Inhibition of L-aromatic amino acid decarboxylase by polychlorinated biphenyls.
PC12 cells were used to examine the mechanisms by which polychlorinated biphenyls (PCBs) reduce cellular levels of dopamine (DA). In cells treated 3 days with Aroclor 1254, 2,2',5,5'-tetrachlorobiphenyl (2,2',5,5'-TCB), or 2,2',3,3',4,4'-hexachlorobiphenyl (2,2',3,3',4,4'-HCB), the PCB-mediated reduction in 3H-tyrosine uptake was observed only at high PCB concentrations that produced a reduction in DNA levels. The PCB congener, 2,2',4,4',5,5'-hexachlorobiphenyl (2,2',4,4',5,5'-HCB) did not produce a reduction in 3H-tyrosine uptake at any concentration tested. Thus, there were PCB concentrations at which a reduction in DA levels did not coincide with a decrease in 3H-tyrosine uptake, suggesting that inhibition of tyrosine uptake was not the primary mechanism by which PCBs reduce DA levels. Aroclor 1254-treated cells also exhibited elevated levels of DOPA, further supporting the conclusion that tyrosine levels were not limiting. Incubation of Aroclor 1254-pretreated cells with 3H-tyrosine resulted in a dose-dependent increase in cellular levels of 3H-DOPA and decrease in cellular levels of 3H-DA, suggesting a PCB-mediated inhibition of the conversion of 3H-DOPA to 3H-DA. When the media was supplemented with DOPA, Aroclor 1254-treated cells still exhibited reduced levels of DA, compared to control cells, even though the control and PCB-treated cells had similar cellular levels of DOPA. Thus, one mechanism by which PCBs may reduce cellular levels of DA is by inhibiting L-aromatic amino acid decarboxylase-mediated conversion of DOPA to DA. The PCB congeners, 2,2',4,4'-TCB, 2,2',5,5'-TCB, and 2,2',4,4',5,5'-HCB, also produced dose-dependent increases in DOPA levels. The congener 2,2',3,3',4,4'-HCB did not produce an increase in DOPA levels, although it did mediate reductions in cellular DA levels. However, when PC12 cells were supplemented with DOPA, all four PCB congeners produced a similar reduction in DA levels, suggesting that the conversion of DOPA to DA was inhibited by the PCBs.
Angus
W G
WG
Department of Pharmacology and Toxicology, Michigan State University, East Lansing 48824, USA.
Mousa
M A
MA
Vargas
V M
VM
Quensen
J F
JF
Boyd
S A
SA
Contreras
M L
ML
D000596:Amino Acids / Q000187:drug effects*; D000818:Animals; D002262:Carboxy-Lyases / Q000187:drug effects*; D002478:Cells, Cultured / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004785:Environmental Pollutants / Q000633:toxicity*; D016716:PC12 Cells / Q000187:drug effects; D011078:Polychlorinated Biphenyls / Q000633:toxicity*; D051381:Rats
D000596:Amino Acids; D004785:Environmental Pollutants; D011078:Polychlorinated Biphenyls; D002262:Carboxy-Lyases; D004298:Dopamine