STRUCTURE-ACTIVITY-RELATIONSHIPS OF POTENTIALLY NEUROTOXIC PCB CONGENERS IN THE RAT

We have explored the effects of PCBs on Ca2+-homeostasis and inositol phosphates in an attempt to understand cellular mechanism(s) for neuro toxicity of PCBs. The selected prototypic congeners have non-dioxin-li ke (2,2'-dichlorobiphenyl; 2,2'-DCB; IUPAC # 4; ortho-substituted and dioxin-like (3,3',4,4',5-pentachlorobiphenyl; 3,3',4,4',5-PeCB; IUPAC # 126; non-ortho substituted) properties. The hypothesis is that some PCBs in vitro alter Ca2+-homeostasis and interfere with intracellular second messengers. One of the consequences of this perturbation is pro tein kinase C (PKC) translocation, and these events could lead to cyto toxicity. Our results indicate that the non-dioxin like PCB (ortho-sub stituted one) is active in vitro and perturbed signal transduction mec hanisms including Ca2+-homeostasis and PKC translocation. The effects were seen at relatively low concentrations (5-50 mu M) whereas higher concentrations (>200 mu M) were required to produce cytotoxicity. Resu lts from SAR, in general, indicate that congeners with chlorine substi tutions at ortho-position or low lateral substitutions (mostly meta-) are active in vitro where as non-ortho congeners are inactive. In summ ary, these results indicate that low lateral substitution (especially without para-substitution that favor coplanarity) or high lateral cont ent in the presence of ortho-substitution (to hinder coplanarity) may be the most critical structural requirement underlying the activity of PCB congeners in vitro. Additional experiments with polychlorinated d iphenyl ethers (PCDEs) and their analogs, where coplanarity is difficu lt regardless of degree and pattern of chlorination, provided importan t information supporting our hypothesis that coplanarity plays a key r ole in the activity of PCBs in vitro. For example, a PCB congener with 3,3',4,4'-chlorine substitutions is not active whereas a PCDE with th e same chlorine substitutions is active. Similarly, 4,4'-DCB is not ac tive whereas PCDE with 4,4'-substitutions is active. One major structu ral difference in PCDE when compared to the corresponding PCB is non-c oplanarity. The PCBs compared here are coplanar and not active, wherea s PCDEs are non-coplanar and active in vitro in neuronal preparations. Molecular mechanics calculations and conformational searches confirme d the extent of coplanarity among PCBs and PCDEs. Non-ortho PCBs are m ore coplanar in nature when compared to ortho-PCBs and PCDEs. These re sults demonstrate that the extent of coplanarity of certain chlorinate d aromatic hydrocarbons can affect their potency in vitro, and ortho-s ubstitutions on the biphenyl, which increase non-coplanarity, are char acteristic of the most active PCB congeners. (C) 1997 Intox Press, Inc .