Non-dioxin-like PCBs inhibit [(3)H]WIN-35,428 binding to the dopamine transporter: a structure-activity relationship study.
Non-dioxin-like polychlorinated biphenyls (NDL-PCBs) are neurotoxic compounds with known effects at the dopaminergic system in the brain. In a previous study we demonstrated that NDL-PCBs inhibit uptake of dopamine into rat brain synaptosomes, an effect most likely mediated by inhibition of the dopamine transporter (DAT). Here, using the cocaine analogue [(3)H]WIN-35,428 binding assay and synaptosomes, we directly investigate whether NDL-PCBs act via DAT and explore the structure-activity relationship of this effect. In total, thirty PCBs were investigated, including a previously selected training set of twenty PCBs covering the structural variation within tri- to hepta-chlorinated NDL-PCBs, and an additional set of ten NDL-PCB congeners selected to validate the structure-activity pattern of neurotoxic PCBs. Since previous work has demonstrated that NDL-PCBs can also inhibit the vesicular monoamine transporter 2 (VMAT2), we additionally examined whether some PCB congeners favour an effect on VMAT2 and others on DAT. Our results show that NDL-PCBs are potent inhibitors of [(3)H]WIN-35,428 binding to DAT. In fact, we identify a PCB congener (PCB 110) with similar potency for [(3)H]WIN-35,428 binding inhibition as cocaine. All active congeners were ortho-chlorinated PCBs, and in particular, tetra- and penta-chlorinated with 2-3 chlorine atoms in the ortho position were potent inhibitors of [(3)H]WIN-35,428 binding. Notably, the most active PCBs are highly prevalent in commercial mixtures of PCBs (Aroclor 1242, 1254 and 1260), which indicates that DAT inhibition could be one of the factors contributing to behavioural effects after Aroclor exposure. Derived data correlated well with the recently derived neurotoxic equivalency factors (NEQs), indicating the generality and applicability of the NEQ scheme in risk assessments of PCBs.
Department of Biochemistry, Institute of Basic Medical Sciences, University of Oslo, NO-0316 Oslo, Norway. Electronic address: m.b.wigestrand@medisin.uio.no.
M B
MB
Wigestrand
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M
Stenberg
S I
SI
Walaas
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F
Fonnum
P L
PL
Andersson
D000818:Animals; D003042:Cocaine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D003342:Corpus Striatum / Q000648:ultrastructure; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism*; D018765:Dopamine Uptake Inhibitors / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004785:Environmental Pollutants / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008297:Male; D008956:Models, Chemical; D011078:Polychlorinated Biphenyls / Q000737:chemistry / Q000494:pharmacology*; D025341:Principal Component Analysis; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D013574:Synaptosomes / Q000187:drug effects*; D014316:Tritium / Q000378:metabolism / Q000493:pharmacokinetics
D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D004785:Environmental Pollutants; D014316:Tritium; C021279:(1R-(exo,exo))-3-(4-fluorophenyl)-8-methyl-8- azabicyclo(3.2.1)octane-2-carboxylic acid, methyl ester; D011078:Polychlorinated Biphenyls; D003042:Cocaine; D004298:Dopamine
DAT; DL-PCB; Dopamine; NDL-PCB; PCA; PCB; PKC; PLS; QSAR; SAR; Structure–activity; TEF; Toxicity; UV; VMAT2; WIN-35,428; dioxin-like PCB; dopamine transporter; non-dioxin-like PCB; partial least squares; polychlorinated biphenyl; principal component analysis; protein kinase C; quantitative structure–activity relationship; structure–activity relationship; toxic equivalent factors; ultraviolet; vesicular monoamine transporter 2