title: Tamoxifen and its active metabolites inhibit dopamine transporter function independently of the estrogen receptors.
abstract: As one of the primary mechanisms by which dopamine signaling is regulated, the dopamine transporter (DAT) is an attractive pharmacological target for the treatment of diseases based in dopaminergic dysfunction. In this work we demonstrate for the first time that the commonly prescribed breast cancer therapeutic tamoxifen and its major metabolites, 4-hydroxytamoxifen and endoxifen, inhibit DAT function. Tamoxifen inhibits [3H]dopamine uptake into human DAT (hDAT)-N2A cells via an uncompetitive or mixed mechanism. Endoxifen, an active metabolite of tamoxifen, asymmetrically inhibits DAT function in hDAT-N2A cells, showing a preference for the inhibition of amphetamine-stimulated dopamine efflux as compared to dopamine uptake. Importantly, we demonstrate that the effects of tamoxifen and its metabolites on the DAT occur independently of its activity as selective estrogen receptor modulators. This work suggests that tamoxifen is inhibiting DAT function through a previously unidentified mechanism.
authors.affiliation: Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors.forename: Sarah R
authors.initials: SR
authors.lastname: Mikelman
authors.affiliation: Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors.forename: Bipasha
authors.initials: B
authors.lastname: Guptaroy
authors.affiliation: Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors.forename: Margaret E
authors.initials: ME
authors.lastname: Gnegy
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D050483:Dopamine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004965:Estrogen Antagonists / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D051379:Mice; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors* / Q000502:physiology*; D020845:Selective Estrogen Receptor Modulators / Q000378:metabolism / Q000494:pharmacology; D013629:Tamoxifen / Q000378:metabolism* / Q000494:pharmacology*
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D004965:Estrogen Antagonists; D011960:Receptors, Estrogen; D020845:Selective Estrogen Receptor Modulators; D013629:Tamoxifen
keywords: amphetamine; dopamine transporter; estrogen receptor; tamoxifen