INCREASED [H-3] PHORBOL ESTER BINDING IN RAT CEREBELLAR GRANULE CELLSAND INHIBITION OF CA-45(2- STRUCTURE-ACTIVITY-RELATIONSHIPS() SEQUESTRATION IN RAT CEREBELLUM BY POLYCHLORINATED DIPHENYL ETHER CONGENERS AND ANALOGS )

Our previous reports indicate that ortho-substituted non-coplanar poly chlorinated biphenyl (PCB) congeners perturbed neuronal Ca2+-homeostas is in vitro, altered agonist-stimulated inositol phosphate accumulatio n, and caused protein kinase C (PKC) translocation. The structure-acti vity relationship (SAR) with 24 PCB congeners was consistent with a ch lorination pattern that favored non-coplanarity while those with chlor ination that favored coplanarity were less active, To test the hypothe sis that coplanarity (or lack thereof) is a significant factor in the activity of PCBs, studies with related classes of chemicals such as th e polychlorinated diphenyl ethers (PCDEs), in which coplanarity is mor e difficult to achieve regardless of degree and pattern of chlorinatio n, were initiated, The selected PCDEs and their analogs are predicted to be active, since they are non-coplanar in nature, The effects of th ese chemicals were studied using the same measures for which PCBs had differential effects based on structural configuration, These measures include PKC translocation as determined by [H-3]-phorbol ester ([H-3] PDBu) binding in cerebellar granule cells and Ca-45(2+) sequestration as determined by Ca-45(2+) uptake by microsomes and mitochondria isola ted from adult rat cerebellum. All the PCDE congeners studied, increas ed [H-3]PDBu binding in a concentration-dependent manner. The order of potency was 2,4,4'-trichlorodiphenyl ether > 4,4'-dichlorodiphenyl et her > diphenyl ether, 3,3',4,4'-tetrachlorodiphenyl ether and, 2,2',4, 4',5- and 2,3',4,4',5-pentachlorodiphenyl ethers. The structurally rel ated diphenyl ether nitrofen and diphenyl ethanes o,p'-1,1,1-trichloro -2,2-bis[p-chlorophenyl]ethane (DDT) and p,p'-DDT increased [H-3]PDBu binding to a similar extent (28-35% stimulation at 100 mu M). All PCDE congeners and their analogs inhibited Ca-45(2+) sequestration by micr osomes and mitochondria. Of all the chemicals, unchlorinated diphenyl ether was the least active, These results are in agreement with previo us SAR findings in which noncoplanar PCBs are active and support our h ypothesis that the extent of coplanarity determined by a pattern of ch lorination on certain aromatic hydrocarbons can weaken their potency i n vitro, although the extent of chlorination is also important. (C) 19 96 Academic Press, Inc.