Journal article
In Vitro Inhibition of Human Hepatic and cDNA-Expressed Sulfotransferase Activity with 3-Hydroxybenzo[a]pyrene by Polychlorobiphenylols
Environmental health perspectives, Vol.113(6), pp.680-687
06/2005
DOI: 10.1289/ehp.7837
PMCID: PMC1257591
PMID: 15929889
Abstract
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 μM, 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 μM 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 (IC
50
) between 0.33 and 1.1 μM] than were OH-PCBs with a 3,5-dichloro-4-hydroxy substitution pattern, which had IC
50
values from 1.3 to 6.7 μM. 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 μM 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.
Details
- Title: Subtitle
- In Vitro Inhibition of Human Hepatic and cDNA-Expressed Sulfotransferase Activity with 3-Hydroxybenzo[a]pyrene by Polychlorobiphenylols
- Creators
- Li-Quan Wang - Department of Pharmacology and Toxicology, University of Alabama, Birmingham, Alabama, USAHans-Joachim Lehmler - Department of Pharmacology and Toxicology, University of Alabama, Birmingham, Alabama, USALarry W Robertson - Department of Pharmacology and Toxicology, University of Alabama, Birmingham, Alabama, USACharles N Falany - Department of Pharmacology and Toxicology, University of Alabama, Birmingham, Alabama, USAMargaret O James - Department of Pharmacology and Toxicology, University of Alabama, Birmingham, Alabama, USA
- Resource Type
- Journal article
- Publication Details
- Environmental health perspectives, Vol.113(6), pp.680-687
- DOI
- 10.1289/ehp.7837
- PMID
- 15929889
- PMCID
- PMC1257591
- NLM abbreviation
- Environ Health Perspect
- ISSN
- 0091-6765
- eISSN
- 1552-9924
- Publisher
- National Institue of Environmental Health Sciences
- Language
- English
- Date published
- 06/2005
- Academic Unit
- Occupational and Environmental Health; Iowa Neuroscience Institute
- Record Identifier
- 9984001091702771
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