Journal article
Polychlorobiphenylols are selective inhibitors of human phenol sulfotransferase 1A1 with 4-nitrophenol as a substrate
Chemico-biological interactions, Vol.159(3), pp.235-246
2006
DOI: 10.1016/j.cbi.2005.12.004
PMID: 16413005
Abstract
Polychlorobiphenylols (OH-PCBs) were reported as potent inhibitors of estrogen sulfotransferase, thyroid hormone and 3-hydroxybenzo(
a)pyrene sulfotransferases. The aim of this study was to examine the effects of selected OH-PCBs on SULT1A1 activity in human liver cytosol, measured with 4
μM 4-nitrophenol, a concentration considered to be diagnostic for selectively detecting SULT1A1. All the OH-PCBs studied inhibited the sulfonation of 4-nitrophenol in human liver cytosol. Among the eighteen OH-PCBs studied, 3′-OH-CB3 (4-chlorobiphenyl-3′-ol) was the most potent inhibitor (IC
50: 0.73
±
0.15
μM, mean
±
S.D.,
n
=
3). The least potent inhibitor studied was 6′-OH-CB35 (3,3′,4-trichlorobiphenyl-6′-ol) with IC
50: 49.1
±
10.8
μM. The IC
50 values of the other OH-PCBs studied ranged from 0.78 to 3.76
μM. Some OH-PCBs with various inhibitory potencies with human liver cytosol were selected for study with recombinant human SULT1A1 and SULT1B1. These OH-PCBs showed more potent inhibition of 4-nitrophenol sulfonation with SULT1A1 than with human liver cytosol. The IC
50 values with human liver cytosol showed a perfect linear correlation with those found with SULT1A1 (
r
2
=
1), but not with SULT1B1 (
r
2
=
0.21). The results suggested that in these human samples SULT1A1 was predominantly responsible for the sulfonation of 4-nitrophenol, with very little or no contribution from SULT1B1. The kinetics of inhibition were studied with 4′-OH-CB165, which is similar in structure to OH-PCBs found in human blood. The 4′-OH-CB165 was a mixed noncompetitive–uncompetitive inhibitor (
K
i
=
1.80
±
0.2
μM,
K
ies
=
0.16
±
0.02
μM). Finally, it was demonstrated that the tested OH-PCBs were themselves only slowly sulfonated by human sulfotransferases in the presence of
35S-PAPS, as measured by the production of
35S-labeled metabolites. Although this series of 18 OH-PCBs was too small to draw conclusions about structure–potency relationships, this work demonstrated that several OH-PCBs were potent inhibitors of 4-nitrophenol sulfonation but poor substrates in human liver cytosol, and suggested that OH-PCBs may inhibit the sulfation rate of those xenobiotics sulfated by SULT1A1.
Details
- Title: Subtitle
- Polychlorobiphenylols are selective inhibitors of human phenol sulfotransferase 1A1 with 4-nitrophenol as a substrate
- Creators
- Li-Quan Wang - Department of Medicinal Chemistry, College of Pharmacy, University of Florida, 32610 Gainesville, FL, USAHans-Joachim Lehmler - Department of Occupational and Environmental Health, College of Public Health, University of Iowa, Iowa City, IA, USALarry W Robertson - Department of Occupational and Environmental Health, College of Public Health, University of Iowa, Iowa City, IA, USAMargaret O James - Department of Medicinal Chemistry, College of Pharmacy, University of Florida, 32610 Gainesville, FL, USA
- Resource Type
- Journal article
- Publication Details
- Chemico-biological interactions, Vol.159(3), pp.235-246
- DOI
- 10.1016/j.cbi.2005.12.004
- PMID
- 16413005
- NLM abbreviation
- Chem Biol Interact
- ISSN
- 0009-2797
- eISSN
- 1872-7786
- Publisher
- Elsevier Ireland Ltd
- Language
- English
- Date published
- 2006
- Academic Unit
- Occupational and Environmental Health; Iowa Neuroscience Institute; Iowa Superfund Research Program
- Record Identifier
- 9984000926802771
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