Increased [3H]Phorbol Ester Binding in Rat Cerebellar Granule Cells and Inhibition of 45Ca2+Buffering in Rat Cerebellum by Hydroxylated Polychlorinated Biphenyls.

Our previous structure–activity relationship (SAR) studies indicated that the effects of polychlorinated biphenyls (PCBs) on neuronal Ca2+ homeostasis and protein kinase C (PKC) translocation were associated with the extent of coplanarity. Chlorine substitutions at ortho position on the biphenyl, which increase the non-coplanarity, are characteristic of the most active congeners in vitro. In the present study, we investigated the effects of selected hydroxylated PCBs, which are major PCB metabolites identified in mammals, on the same measures where PCBs had differential effects based on structural configuration. These measures include PKC translocation as determined by [3H]phorbol ester ([3H]PDBu) binding in cerebellar granule cells, and Ca2+ sequestration as determined by 45Ca2+ uptake by microsomes isolated from adult rat cerebellum. All the selected hydroxy-PCBs with ortho-chlorine substitutions increased [3H]PDBu binding in a concentration-dependent manner and the order of potency as determined by E50 (concentration that increases control activity by 50%) is 2′,4′,6′-trichloro-4-biphenylol (32 ± 4 μM), 2′,5′-dichloro-4-biphenylol (70 ± 9 μM), 2,2′,4′,5,5′-pentachloro-4-biphenylol (80 ± 7 μM) and 2,2′,5′-trichloro-4-biphenylol (93 ± 14 μM). All the selected hydroxy-PCBs inhibited microsomal 45Ca2+ uptake to a different extent. Among the hydroxy-PCBs selected, 2′,4′,6′-trichloro-4-biphenylol is the most active in increasing [3H]PDBu binding as well as inhibiting microsomal 45Ca2+ uptake. 3,5-Dichloro-4-biphenylol and 3,4′,5-trichloro-4-biphenylol did not increase [3H]PDBu binding, but inhibited microsomal 45Ca2+ uptake. This effect was not related to ionization of these two hydroxy-PCBs. Hydroxylated PCBs seemed to be as active as parent PCBs in vitro. These studies indicate that PCB metabolites such as hydroxy-PCBs might contribute significantly to the neurotoxic responses of PCBs. [Copyright &y& Elsevier]