SPECIES-SPECIFIC ANTAGONISM OF AH RECEPTOR ACTION BY 2,2',5,5'-TETRACHLOROBIPHENYL AND 2,2',3,3',4,4'-HEXACHLOROBIPHENYL

Using recombinant cell lines showing Ah receptor-controlled expression of a luciferase reporter gene, the interaction of di-ortho-substitute d polychlorinated biphenyls (PCBs) with Ah receptor agonists was studi ed. In the recombinant Hepa1c1c7 mouse hepatoma (H1L1.1c7) cells stron g antagonistic interaction of 2,2',5,5'-tetrachlorobiphenyl (PCB52) wi th luciferase expression induced by 2,3,7,8-tetrachlorodibenzo-p-dioxi n (TCDD) or 3,3',4,4'-tetrachlorobiphenyl (PCB77) was observed, and si milarly, between 2,2',3,3',4,4'-hexachlorobiphenyl (PCB128) and PCB77. Accordingly, PCB52 was found to inhibit ethoxyresorufin-O-deethylase (EROD) induction by PCB77 in wild-type Hepa1c1c7 cells. In contrast, t he antagonistic effect of PCB52 on TCDD-induced luciferase expression was only minor in recombinant guinea pig GPC16 colon adenocarcinoma (G 16L1.1c8) and human HepG2 hepatoma (HG2L1.1c3) cells, and intermediate in recombinant H4IIE rat hepatoma (H4L1.1c4) cells. Gel retardation s tudies using a P-32-labelled dioxin responsive element (DRE)-containin g oligonucleotide, and ligand binding studies using [H-3]TCDD, demonst rated that the species-specific antagonistic activity of PCB52 on Ah r eceptor-controlled luciferase expression is due to inhibition of Ah re ceptor ligand and DNA binding. We conclude, that Ah-mediated luciferas e expression provides a useful tool to study the species specificity o f Ah receptor (ant)agonists.