STRUCTURE-DEPENDENT, COMPETITIVE INTERACTION OF HYDROXY-POLYCHLOROBIPHENYLS, HYDROXY-DIBENZO-P-DIOXINS AND HYDROXY-DIBENZOFURANS WITH HUMANTRANSTHYRETIN

Previous results from our laboratory indicated specific and competitiv e interactions of hydroxylated metabolites of 3,3',4,4'-tetrachlorobip henyl with the plasma thyroid hormone transport protein, transthyretin (TTR), in rats in vivo and with human TTR in vitro. In the present st udy the structural requirements for competition with thyroxine (T4) fo r TTR-binding were investigated in more detail. Several hydroxylated p olychlorinated biphenyls (PCBs), dibenzo-p-dioxins (PCDDs) and dibenzo furans (PCDFs) were tested in an in vitro competitive binding assay, u sing purified human TTR and I-125!T4 as a displaceable radioligand. A ll hydroxylated PCBs, but not the single PCB tested, competitively dis placed I-125!T4 from TTR with differential potency. The highest compe titive binding potency was observed for hydroxylated PCB congeners wit h the hydroxygroup substituted on meta or para positions and one or mo re chlorine atoms substituted adjacent to the hydroxy group on either or both aromatic rings (IC50 range 6.5 - 25 nM; K(a) range: 0.78 - 3.9 5 x 10(8) M-1). The relative potency of all meta or para hydroxylated PCBs was higher than that of the physiological ligand, T4 (relative po tency range: 3.5 - 13.6 compared to T4). There were no marked distinct ions in TTR-T4 competitive binding potencies between the ortho- and no n-ortho-chlorine substituted hydroxy-PCB congeners tested. Marked diff erences in TTR-T4 binding competition potency were observed between th e limited number of hydroxylated PCDDs and PCDFs tested. The hydroxy-P CDD/Fs, with chlorine substitution adjacent to the hydroxy-group, i.e. 7-OH-2,3,8-trichlorodibenzo-p-dioxin, 2-OH-1,3,7,8-tetrachlorodibenzo -p-dioxin and 3-OH-2,6,7,8-tetrachlorodibenzofuran, all showed a simil ar or higher relative binding potency, i.e. 1, 4.4 and 4.5 times highe r, respectively, than T4. No detectable I-125!T4 displacement was obs erved with 2-OH-7,8-dichlorodibenzofuran, 8-OH-2,3,4-trichlorodibenzof uran and 8-OH-2,3-dichlorodibenzo-p-dioxin, which did not contain chlo rine substitution adjacent to the OH-group. These results indicate a p rofound similarity in structural requirements for TTR binding between hydroxy-PCB, -PCDD and -PCDF metabolites and the physiological ligand, T4, e.g. halogen substitution adjacent to the para hydroxy group, whi le planarity does not seem to influence the ligand-binding potency.