INHIBITION OF MICROSOMAL AND MITOCHONDRIAL CA2- STRUCTURE-ACTIVITY-RELATIONSHIPS( SEQUESTRATION IN RAT CEREBELLUM BY POLYCHLORINATED BIPHENYL MIXTURES AND CONGENERS )

Recent studies from our laboratory indicate that polychlorinated biphe nyl(PCB) congeners in vitro perturbed signal transduction mechanisms i ncluding cellular Ca2+-homeostasis and protein kinase C translocation. We have now investigated the structure-activity relationship (SAR) of three PCB mixtures, 24 PCB congeners and one dibenzofuran for their e ffects on microsomal and mitochondrial Ca2+-sequestration in rat cereb ellum. Ca2+-sequestration by these intracellular organelles was determ ined using radioactive (CaCl2)-Ca-45. All three mixtures studied, Aroc lor 1016, Aroclor 1254 and Aroclor 1260, were equally potent in inhibi ting microsomal and mitochondrial Ca2+-sequestration with IC50 values of 6-8 mu M 1,2,3,7,8-Pentachlorodibenzofuran had no effect on Ca2+-se questration by these organelles. The SAR among the congeners revealed: (1) congeners with ortho-/meta- or ortho-, para-chlorine substitution s were the most potent in inhibiting microsomal and mitochondrial Ca2 -sequestration (IC50 = 2.4-22.3 mu M); (2) congeners with only para- but without ortho-substitutions were not effective in inhibiting Ca2+- sequestration by microsomes and mitochondria; (3) increased chlorinati on was not related to the effectiveness of these congeners. The presen t SAR studies indicate that the effects of most PCB congeners in vitro may be related to an interaction at specific sites having preference for low lateral substitution or lateral content (Meta- or para) in the presence of ortho-substitution.