In Vitro Inhibition of Thyroid Hormone Sulfation by Polychlorobiphenylols: Isozyme Specificity and Inhibition Kinetics |
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Authors: | Schuur, A. Gerlienke van Leeuwen-Bol, Ingeborg Jong, Willeke M. C. Bergman, Ake Coughtrie, Michael W. H. Brouwer, Abraham Visser, Theo J. |
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Affiliation: | *Toxicology Group, Department of Food Technology and Nutritional Sciences, Agricultural University Wageningen Wageningen, The Netherlands Environmental Chemistry, Wallenberg Laboratory, Stockholm University Stockholm, Sweden Department of Molecular and Cellular Pathology, University of Dundee Dundee, Scotland Department of Internal Medicine III, Erasmus University Medical School Rotterdam, the Netherlands Received February 16, 1998; accepted May 19, 1998 |
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Abstract: | It was recently demonstrated by our laboratory that hydroxylatedmetabolites of polychlorinated biphenyls (PCB-OHs) are inhibitorsof thyroid hormone sulfation. In this study, a more detailedinvestigation on sulfotransferase isozyme specificity and thekinetics of inhibition was performed. Thyroid hormone sulfationwas determined using 3,3'-diiadothyronine (T2) as a substrate,and various sources of sulfotransferase (SULT) enzyme were used;e.g., female and male rat liver cytosol, male brain cytosoland cytclsolic preparations of V79 cells transfected with ratSULT1C1, and human SULT1A1 and human SULT1A3. The inhibitionpattern and IC50 values were very similar for male and femalerat liver and rSULT1C1 and hSULT1A1. PCB-OHs were not able toinhibit the T2 sulfotranferase activity using hSULT1A3. Metabolite3-hydroxy-2,3',4,4',5-pentachlorobiphenyl did not inhibit T2sulfotransferase activity in male brain cytosol, while it wasa very potent inhibitor in male and female rat liver cytosol.IC50 values for the tested PCB-OHs were not different with eitherT2 or 3,3',5-triiodothyronine (T3) as substrate, supportingthe hypothesis that T2 is the preferred iodothyronine substratefor the sulfotransferases catalyzing the sulfation of the activehormone T3. The Lineweaver-Burk plot obtained with rat livercytosol and T2 suggested that the nature of the T2 sulfationinhibition by 4-hydroxy-2',3,3',4',5-pentachlorobipheny is competitive.Finally, it was demonstrated that tested hydroxylated polychlorinateddibenzo-p-dioxins and biphenyls were, albeit poorly, sulfatedby sulfotransferases as measured by the production of 35S-labeledmetabolites. |
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