Increased ( 3H) Phorbol Ester Binding in Rat Cerebellar Granule Cells by Polychlorinated Biphenyl Mixtures and Congeners: Structure-Activity Relationships

• Published in: Toxicology and applied pharmacology 1995, Vol.130 (1), p.140-148
• Main Authors: Kodavanti, P.R.S., Ward, T.R., Mckinney, J.D., Tilson, H.A.
• Format: Article
• Language: English
• Subjects: Analysis of Variance; Animals; Aroclors - toxicity; Benzofurans - chemistry; Benzofurans - metabolism; Benzofurans - toxicity; Binding Sites; Biological and medical sciences; Cells, Cultured; Cerebellum - cytology; Cerebellum - drug effects; Cerebellum - metabolism; Chemical and industrial products toxicology. Toxic occupational diseases; Chlorodiphenyl (54% Chlorine); Computer Simulation; Dose-Response Relationship, Drug; Female; Medical sciences; Phorbol 12,13-Dibutyrate - metabolism; Polychlorinated Biphenyls - chemistry; Polychlorinated Biphenyls - metabolism; Polychlorinated Biphenyls - toxicity; Pregnancy; Protein Kinase C - metabolism; Rats; Stereoisomerism; Structure-Activity Relationship; Toxicology; Various organic compounds
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1006/taap.1995.1018

Our previous reports indicate that polychlorinated biphenyl (PCB) congeners in vitro perturbed cellular Ca 2+ homeostasis and protein kinase C (PKC) translocation. We have now studied the structure-activity relationship (SAR) of 3 PCB mixtures, 24 PCB congeners, and 1 dibenzofuran for their effects on PKC translocation by measuring [ 3H]phorbol ester ([ 3H]PDBu) binding in cerebellar granule cells (7 days in culture). All the PCB mixtures studied increased [ 3H]PDBu binding significantly and in a concentration-dependent manner. However, Aroclor 1016 and Aroclor 1254 were more potent than Aroclor 1260. Of the 24 congeners studied, 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′-dichlorobiphenyl (-DCB) were the most potent (E50 = 28-43 μM) 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-pentachlorodibenzofuran had no significant effect on [ 3H]PDBu binding. The SAR among these congeners revealed: (i) congeners with ortho-chlorine substitution such as 2,2′-DCB (E50 = 43 ± 3 μM) or ortho-lateral ( meta, para) chlorine substitution such as 2,2′,5,5′-TeCB (E50 = 28 ± 3 μM) and 2,2′,4,6-TeCB (E50 = 41 ± 6 μM) were most potent; (ii) congeners with only para-substitution such as 4,4′-DCB or high lateral 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 clearly 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 lateral content in the presence of ortho-substitution, may be the most important structural requirement for the in vitro activity of these PCB congeners in neuronal preparations.