Immunosuppressive and monooxygenase induction activities of polychlorinated diphenyl ether congeners in C57BL/6N mice: quantitative structure-activity relationships.
The dose-response effects of several polychlorinated diphenyl ether (polyCDE) congeners on the inhibition of the splenic plaque-forming cell (PFC) response to sheep red blood cell antigen and the induction of hepatic microsomal aryl hydrocarbon hydroxylase (AHH) and ethoxyresorufin O-deethylase (EROD) activities were determined in male C57BL/6 mice. The immunotoxic potencies for the polyCDE congeners (ED50 values for the suppression of PFCs/spleen and PFCs/10(6) cells) followed the order 2,3,3',4,4',5-hexaCDE (0.5 and 2.2 mumols/kg) greater than 3,3',4,4',5-pentaCDE (8.8 and 5.1 mumols/kg) greater than 2,3',4,4',5-pentaCDE (21.8 and 14.2 mumols/kg) greater than 3,3',4,4'-tetraCDE (50.6 and 28.7 mumols/kg) greater than 2,2',4,4',5,5'-hexaCDE (81.2 and 56.5 mumols/kg) greater than 2,2',4,5,5'-pentaCDE (258 and 228 mumols/kg) greater than 2,2',4,4',5,6'-hexaCDE (greater than 400 mumols/kg for both responses). The potencies of the polyCDE congeners as inducers of hepatic microsomal AHH and EROD activities were similar to their immunotoxicities and only one compound, namely, 2,3',4,4',5,5'-hexaCDE, did not cause dose-response immunosuppressive effects in the mice. The structure-activity relationships for the polyCDEs exhibited both differences and similarities. For example, the coplanar 3,3',4,4'-tetraCDE and 3,3',4,4',5-pentaCDE congeners were less immunotoxic than their monoortho 2,3',4,4',5-pentaCDE and 2,3,3',4,4',5-hexaCDE analogs, respectively, and similar results were also observed for their enzyme induction potencies. For the corresponding polychlorinated biphenyls (PCB) congeners the coplanar compounds were significantly more active than their monoortho analogs. In addition, two diortho-substituted compounds, namely, 2,2',4,5,5'-pentaCDE and 2,2',4,4',5,5'-hexaCDE, were also immunotoxic at a dose of 400 mumols/kg whereas, their PCB analogs were inactive. These studies clearly demonstrate that for the polyCDE congeners, increasing ortho-chloro substitution is less effective in reducing the activity of these congeners compared to the well-recognized ortho effects reported for the PCBs. The differences in the structure-activity relationships between polyCDEs and PCBs are related to the ether bridge in the polyCDEs in which the resultant increased bond length between the two phenyl rings thereby diminishes the effects of ortho substituents on the biochemical and toxic potencies of these compounds.
Howie
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L
Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station 77843.
Dickerson
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R
Davis
D
D
Safe
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S
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis*; D004790:Enzyme Induction; D007108:Immune Tolerance; D007166:Immunosuppressive Agents; D007700:Kinetics; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D015394:Molecular Structure; D011078:Polychlorinated Biphenyls / Q000494:pharmacology*; D012016:Reference Values; D013154:Spleen / Q000276:immunology; D013329:Structure-Activity Relationship
D007166:Immunosuppressive Agents; D011078:Polychlorinated Biphenyls; D001189:Aryl Hydrocarbon Hydroxylases