IN-VITRO INHIBITION OF THYROID-HORMONE SULFATION BY HYDROXYLATED METABOLITES OF HALOGENATED AROMATIC-HYDROCARBONS

Earlier studies in our laboratory showed that hydroxylated metabolites of polychlorinated biphenyls (PCBs), dibenzo-p-dioxins (PCDDs), and d ibenzofurans (PCDFs) competitively inhibit thyroxine (T4) binding to t ransthyretin (TTR) and type I deiodinase (D1) activity. In this study, we investigated the possible inhibitory effects of hydroxylated metab olites of polyhalogenated aromatic hydrocarbons (PHAHs) on iodothyroni ne sulfotransferase activity. Rat liver cytosol was used as a source o f sulfotransferase enzyme in an in vitro assay with I-125-labeled 3,3' -diiodothyronine (T2) as a model substrate. Increasing amounts of hydr oxylated PCBs, PCDDs, or PCDFs or extracts from incubation mixtures of PHAHs and induced liver microsomes were added as potential inhibitors of T2 sulfotransferase activity. Hydroxylated metabolites of PCBs, PC DDs, and PCDFs were found to be potent inhibitors of T2 sulfotransfera se activity in vitro with IC50 values in the low micromolar range (0.2 -3.8 mu M). The most potent inhibitor of T2 sulfotransferase activity in our experiments was the PCB metabolite 3-hydroxy-2,3',4,4',5-pentac hlorobiphenyl with an IC50 value of 0.2 mu M. A hydroxyl group in the para or meta position appeared to be an important structural requireme nt for T2 sulfotransferase inhibition by PCB metabolites. Ortho hydrox y PCBs were much less potent, and none of the parent PHAHs was capable of inhibiting T2 sulfotransferase activity. In addition, the formatio n of T2 sulfotransferase-inhibiting metabolites of individual brominat ed diphenyl ethers and nitrofen as well as from some commercial PHAH m ixtures (e.g.,Bromkal, Clophen A50, and Aroclor 1254) was also demonst rated. These results indicate that hydroxylated PHAHs are potent inhib itors of thyroid hormone sulfation. Since thyroid hormone sulfation ma y play an important role in regulating free hormone levels in the fetu s, and PCB metabolites are known to accumulate in fetal tissues after maternal exposure to PCBs, these observations may have implications fo r fetal thyroid hormone homeostasis and development.