In vitro inhibition of human hepatic and cDNA-expressed sulfotransferase activity with 3-hydroxybenzo[a]pyrene by polychlorobiphenylols.
Sulfonation is a major phase II biotransformation reaction. In this study, we found that several polychlorobiphenylols (OH-PCBs) inhibited the sulfonation of 3-hydroxybenzo[a]pyrene (3-OH-BaP) by human liver cytosol and some cDNA-expressed sulfotransferases. At concentrations > 0.15 microM, 3-OH-BaP inhibited its own sulfonation in cytosol fractions that were genotyped for SULT1A1 variants, as well as with expressed SULT1A1*1, SULT1A1*2, and SULT1E1, but not with SULT1A3 or SULT1B1. The inhibition fit a two-substrate kinetic model. We examined the effects of OH-PCBs on the sulfonation of 0.1 or 1.0 microM 3-OH-BaP, noninhibitory and inhibitory substrate concentrations, respectively. At the lower 3-OH-BaP concentration, OH-PCBs with a 3-chloro-4-hydroxy substitution pattern were more potent inhibitors of cytosolic sulfotransferase activity [with concentrations that produced 50% inhibition (IC50) between 0.33 and 1.1 microM] than were OH-PCBs with a 3,5-dichloro-4-hydroxy substitution pattern, which had IC50 values from 1.3 to 6.7 microM. We found similar results with expressed SULT1A1*1 and SULT1A1*2. The OH-PCBs were considerably less potent inhibitors when assay tubes contained 1.0 microM 3-OH-BaP. The inhibition mechanism was noncompetitive, and our results suggested that the OH-PCBs competed with 3-OH-BaP at an inhibitory site on the enzyme. The OH-PCBs tested inhibited sulfonation of 3-OH-BaP by SULT1E1, but the order of inhibitory potency was different than for SULT1A1. SULT1E1 inhibitory potency correlated with the dihedral angle of the OH-PCBs. The OH-PCBs tested were generally poor inhibitors of SULT1A3- and SULT1B1-dependent activity with 3-OH-BaP. These findings demonstrate an interaction between potentially toxic hydroxylated metabolites of PCBs and polycyclic aromatic hydrocarbons, which could result in reduced clearance by sulfonation.
Wang
Li-Quan
LQ
Department of Medicinal Chemistry, University of Florida, Gainesville, Florida 32610-0485, USA.
Lehmler
Hans-Joachim
HJ
Robertson
Larry W
LW
Falany
Charles N
CN
James
Margaret O
MO
D015239:Arylsulfotransferase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D001580:Benzopyrenes / Q000378:metabolism*; D001711:Biotransformation; D003600:Cytosol; D018076:DNA, Complementary / Q000378:metabolism; D004785:Environmental Pollutants / Q000378:metabolism* / Q000633:toxicity*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D005838:Genotype; D006801:Humans; D006900:Hydroxylation; D008099:Liver / Q000201:enzymology; D011078:Polychlorinated Biphenyls / Q000633:toxicity*
D001580:Benzopyrenes; D018076:DNA, Complementary; D004785:Environmental Pollutants; C021338:3-hydroxybenzo(a)pyrene; D011078:Polychlorinated Biphenyls; D015239:Arylsulfotransferase