title: Genotoxicity of the neurotransmitter dopamine in vitro.
abstract: Alterations in dopamine levels play a role in several human pathological conditions and their pharmacological treatment. Here we describe an induction of genomic damage detected as micronucleus formation by concentrations in the low micromolar range (6.25-25 microM) in three cell lines in vitro. Rat neuronal PC12 cells exhibited a more pronounced induction (about 10-fold over control at 100 microM) than human lymphoblastoid TK6 cells and rat kidney NRK cells (about 2-fold over control at 100 microM). The role of transporters and receptors in the formation of genomic damage was investigated in PC12 cells, in which the effect of dopamine was reduced by addition of the antioxidants TEMPOL and dimethylthiourea, by inhibitors of the dopamine transporter (GBR 12909 and nomifensine) and by a D2 antagonist (sulpiride). Antioxidative effects of nomifensine and sulpiride, but not of GBR 12909, were excluded, since they did not protect oxidative stress sensitive HL-60 cells from hydrogen peroxide-induced damage in the comet assay. Thus, the transport of dopamine into the cell and the signalling upon binding to D2 receptors was required for the genotoxic effect of dopamine in PC12 cells, which was mediated by intracellular dopamine oxidation products and/or reactive oxygen species.
authors.affiliation: Department of Toxicology, University of Wuerzburg, Versbacher Strasse 9, D-97078 Wuerzburg, Germany. stopper@toxi.uni-wuerzburg.de
authors.forename: Helga
authors.initials: H
authors.lastname: Stopper
authors.forename: Nicole
authors.initials: N
authors.lastname: Schupp
authors.forename: Gholamreza
authors.initials: G
authors.lastname: Fazeli
authors.forename: Barbara
authors.initials: B
authors.lastname: Dietel
authors.forename: Nina
authors.initials: N
authors.lastname: Queisser
authors.forename: Susanne
authors.initials: S
authors.lastname: Walitza
authors.forename: Manfred
authors.initials: M
authors.lastname: Gerlach
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D004298:Dopamine / Q000633:toxicity*; D006801:Humans; D015162:Micronucleus Tests; D009152:Mutagenicity Tests; D009627:Nomifensine / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D010300:Parkinson Disease / Q000188:drug therapy / Q000235:genetics; D010879:Piperazines / Q000494:pharmacology; D051381:Rats; D013469:Sulpiride / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D010879:Piperazines; D009627:Nomifensine; D013469:Sulpiride; C043425:vanoxerine; D004298:Dopamine