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

Grimm FA, Lehmler HJ, He X, Robertson LW, Duffel MW - Environ. Health Perspect. (2013)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: 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.

ABSTRACT

Background: 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.

Objectives: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

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Related in: MedlinePlus

OH-PCBs are substrates for human SULT1A1. The sulfation of 2´OH-PCB 3, 3´OH-PCB 3, 4´OH-PCB 3, 4´OH-PCB 11, and 4´OH-PCB 12 is catalyzed by a cytosolic extract of E. coli expressing recombinant hSULT1A1.*p < 0.05, and **p < 0.001 compared with 0 µM OH-PCB
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f4: OH-PCBs are substrates for human SULT1A1. The sulfation of 2´OH-PCB 3, 3´OH-PCB 3, 4´OH-PCB 3, 4´OH-PCB 11, and 4´OH-PCB 12 is catalyzed by a cytosolic extract of E. coli expressing recombinant hSULT1A1.*p < 0.05, and **p < 0.001 compared with 0 µM OH-PCB

Mentions: OH-PCBs as substrates for hSULT1A1. Because formation of PCB sulfates requires their metabolic formation from OH-PCBs, we determined the rate of sulfation of OH-PCBs by recombinant hSULT1A1. The five OH-PCBs that were tested in this study were substrates for the enzyme and exhibited a concentration-dependent increase in the rate of sulfation (Figure 4). The highest specific activities were determined for the ortho-hydroxylated 2´OH-PCB 3 and for the meta-hydroxylated 3´OH-PCB 3. The para-hydroxylated 4´OH-PCB 3, 4´OH-PCB 11, and 4´OH-PCB 12 exhibited slightly lower specific activities. Thus, the hSULT1A1, a major human cytosolic sulfotransferase, catalyzes the sulfation of these OH-PCBs.


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

Grimm FA, Lehmler HJ, He X, Robertson LW, Duffel MW - Environ. Health Perspect. (2013)

OH-PCBs are substrates for human SULT1A1. The sulfation of 2´OH-PCB 3, 3´OH-PCB 3, 4´OH-PCB 3, 4´OH-PCB 11, and 4´OH-PCB 12 is catalyzed by a cytosolic extract of E. coli expressing recombinant hSULT1A1.*p < 0.05, and **p < 0.001 compared with 0 µM OH-PCB
© Copyright Policy - public-domain
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3672920&req=5

f4: OH-PCBs are substrates for human SULT1A1. The sulfation of 2´OH-PCB 3, 3´OH-PCB 3, 4´OH-PCB 3, 4´OH-PCB 11, and 4´OH-PCB 12 is catalyzed by a cytosolic extract of E. coli expressing recombinant hSULT1A1.*p < 0.05, and **p < 0.001 compared with 0 µM OH-PCB
Mentions: OH-PCBs as substrates for hSULT1A1. Because formation of PCB sulfates requires their metabolic formation from OH-PCBs, we determined the rate of sulfation of OH-PCBs by recombinant hSULT1A1. The five OH-PCBs that were tested in this study were substrates for the enzyme and exhibited a concentration-dependent increase in the rate of sulfation (Figure 4). The highest specific activities were determined for the ortho-hydroxylated 2´OH-PCB 3 and for the meta-hydroxylated 3´OH-PCB 3. The para-hydroxylated 4´OH-PCB 3, 4´OH-PCB 11, and 4´OH-PCB 12 exhibited slightly lower specific activities. Thus, the hSULT1A1, a major human cytosolic sulfotransferase, catalyzes the sulfation of these OH-PCBs.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: 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.

ABSTRACT

Background: 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.

Objectives: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Show MeSH
Related in: MedlinePlus