IN-VITRO INHIBITION OF THYROID-HORMONE SULFATION BY POLYCHLOROBIPHENYLOLS - ISOZYME SPECIFICITY AND INHIBITION-KINETICS

It was recently demonstrated by our laboratory that hydroxylated metab olites of polychlorinated biphenyls (PCB-OHs) are inhibitors of thyroi d hormone sulfation. In this study, a more detailed investigation on s ulfotransferase isozyme specificity and the kinetics of inhibition was performed. Thyroid hormone sulfation was determined using 3,3'-diiodo thyronine (T2) as a substrate, and various sources of sulfotransferase (SULT) enzyme were used; e.g., female and male rat liver cytosol, mal e brain cytosol and cytosolic preparations of V79 cells transfected wi th rat SULT1C1, and human SULT1A1 and human SULT1A3. The inhibition pa ttern 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 sul fotranferase activity using hSULT1A3. Metabolite 3-hydroxy-2,3',4,4',5 -pentachlorobiphenyl did not inhibit T2 sulfotransferase activity in m ale brain cytosol, while it was a very potent inhibitor in male and fe male rat liver cytosol. IC50 values for the tested PCB-OHs were not di fferent with either T2 or 3,3',5-triiodothyronine (T3) as substrate, s upporting the hypothesis that T2 is the preferred iodothyronine substr ate for the sulfotransferases catalyzing the sulfation of the active h ormone T3. The Lineweaver-Burk plot obtained with rat liver cytosol an d T2 suggested that the nature of the T2 sulfation inhibition by 4-hyd roxy-2',3,3',4',5-pentachlorobiphenyl is competitive. Finally, it was demonstrated that tested hydroxylated polychlorinated dibenzo-p-dioxin s and biphenyls were, albeit poorly, sulfated by sulfotransferases as measured by the production of S-35-labeled metabolites. (C) 1998 Socie ty of Toxicology.