034 Madrid, Spain. jserna_87@hotmail.com.
authors.forename: Jorge
authors.initials: J
authors.lastname: Serna
authors.affiliation: Servicio de Bioquímica-Clínica, Hospital Universitario Ramón y Cajal, IRyCIS, 28034 Madrid, Spain. oscar.pastor@salud.madrid.org.
authors.forename: Oscar
authors.initials: O
authors.lastname: Pastor
authors.affiliation: Servicio de Bioquímica-Investigación, Hospital Universitario Ramón y Cajal, IRyCIS, 28034 Madrid, Spain. miguel.a.lasuncion@hrc.es.|CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain. miguel.a.lasuncion@hrc.es.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Lasunción
authors.affiliation: Servicio de Bioquímica-Investigación, Hospital Universitario Ramón y Cajal, IRyCIS, 28034 Madrid, Spain. rebeca.busto@hrc.es.|CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain. rebeca.busto@hrc.es.
authors.forename: Rebeca
authors.initials: R
authors.lastname: Busto
mesh_terms: D014150:Antipsychotic Agents / Q000009:adverse effects / Q000494:pharmacology*; D002784:Cholesterol / Q000378:metabolism; D011992:Endosomes / Q000187:drug effects* / Q000378:metabolism; D006220:Haloperidol / Q000009:adverse effects / Q000494:pharmacology*; D056945:Hep G2 Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D050356:Lipid Metabolism; D008246:Lysophospholipids / Q000378:metabolism; D052119:Lysosomal-Associated Membrane Protein 2 / Q000378:metabolism; D008247:Lysosomes / Q000187:drug effects* / Q000378:metabolism; D010447:Peptide Hydrolases / Q000378:metabolism; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: D014150:Antipsychotic Agents; D008246:Lysophospholipids; D052119:Lysosomal-Associated Membrane Protein 2; D002784:Cholesterol; D001616:beta-Galactosidase; D010447:Peptide Hydrolases; D006220:Haloperidol; C032881:lysophosphatidic acid
keywords: antipsychotic; cholesterol; haloperidol; intracellular lipid traffic; late endosome/lysosome; pH