Abstract
Hydroxylated metabolites of polychlorinated biphenyls (OH-PCBs) are inhibitors and substrates for various human sulfotransferases (SULTs). Although the rat is often used in toxicological studies on PCBs, the interactions of OH-PCBs with rat SULTs are less well understood. In the present study, 15 OH-PCBs were investigated as potential substrates or inhibitors of purified recombinant rSULT1A1 and rSULT2A3, the major family 1 and family 2 SULTs present in rat liver, respectively. None of these OH-PCBs were substrates for rSULT2A3, 11 weakly inhibited rSULT2A3-catalyzed sulfation of dehydroepiandrosterone, and 4 had no effect on the reaction. With rSULT1A1, 4-OH-PCB 8, 4′-OH-PCB 3, 9, 12, 35, and 6′-OH-PCB 35 were substrates, whereas 4′-OH-PCB 6, 4-OH-PCB 14, 4′-OH-PCB 25, 4′-OH-PCB 33, 4-OH-PCB 34, 4-OH-PCB36, 4′-OH-PCB 36, 4′-OH-PCB 68, and 4-OH-PCB 78 inhibited the sulfation of 2-naphthol catalyzed by this enzyme. OH-PCBs with a 3,5-dichloro-4-hydroxy substitution were the most potent inhibitors of rSULT1A1, and the placement of chlorine atoms in the ortho- and meta-positions on either ring of para-OH-PCBs resulted in significant differences in activity as substrates and inhibitors. The specificity of rSULT1A1 for several inhibitory OH-PCBs was altered by pretreatment of the enzyme with oxidized glutathione (GSSG). Four OH-PCBs that were inhibitors of rSULT1A1 under reducing conditions became substrates after pretreatment of the enzyme with GSSG. This alteration in specificity of rSULT1A1 for certain OH-PCBs suggests that conditions of oxidative stress may significantly alter the sulfation of some OH-PCBs in the rat.
Footnotes
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This work was supported in part by the National Institutes of Health National Institute of Environmental Health Sciences [Grants P42-ES013661, K25-ES012475, P30-ES05605]; and the National Institutes of Health National Cancer Institute [Grant R01-CA038683]. We also acknowledge programmatic support through the University of Iowa Environmental Health Sciences Research Center.
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.108.026021.
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ABBREVIATIONS: PCB, polychlorinated biphenyl; OH-PCB, hydroxylated polychlorinated biphenyl; SULT, sulfotransferase; h, human; r, rat; DHEA, dehydroepiandrosterone; GC, gas chromatography; MS, mass spectrometry; PAPS, adenosine 3′-phosphate 5′-phosphosulfate; PAP, adenosine 3′,5′-diphosphate; DTT, dithiothreitol; DTNB, 5,5′-dithiobis(2-nitrobenzoic acid); GSH, reduced glutathione; GSSG, oxidized glutathione.
- Received December 5, 2008.
- Accepted January 29, 2009.
- The American Society for Pharmacology and Experimental Therapeutics
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