Structure-dependent, competitive interaction of hydroxy-polychlorobiphenyls, -dibenzo-p-dioxins and -dibenzofurans with human transthyretin.
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abstract
Previous results from our laboratory indicated specific and competitive interactions of hydroxylated metabolites of 3,3', 4,4'-tetrachlorobiphenyl with the plasma thyroid hormone transport protein, transthyretin (TTR), in rats in vivo and with human TTR in vitro. In the present study the structural requirements for competition with thyroxine (T4) for TTR-binding were investigated in more detail. Several hydroxylated polychlorinated biphenyls (PCBs), dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs) were tested in an in vitro competitive binding assay, using purified human TTR and [125I]T4 as a displaceable radioligand. All hydroxylated PCBs, but not the single PCB tested, competitively displaced [125I]T4 from TTR with differential potency. The highest competitive binding potency was observed for hydroxylated PCB congeners with the hydroxygroup substituted on meta or para positions and one or more chlorine atoms substituted adjacent to the hydroxy group on either or both aromatic rings (IC50 range 6.5-25 nM; Ka range: 0.78-3.95 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 potency range: 3.5-13.6 compared to T4). There were no marked distinctions in TTR-T4 competitive binding potencies between the ortho- and non-ortho-chlorine substituted hydroxy-PCB congeners tested. Marked differences in TTR-T4 binding competition potency were observed between the limited number of hydroxylated PCDDs and PCDFs tested. The hydroxy-PCDD/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 similar or higher relative binding potency, i.e. 1, 4.4 and 4.5 times higher, respectively, than T4. No detectable [125I]T4 displacement was observed with 2-OH-7,8-dichlorodibenzofuran, 8-OH-2,3,4-trichlorodibenzofuran and 8-OH-2,3-dichlorodibenzo-p-dioxin, which did not contain chlorine substitution adjacent to the OH-group. These results indicate a profound 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, while planarity does not seem to influence the ligand-binding potency.
