Potent inhibition of estrogen sulfotransferase by hydroxylated metabolites of polyhalogenated aromatic hydrocarbons reveals alternative mechanism for estrogenic activity of endocrine disrupters

M.H.A. Kester, S. Bulduk, H. van Toor, D. Tibboel, W. Meinl, H. Glatt, C.N. Falany, M.W.H. Coughtrie, A.G. Schuur, A. Brouwer, T.J. Visser

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

Polyhalogenated aromatic hydrocarbons (PHAHs), such as polychlorinated dibenzo-p-dioxins and dibenzofurans, polybrominated diphenylethers, and bisphenol A derivatives are persistent environmental pollutants, which are capable of interfering with reproductive and endocrine function in birds, fish, reptiles, and mammals. PHAHs exert estrogenic effects that may be mediated in part by their hydroxylated metabolites (PHAH-OHs), the mechanisms of which remain to be identified. PHAH-OHs show low affinity for the ER. Alternatively, they may exert their estrogenic effects by inhibiting E2 metabolism. As sulfation of E2 by estrogen sulfotransferase (SULT1E1) is an important pathway for E2 inactivation, inhibition of SULT1E1 may lead to an increased bioavailability of estrogens in tissues expressing this enzyme. Therefore, we studied the possible inhibition of human SULT1E1 by hydroxylated PHAH metabolites and the sulfation of the different compounds by SULT1E1. We found marked inhibition of SULT1E1 by various PHAH-OHs, in particular by compounds with two adjacent halogen substituents around the hydroxyl group that were effective at (sub)nanomolar concentrations. Depending on the structure, the inhibition is primarily competitive or noncompetitive. Most PHAH-OHs are also sulfated by SULT1E1. We also investigated the inhibitory effects of the various PHAH-OHs on E2 sulfation by human liver cytosol and found that the effects were strongly correlated with their inhibitions of recombinant SULT1E1 (r = 0.922). Based on these results, we hypothesize that hydroxylated PHAHs exert their estrogenic effects at least in part by inhibiting SULT1E1-catalyzed E2 sulfation.
Original languageEnglish
Pages (from-to)1142-1150
Number of pages9
JournalJournal of Clinical Endocrinology and Metabolism
Volume87
Issue number3
DOIs
Publication statusPublished - 2002

Fingerprint

Dive into the research topics of 'Potent inhibition of estrogen sulfotransferase by hydroxylated metabolites of polyhalogenated aromatic hydrocarbons reveals alternative mechanism for estrogenic activity of endocrine disrupters'. Together they form a unique fingerprint.

Cite this