title: Structure-activity relationships for hydroxylated polychlorinated biphenyls as substrates and inhibitors of rat sulfotransferases and modification of these relationships by changes in thiol status.
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.
authors.affiliation: Division of Medicinal and Natural Products Chemistry, College of Pharmacy, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Yungang
authors.initials: Y
authors.lastname: Liu
authors.forename: Jason T
authors.initials: JT
authors.lastname: Smart
authors.forename: Yang
authors.initials: Y
authors.lastname: Song
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Lehmler
authors.forename: Larry W
authors.initials: LW
authors.lastname: Robertson
authors.forename: Michael W
authors.initials: MW
authors.lastname: Duffel
mesh_terms: D000818:Animals; D004785:Environmental Pollutants / Q000737:chemistry* / Q000493:pharmacokinetics* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism; D006900:Hydroxylation; D010084:Oxidation-Reduction; D011078:Polychlorinated Biphenyls / Q000737:chemistry* / Q000493:pharmacokinetics* / Q000494:pharmacology*; D051381:Rats; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D019163:Reducing Agents / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013431:Sulfates / Q000378:metabolism; D013438:Sulfhydryl Compounds / Q000737:chemistry / Q000378:metabolism*; D015238:Sulfotransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D004785:Environmental Pollutants; D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; D019163:Reducing Agents; D013431:Sulfates; D013438:Sulfhydryl Compounds; D011078:Polychlorinated Biphenyls; D015238:Sulfotransferases; D005978:Glutathione