In vitro inhibition of thyroid hormone sulfation by polychlorobiphenylols: isozyme specificity and inhibition kinetics.
It was recently demonstrated by our laboratory that hydroxylated metabolites of polychlorinated biphenyls (PCB-OHs) are inhibitors of thyroid hormone sulfation. In this study, a more detailed investigation on sulfotransferase isozyme specificity and the kinetics of inhibition was performed. Thyroid hormone sulfation was determined using 3,3'-diiodothyronine (T2) as a substrate, and various sources of sulfotransferase (SULT) enzyme were used; e.g., female and male rat liver cytosol, male brain cytosol and cytosolic preparations of V79 cells transfected with rat SULT1C1, and human SULT1A1 and human SULT1A3. The inhibition pattern and IC50 values were very similar for male and female rat liver and rSULT1C1 and hSULT1A1. PCB-OHs were not able to inhibit the T2 sulfotransferase activity using hSULT1A3. Metabolite 3-hydroxy-2,3',4,4',5-pentachlorobiphenyl did not inhibit T2 sulfotransferase activity in male brain cytosol, while it was a very potent inhibitor in male and female rat liver cytosol. IC50 values for the tested PCB-OHs were not different with either T2 or 3,3',5-triiodothyronine (T3) as substrate, supporting the hypothesis that T2 is the preferred iodothyronine substrate for the sulfotransferases catalyzing the sulfation of the active hormone T3. The Lineweaver-Burk plot obtained with rat liver cytosol and T2 suggested that the nature of the T2 sulfation inhibition by 4-hydroxy-2',3,3',4',5-pentachlorobiphenyl is competitive. Finally, it was demonstrated that tested hydroxylated polychlorinated dibenzo-p-dioxins and biphenyls were, albeit poorly, sulfated by sulfotransferases as measured by the production of 35S-labeled metabolites.
Schuur
A G
AG
Department of Food Technology and Nutritional Sciences, Agricultural University Wageningen, The Netherlands.
van Leeuwen-Bol
I
I
Jong
W M
WM
Bergman
A
A
Coughtrie
M W
MW
Brouwer
A
A
Visser
T J
TJ
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology*; D003600:Cytosol / Q000201:enzymology; D004104:Diiodothyronines / Q000378:metabolism; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D011078:Polychlorinated Biphenyls / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D015238:Sulfotransferases / Q000037:antagonists & inhibitors*; D014284:Triiodothyronine / Q000378:metabolism*
C111120:2,3,3',4',5-pentachloro-4-hydroxybiphenyl; D004104:Diiodothyronines; D007527:Isoenzymes; D014284:Triiodothyronine; C067423:4'-hydroxy-3,4,5,3',5'-pentachlorobiphenyl; C030629:3,3'-diiodothyronine; D011078:Polychlorinated Biphenyls; D015238:Sulfotransferases; C109377:iodothyronine sulfotransferase