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 dibenzofurans (PCDFs) competitively inhibit thyroxine (T4) binding to transthyretin (TTR) and type I deiodinase (D1) activity. In this study, we investigated the possible inhibitory effects of hydroxylated metabolites of polyhalogenated aromatic hydrocarbons (PHAHs) on iodothyronine sulfotransferase activity. Rat liver cytosol was used as a source of sulfotransferase enzyme in an in vitro assay with 125I-labeled 3,3'-diiodothyronine (T2) as a model substrate. Increasing amounts of hydroxylated 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, PCDDs, and PCDFs were found to be potent inhibitors of T2 sulfotransferase activity in vitro with IC50 values in the low micromolar range (0.2-3.8 microM). The most potent inhibitor of T2 sulfotransferase activity in our experiments was the PCB metabolite 3-hydroxy-2,3',4, 4',5-pentachlorobiphenyl with an IC50 value of 0.2 microM. A hydroxyl group in the para or meta position appeared to be an important structural requirement for T2 sulfotransferase inhibition by PCB metabolites. Ortho hydroxy PCBs were much less potent, and none of the parent PHAHs was capable of inhibiting T2 sulfotransferase activity. In addition, the formation of T2 sulfotransferase-inhibiting metabolites of individual brominated diphenyl ethers and nitrofen as well as from some commercial PHAH mixtures (e.g., Bromkal, Clophen A50, and Aroclor 1254) was also demonstrated. These results indicate that hydroxylated PHAHs are potent inhibitors of thyroid hormone sulfation. Since thyroid hormone sulfation may play an important role in regulating free hormone levels in the fetus, and PCB metabolites are known to accumulate in fetal tissues after maternal exposure to PCBs, these observations may have implications for fetal thyroid hormone homeostasis and development.
Schuur
A G
AG
Toxicology Group, Department of Food Technology and Nutritional Sciences, Agricultural University Wageningen, 6700 EA Wageningen, The Netherlands. Gerlienke.Schuur@algemeen.tox.wau.nl
Legger
F F
FF
van Meeteren
M E
ME
Moonen
M J
MJ
van Leeuwen-Bol
I
I
Bergman
A
A
Visser
T J
TJ
Brouwer
A
A
D000818:Animals; D001572:Benzofurans / Q000493:pharmacokinetics / Q000494:pharmacology; D001711:Biotransformation; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000378:metabolism; D004104:Diiodothyronines / Q000378:metabolism; D004147:Dioxins / Q000493:pharmacokinetics / Q000494:pharmacology; D006846:Hydrocarbons, Halogenated / Q000493:pharmacokinetics / Q000494:pharmacology*; D006900:Hydroxylation; D007527:Isoenzymes / Q000096:biosynthesis / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D010634:Phenobarbital / Q000494:pharmacology; D011078:Polychlorinated Biphenyls / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D015238:Sulfotransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013455:Sulfur / Q000378:metabolism*; D014284:Triiodothyronine / Q000378:metabolism*; D019324:beta-Naphthoflavone / Q000494:pharmacology
D001572:Benzofurans; D004104:Diiodothyronines; D004147:Dioxins; D006846:Hydrocarbons, Halogenated; D007527:Isoenzymes; D014284:Triiodothyronine; D019324:beta-Naphthoflavone; C030629:3,3'-diiodothyronine; D013455:Sulfur; D003577:Cytochrome P-450 Enzyme System; D011078:Polychlorinated Biphenyls; D015238:Sulfotransferases; C109377:iodothyronine sulfotransferase; C020887:dibenzo(1,4)dioxin; D010634:Phenobarbital