Complex roles for sulfation in the toxicities of polychlorinated biphenyls

Abstract

Polychlorinated biphenyls (PCBs) are persistent organic toxicants derived from legacy pollution sources and their formation as inadvertent byproducts of some current manufacturing processes. Metabolism of PCBs is often a critical component in their toxicity, and relevant metabolic pathways usually include their initial oxidation to form hydroxylated polychlorinated biphenyls (OH-PCBs). Subsequent sulfation of OH-PCBs was originally thought to be primarily a means of detoxication; however, there is strong evidence that it may also contribute to toxicities associated with PCBs and OH-PCBs. These contributions include either the direct interaction of PCB sulfates with receptors or their serving as a localized precursor for OH-PCBs. The formation of PCB sulfates is catalyzed by cytosolic sulfotransferases, and, when transported into the serum, these metabolites may be retained, taken up by other tissues, and subjected to hydrolysis catalyzed by intracellular sulfatase(s) to regenerate OH-PCBs. Dynamic cycling between PCB sulfates and OH-PCBs may lead to further metabolic activation of the resulting OH-PCBs. Ultimate toxic endpoints of such processes may include endocrine disruption, neurotoxicities, and many others that are associated with exposures to PCBs and OH-PCBs. This review highlights the current understanding of the complex roles that PCB sulfates can have in the toxicities of PCBs and OH-PCBs and research on the varied mechanisms that control these roles.

Keywords: OH-PCB; PCB; PCB sulfate; STS; SULT; Sulfation; detoxication; endocrine disruption; inhibition; metabolic activation; neurotoxicity; polychlorinated biphenyl; sulfatase; sulfotransferase; toxicity.

Figure 1.

Reactions catalyzed by cytosolic sulfotransferases and microsomal sulfatase(s).

Figure 2.

The interactions of selected PCB sulfates with Sites I and II of human serum albumin. Site I is identified by the x-ray crystal structure of human serum albumin complexed with warfarin (Protein Data Bank File: PDB 2BXD; warfarin structure shown in red). Site II is identified by the x-ray crystal structure of human serum albumin complexed with diazepam (Protein Data Bank File: PDB 2BXF; diazepam structure shown in yellow).

Figure 3.

Potential consequences of high affinity reversible binding of a PCB sulfate to transthyretin (TTR). 4-PCB 11 sulfate is shown as a model PCB sulfate, and TTR is represented by the x-ray crystal structure of human TTR (Protein Data Bank File: PDB 4MRB).

Figure 4.

Proposed role of PCB sulfates and OH-PCBs in retention, transport, cellular uptake, and cellular toxicities due to metabolic cycling. TTR = transthyretin, HSA = human serum albumin, STS = Microsomal Steroid Sulfatase or other sulfatase(s); SULT = Cytosolic sulfotransferase(s) relevant to the PCB sulfate congener; ROS = Reactive oxygen species.

Figure 5.

OH-PCB mediated disruption of estrogen signaling at estrogen receptors (ERs) by inhibition of human estrogen sulfotransferase SULT1E1.

Figure 6.

Potential role of PCB sulfates as precursors in the formation of ROS and electrophilic quinones. Enzymes are shown in blue, and reactive metabolites are in red. STS = Microsomal Steroid Sulfatase or other sulfatase(s); SULT = Cytosolic sulfotransferase(s) relevant to the PCB sulfate congener; CYP = Cytochrome P450 enzymes as relevant to the OH-PCB congener; A = Heme-containing peroxidases + H₂O₂; B= Xanthine Oxidase or flavoproteins with 1-electron reductive mechanisms (e.g., NADPH Cytochrome P450 reductase); NQO1 = NAD(P)H:quinone oxidoreductase 1; AKR = Aldo-keto Reductase(s) asrelevant to the PCB quinone congener.