Journal article
Structure-Activity Relationships for Hydroxylated Polychlorinated Biphenyls as Substrates and Inhibitors of Rat Sulfotransferases and Modification of These Relationships by Changes in Thiol Status
Drug metabolism and disposition, Vol.37(5), pp.1065-1072
05/2009
DOI: 10.1124/dmd.108.026021
PMCID: PMC2677757
PMID: 19196841
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.
Details
- Title: Subtitle
- Structure-Activity Relationships for Hydroxylated Polychlorinated Biphenyls as Substrates and Inhibitors of Rat Sulfotransferases and Modification of These Relationships by Changes in Thiol Status
- Creators
- Yungang Liu - Division of Medicinal and Natural Products Chemistry, College of Pharmacy (Y.L., J.T.S., M.W.D.), and Department of Occupational and Environmental Health, College of Public Health (Y.S., H.-J.L., L.W.R.), University of Iowa, Iowa City, IowaJason T Smart - Division of Medicinal and Natural Products Chemistry, College of Pharmacy (Y.L., J.T.S., M.W.D.), and Department of Occupational and Environmental Health, College of Public Health (Y.S., H.-J.L., L.W.R.), University of Iowa, Iowa City, IowaYang Song - Division of Medicinal and Natural Products Chemistry, College of Pharmacy (Y.L., J.T.S., M.W.D.), and Department of Occupational and Environmental Health, College of Public Health (Y.S., H.-J.L., L.W.R.), University of Iowa, Iowa City, IowaHans-Joachim Lehmler - Division of Medicinal and Natural Products Chemistry, College of Pharmacy (Y.L., J.T.S., M.W.D.), and Department of Occupational and Environmental Health, College of Public Health (Y.S., H.-J.L., L.W.R.), University of Iowa, Iowa City, IowaLarry W Robertson - Division of Medicinal and Natural Products Chemistry, College of Pharmacy (Y.L., J.T.S., M.W.D.), and Department of Occupational and Environmental Health, College of Public Health (Y.S., H.-J.L., L.W.R.), University of Iowa, Iowa City, IowaMichael W Duffel - Division of Medicinal and Natural Products Chemistry, College of Pharmacy (Y.L., J.T.S., M.W.D.), and Department of Occupational and Environmental Health, College of Public Health (Y.S., H.-J.L., L.W.R.), University of Iowa, Iowa City, Iowa
- Resource Type
- Journal article
- Publication Details
- Drug metabolism and disposition, Vol.37(5), pp.1065-1072
- DOI
- 10.1124/dmd.108.026021
- PMID
- 19196841
- PMCID
- PMC2677757
- NLM abbreviation
- Drug Metab Dispos
- ISSN
- 0090-9556
- eISSN
- 1521-009X
- Publisher
- American Society for Pharmacology and Experimental Therapeutics
- Language
- English
- Date published
- 05/2009
- Academic Unit
- Occupational and Environmental Health; Pharmaceutical Sciences and Experimental Therapeutics; Iowa Superfund Research Program; Medicinal and Natural Products Chemistry
- Record Identifier
- 9984001092602771
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