INCREASED [H-3] PHORBOL ESTER BINDING IN RAT CEREBELLAR GRANULE CELLSBY POLYCHLORINATED BIPHENYL MIXTURES AND CONGENERS - STRUCTURE-ACTIVITY-RELATIONSHIPS

Our previous reports indicate that polychlorinated biphenyl (PCB) cong eners in vitro perturbed cellular Ca2+ homeostasis and protein kinase C (PKC) translocation. We have now studied the structure-activity rela tionship (SAR) of 3 PCB mixtures, 24 PCB congeners, and 1 dibenzofuran for their effects on PKC translocation by measuring [H-3]phorbol este r ([H-3]PDBu) binding in cerebellar granule cells (7 days in culture). All the PCB mixtures studied increased [H-3]PDBu binding significantl y and in a concentration-dependent manner. However, Aroclor 1016 and A roclor 1254 were more potent than Aroclor 1260. Of the 24 congeners st udied, di-ortho congeners such as 2,2',5,5'tetrachlorobiphenyl (-TeCB) , 2,2',4,6,6'-pentachlorobiphenyl (-PeCB), 2,2',4,6-TeCB, and 2,2'-dic hlorobiphenyl (-DCB) were the most potent (E50 = 28-43 mu M) while non -ortho congeners such as 3,3',4,4'-TeCB and 3,3',4,4',5-PeCB were not effective. The potential contaminant of PCB mixtures, 1,2,3,7,8-pentac hlorodibenzofuran had no significant effect on [3H]PDBu binding. The S AR among these congeners revealed: (i) congeners with ortho-chlorine s ubstitution such as 2,2'-DCB (E50 = 43 +/- 3 mu M) Or ortho-lateral (m eta, para) chlorine substitution such as 2,2',5,5'-TeCB (E50 = 28 +/- 3 mu M) and 2,2',4,6-TeCB (E50 = 41 +/- 6 mu M) were most potent; (ii) congeners with only para-substitution such as 4,4'-DCB or high latera l content in the absence of ortho-substitution such as 3,3',4,4',5,5'- HCB were not effective; and (iii) increased chlorination was not clear ly related to the effectiveness of these congeners, although hexa- and heptachlorination was less effective than di- and tetrachlorination. Low lateral substitution, especially without para-substitution, or lat eral content in the presence of ortho-substitution, may be the most im portant structural requirement for the in vitro activity of these PCB congeners in neuronal preparations. (C) 1995 Academic Press, Inc.