Oxidative Modification of Rat Sulfotransferase 1A1 Activity in Hepatic Tissue Slices Correlates with Effects on the Purified Enzyme

Dammanahalli, Jagadeesha K; Duffel, Michael W.

doi:10.1124/dmd.111.042044

Cited by 13 publications

(18 citation statements)

References 34 publications

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“…Previous studies with rSULT1A1 have shown that oxidative effects on the catalytic function of the purified enzyme (Marshall et al, 1997(Marshall et al, , 2000Duffel et al, 2001) are consistent with effects seen in precision cut tissue slices (Dammanahalli and Duffel, 2012). Similarities in the mechanisms of catalytic alterations seen with the two SULTs suggest that regulation by disulfide bond formation may occur within intact cells; however, the response of hSULT2A1 to disulfide bond formation within intact cells remains to be determined.…”

Section: Discussionmentioning

confidence: 71%

“…Although the various isoforms often have distinct, but overlapping, specificities for substrates and inhibitors, it is becoming increasingly apparent that other factors, such as the redox environment of these enzymes, can have additional effects on catalysis. For example, several family 1 SULTs are sensitive to oxidants that cause the formation of disulfide bonds (Marshall et al, 1997(Marshall et al, , 2000Duffel et al, 2001;Maiti et al, 2005Maiti et al, , 2007Liu et al, 2011;Dammanahalli and Duffel, 2012). Moreover, it is clear that, in addition to the rates of catalysis, substrate specificity may be altered by disulfide bond formation in family 1 SULTs (Marshall et al, 2000;Duffel et al, 2001;Liu et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 71%

Section: Introductionmentioning

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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“…41,55,57,65–68 While most of these SULTs have been members of family 1, we have recently reported that the catalytic activity of human hydroxysteroid sulfotransferase hSULT2A1 is also sensitive to formation of disulfide bonds at key cysteine residues. 41 Alteration of the structure and function of hSULT2A1 through oxidative post-translational changes at cysteine residues led us to hypothesize that changes in catalytic function may also result from reaction of the enzyme with electrophiles that form adducts at those cysteine residues.…”

Section: Discussionmentioning

confidence: 99%

“…55 More recently, this oxidative regulation of rSULT1A1 has also been observed within intact hepatic tissue slices. 65 …”

Section: Discussionmentioning

confidence: 99%

Chlorinated Biphenyl Quinones and Phenyl-2,5-benzoquinone Differentially Modify the Catalytic Activity of Human Hydroxysteroid Sulfotransferase hSULT2A1

Qin

Lehmler

Teesch

et al. 2013

Chem. Res. Toxicol.

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Human hydroxysteroid sulfotransferase (hSULT2A1) catalyzes the sulfation of a broad range of environmental chemicals, drugs, and other xenobiotics in addition to endogenous compounds that include hydroxysteroids and bile acids. Polychlorinated biphenyls (PCBs) are persistent environmental contaminants, and oxidized metabolites of PCBs may play significant roles in the etiology of their adverse health effects. Quinones derived from oxidative metabolism of PCBs (PCB-quinones) react with nucleophilic sites in proteins and also undergo redox cycling to generate reactive oxygen species. This, along with the sensitivity of hSULT2A1 to oxidative modification at cysteine residues led us to hypothesize that electrophilic PCB-quinones react with hSULT2A1 to alter its catalytic function. Thus, we examined the effects of four phenylbenzoquinones on the ability of hSULT2A1 to catalyze the sulfation of the endogenous substrate, dehydroepiandrosterone (DHEA). The quinones studied were 2′-chlorophenyl-2,5-benzoquinone (2′-Cl-BQ), 4′-chlorophenyl-2,5-benzoquinone (4′-Cl-BQ), 4′-chlorophenyl-3,6-dichloro-2,5-benzoquinone (3,6,4′-triCl-BQ), and phenyl-2,5-benzoquinone (PBQ). At all concentrations examined, pretreatment of hSULT2A1 with the PCB-quinones decreased catalytic activity of hSULT2A1. Pretreatment with low concentrations of PBQ, however, increased the catalytic activity of the enzyme, while higher concentrations inhibited catalysis. A decrease in substrate inhibition with DHEA was seen following preincubation of hSULT2A1 with all of the quinones. Proteolytic digestion of the enzyme followed by LC/MS analysis indicated PCB-quinone- and PBQ-adducts at Cys55 and Cys199, as well as oxidation products at methionines in the protein. Equilibrium binding experiments and molecular modeling suggested that changes due to these modifications may affect the nucleotide binding site and the entrance to the sulfuryl acceptor binding site of hSULT2A1.

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“…28, 40 The liver slices (8 mm in diameter; 200–300 µm thick) were prepared using a Krumdieck tissue slicer (Alabama Research and Development Corporation, Munsford, AL, USA) and collected in ice-cold K-H buffer as described previously. 28, 40 …”

Section: Methodsmentioning

confidence: 99%

Oxidation of Polychlorinated Biphenyls by Liver Tissue Slices from Phenobarbital-Pretreated Mice Is Congener-Specific and Atropselective

Duffel

Lehmler

2013

Chem. Res. Toxicol.

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Mouse models are powerful tools to study the developmental neurotoxicity of polychlorinated biphenyls (PCBs); however, studies of the oxidation of chiral PCB congeners to potentially neurotoxic hydroxylated metabolites (OH-PCBs) in mice have not been reported. Here we investigate the atropselective oxidation of chiral PCB 91 (2,2',3,4',6-pentachlorobiphenyl), PCB 95 (2,2',3,5',6-pentachlorobiphenyl), PCB 132 (2,2',3,3',4,6'-hexachlorobiphenyl), PCB 136 (2,2',3,3',6,6'-hexachlorobiphenyl) and PCB 149 (2,2',3,4',5',6-hexachlorobiphenyl) to OH-PCBs in liver tissue slices prepared from female mice. The metabolite profile of PCB 136 typically followed the rank order 5-OH-PCB > 4-OH-PCB > 4,5-OH-PCB, and metabolite levels increased with PCB concentration and incubation time. A similar OH-PCB profile was observed with the other PCB congeners, with 5-OH-PCB:4-OH-PCB ratios ranging from 2 to 12. More 5-OH-PCB 136 was formed in liver tissue slices obtained from animals pretreated with phenobarbital (P450 2B inducer) or, to a lesser extent, dexamethasone (P450 2B and 3A enzyme inducer) compared to tissue slices prepared from vehicle-pretreated animals. The apparent rate of 5-OH-PCBs formation followed the approximate rank order PCB 149 > PCB 91 > PCB 132 ~ PCB 136 > PCB 95. Atropselective gas chromatography revealed a congener-specific atropisomeric enrichment of major OH-PCB metabolites. Comparison of our results with published OH-PCB patterns and chiral signatures (i.e., the direction and extent of the atropisomeric enrichment) from rat liver microsomal revealed drastic differences between both species, especially following induction of P450 2B enzymes. These species differences in the metabolism of chiral PCBs should be considered in developmental neurotoxicity studies of PCBs.

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Oxidative Modification of Rat Sulfotransferase 1A1 Activity in Hepatic Tissue Slices Correlates with Effects on the Purified Enzyme

Cited by 13 publications

References 34 publications

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

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

Chlorinated Biphenyl Quinones and Phenyl-2,5-benzoquinone Differentially Modify the Catalytic Activity of Human Hydroxysteroid Sulfotransferase hSULT2A1

Oxidation of Polychlorinated Biphenyls by Liver Tissue Slices from Phenobarbital-Pretreated Mice Is Congener-Specific and Atropselective

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