Polychlorobiphenylols are selective inhibitors of human phenol sulfotransferase 1A1 with 4-nitrophenol as a substrate.
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 4microM 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+/-0.15microM, 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+/-10.8microM. The IC(50) values of the other OH-PCBs studied ranged from 0.78 to 3.76microM. 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+/-0.2microM, K(ies)=0.16+/-0.02microM). Finally, it was demonstrated that the tested OH-PCBs were themselves only slowly sulfonated by human sulfotransferases in the presence of (35)S-PAPS, as measured by the production of (35)S-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.
Wang
Li-Quan
LQ
Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville 32610-0485, USA.
Lehmler
Hans-Joachim
HJ
Robertson
Larry W
LW
James
Margaret O
MO
D000483:Alleles; D015239:Arylsulfotransferase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D002733:Chlorophenols / Q000737:chemistry* / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D005838:Genotype; D006801:Humans; D006900:Hydroxylation; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D015394:Molecular Structure; D009596:Nitrophenols / Q000378:metabolism*; D012680:Sensitivity and Specificity; D013379:Substrate Specificity
D002733:Chlorophenols; D004791:Enzyme Inhibitors; D009596:Nitrophenols; D015239:Arylsulfotransferase; C117544:SULT1A1 protein, human; C024836:4-nitrophenol