Sulfated metabolites of polychlorinated biphenyls are high-affinity ligands for the thyroid hormone transport protein transthyretin

Fabian A Grimm; Hans-Joachim Lehmler; Xianran He; Larry W Robertson; Michael W Duffel

doi:10.1289/ehp.1206198

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Sulfated metabolites of polychlorinated biphenyls are high-affinity ligands for the thyroid hormone transport protein transthyretin

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Sulfated metabolites of polychlorinated biphenyls are high-affinity ligands for the thyroid hormone transport protein transthyretin

Fabian A Grimm, Hans-Joachim Lehmler, Xianran He, Larry W Robertson and Michael W Duffel

Environmental health perspectives, Vol.121(6), pp.657-662

06/2013

DOI: 10.1289/ehp.1206198

PMCID: PMC3672920

PMID: 23584369

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Abstract

The displacement of l-thyroxine (T4) from binding sites on transthyretin (TTR) is considered a significant contributing mechanism in polychlorinated biphenyl (PCB)-induced thyroid disruption. Previous research has discovered hydroxylated PCB metabolites (OH-PCBs) as high-affinity ligands for TTR, but the binding potential of conjugated PCB metabolites such as PCB sulfates has not been explored. We evaluated the binding of five lower-chlorinated PCB sulfates to human TTR and compared their binding characteristics to those determined for their OH-PCB precursors and for T4. We used fluorescence probe displacement studies and molecular docking simulations to characterize the binding of PCB sulfates to TTR. The stability of PCB sulfates and the reversibility of these interactions were characterized by HPLC analysis of PCB sulfates after their binding to TTR. The ability of OH-PCBs to serve as substrates for human cytosolic sulfotransferase 1A1 (hSULT1A1) was assessed by OH-PCB-dependent formation of adenosine-3',5'-diphosphate, an end product of the sulfation reaction. All five PCB sulfates were able to bind to the high-affinity binding site of TTR with equilibrium dissociation constants (Kd values) in the low nanomolar range (4.8-16.8 nM), similar to that observed for T4 (4.7 nM). Docking simulations provided corroborating evidence for these binding interactions and indicated multiple high-affinity modes of binding. All OH-PCB precursors for these sulfates were found to be substrates for hSULT1A1. Our findings show that PCB sulfates are high-affinity ligands for human TTR and therefore indicate, for the first time, a potential relevance for these metabolites in PCB-induced thyroid disruption.

Sulfates - metabolism

Prealbumin - metabolism

Humans

Thyroxine - metabolism

Ligands

Molecular Docking Simulation

Polychlorinated Biphenyls - metabolism

Arylsulfotransferase - metabolism

Details

Title: Subtitle: Sulfated metabolites of polychlorinated biphenyls are high-affinity ligands for the thyroid hormone transport protein transthyretin
Creators: Fabian A Grimm - Interdisciplinary Graduate Program in Human Toxicology, Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, College of Public Health, The University of Iowa, Iowa City, Iowa 52246, USA
Hans-Joachim Lehmler
Xianran He
Larry W Robertson
Michael W Duffel
Resource Type: Journal article
Publication Details: Environmental health perspectives, Vol.121(6), pp.657-662
DOI: 10.1289/ehp.1206198
PMID: 23584369
PMCID: PMC3672920
NLM abbreviation: Environ Health Perspect
ISSN: 0091-6765
eISSN: 1552-9924
Publisher: United States
Grant note: P42 ES013661 / NIEHS NIH HHS P30 ES005605 / NIEHS NIH HHS P30 ES05605 / NIEHS NIH HHS
Language: English
Date published: 06/2013
Academic Unit: Occupational and Environmental Health; Iowa Neuroscience Institute; Pharmaceutical Sciences and Experimental Therapeutics; Iowa Superfund Research Program; Medicinal and Natural Products Chemistry
Record Identifier: 9984001084602771

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