Structure-Activity Relationships for Hydroxylated Polychlorinated Biphenyls as Substrates and Inhibitors of Rat Sulfotransferases and Modification of These Relationships by Changes in Thiol Status

Liu, Yungang; Smart, Jason T.; Song, Yang; Lehmler, Hans‐Joachim; Robertson, Larry W.; Duffel, Michael W.

doi:10.1124/dmd.108.026021

Cited by 43 publications

(69 citation statements)

References 36 publications

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“…Initial studies using rats exposed to PCB 11 by inhalation exposure, however, clearly indicate their rapid hydroxylation and subsequent elimination (Hu et al, 2014, Hu et al, 2013). While many OH-PCB metabolites are good substrates for conjugation reactions (James, 2001), the ease of formation of glucuronic acid and sulfate conjugates is highly structure-dependent, an observation that is supported by the persistence of certain OH-PCBs in serum (Tampal et al, 2002, Liu et al, 2009, Bergman et al, 1994b, Gutleb et al, 2010). In addition, both conjugation reactions, glucuronidation and sulfation, may be inhibited by OH-PCBs (Ekuase et al, 2011, James, 2001, Kester et al, 2000, Liu et al, 2006, Liu et al, 2011, Liu et al, 2009, Schuur et al, 1998b, van den Hurk et al, 2002, Wang et al, 2006).…”

Section: Pcb Metabolism and Relevant Classes Of Pcb Metabolitesmentioning

confidence: 99%

Metabolism and metabolites of polychlorinated biphenyls

Grimm

Kania-Korwel

et al. 2015

Critical Reviews in Toxicology

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414

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The metabolism of polychlorinated biphenyls (PCBs) is complex and has an impact on toxicity and thereby assessment of PCB risks. A large number of reactive and stable metabolites are formed in the processes of biotransformation in biota in general and in humans in particular. The aim of this document is to provide an overview of PCB metabolism and to identify metabolites of concern and their occurrence. Emphasis is given to mammalian metabolism of PCBs and their hydroxyl, methylsulfonyl, and sulfated metabolites, especially those that persist in human blood. Potential intracellular targets and health risks are also discussed.

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Section: Pcb Metabolism and Relevant Classes Of Pcb Metabolitesmentioning

confidence: 99%

Metabolism and metabolites of polychlorinated biphenyls

Grimm

Kania-Korwel

et al. 2015

Critical Reviews in Toxicology

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338

414

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“…The eluate was collected at the first increase in UV absorbance at 280 nm. The eluted hSULT2A1 was concentrated using a 10-ml Amicon stirred cell with PM-10 membrane (Millipore Corporation, Billerica, MA) to a protein concentration of at least 1 mg/ml (Liu et al, 2009). A standard assay for thiols (Jocelyn, 1987) was used to determine the residual concentration of DTT, which was in all cases less than 0.01 mM.…”

Section: Methodsmentioning

confidence: 99%

Modification of the Catalytic Function of Human Hydroxysteroid Sulfotransferase hSULT2A1 by Formation of Disulfide Bonds

Qin¹,

Teesch²,

Duffel³

2013

Drug Metab Dispos

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The human cytosolic sulfotransferase hSULT2A1 catalyzes the sulfation of a broad range of xenobiotics, as well as endogenous hydroxysteroids and bile acids. Reversible modulation of the catalytic activity of this enzyme could play important roles in its physiologic functions. Whereas other mammalian sulfotransferases are known to be reversibly altered by changes in their redox environment, this has not been previously shown for hSULT2A1. We have examined the hypothesis that the formation of disulfide bonds in hSULT2A1 can reversibly regulate the catalytic function of the enzyme. Three thiol oxidants were used as model compounds to investigate their effects on homogeneous preparations of hSULT2A1: glutathione disulfide, 5,59-dithiobis(2-nitrobenzoic acid), and 1,1'-azobis(N,N-dimethylformamide) (diamide). Examination of the effects of disulfide bond formation with these agents indicated that the activity of the enzyme is reversibly altered. Studies on the kinetics of the hSULT2A1-catalyzed sulfation of dehydroepiandrosterone (DHEA) showed the effects of disulfide bond formation on the substrate inhibition characteristics of the enzyme. The effects of these agents on the binding of substrates and products, liquid chromatography-mass spectrometry identification of the disulfides formed, and structural modeling of the modified enzyme were examined. Our results indicate that conformational changes at cysteines near the nucleotide binding site affect the binding of both the nucleotide and DHEA to the enzyme, with the specific effects dependent on the structure of the resulting disulfide. Thus, the formation of disulfide bonds in hSULT2A1 is a potentially important reversible mechanism for alterations in the rates of sulfation of both endogenous and xenobiotic substrates.

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“…Since OH-PCBs are both substrates and inhibitors of these enzymes, they may directly influence the circulating levels of steroids and thyroid hormones by affecting the rates of sulfation (Schuur et al, 1998b, c;Kester et al, 2000;Liu et al, 2009;Ekuase et al, 2011).…”

Section: (F) Direct and Indirect Endocrine Disruptionmentioning

confidence: 99%

Polychlorinated Biphenyls and Polybrominated Biphenyls

Agudo

Aronson²,

Bonefeld-Jörgensen³

et al. 2008

Organic Pollutants

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Structure-Activity Relationships for Hydroxylated Polychlorinated Biphenyls as Substrates and Inhibitors of Rat Sulfotransferases and Modification of These Relationships by Changes in Thiol Status

Cited by 43 publications

References 36 publications

Metabolism and metabolites of polychlorinated biphenyls

Metabolism and metabolites of polychlorinated biphenyls

Modification of the Catalytic Function of Human Hydroxysteroid Sulfotransferase hSULT2A1 by Formation of Disulfide Bonds

Polychlorinated Biphenyls and Polybrominated Biphenyls

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