Effects of Dexamethasone on Aryl (SULT1A1)- and Hydroxysteroid (SULT2A1)-Sulfotransferase Gene Expression in Primary Cultured Human Hepatocytes

Duanmu, Zhengbo; Locke, Deborah; Smigelski, Jeffrey; Wu, Wei; Dahn, Michael S.; Falany, Charles N.; Kocarek, Thomas A.; Runge‐Morris, Melissa

doi:10.1124/dmd.30.9.997

Cited by 76 publications

(61 citation statements)

References 35 publications

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“…These observations indicate that upregulation of cFLIP L -p43 by DEX is not associated with either the PI3K/Akt or NF-kB signaling pathways. Previous studies have shown that DEX can transcriptionally increase the expression levels of several genes in hepatocytes, such as sulfotransferase, 36 cytochrome P450 3A1, 37 connexin, 38 and multidrug-resistance protein 2. 39 Similarly, we here showed that increased cFLIP mRNA and protein levels by DEX treatment were markedly suppressed by the transcription inhibitor ActD, indicating that DEX increased cFLIP expression at the transcriptional step.…”

Section: Discussionmentioning

confidence: 99%

Dexamethasone protects primary cultured hepatocytes from death receptor-mediated apoptosis by upregulation of cFLIP

Namkoong

et al. 2005

Cell Death Differ

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Dexamethasone (DEX) pretreatment protected hepatocytes from TNF-a plus actinomycin D (ActD)-induced apoptosis by suppressing caspase-8 activation and the mitochondriadependent apoptosis pathway. DEX treatment upregulated cellular FLICE inhibitory protein (cFLIP) expression, but did not alter the protein levels of Bcl-2, Bcl-xL, Mcl-1, and cIAP as well as Akt activation. The increased cFLIP mRNA level by DEX was inhibited by ActD, indicating that DEX upregulates cFLIP expression at the transcriptional step. DEX also inhibited Jo2-mediated hepatocyte apoptosis by blocking the formation of the death-inducing signaling complex and caspase-8 activation. Specific downregulation of cFLIP expression using siRNA reversed the antiapoptotic effect of DEX by increasing caspase-8 activation. Moreover, DEX administration into mice increased cFLIP expression in the liver and prevented Jo2-induced hepatic injury by inhibiting caspase-8 and -3 activities. Our results indicate that DEX exerts a protective role in death receptor-induced in vitro and in vivo hepatocyte apoptosis by upregulating cFLIP expression.

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Section: Discussionmentioning

confidence: 99%

Dexamethasone protects primary cultured hepatocytes from death receptor-mediated apoptosis by upregulation of cFLIP

Namkoong

et al. 2005

Cell Death Differ

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“…Glucocorticoids have been known as important regulatory factors in the control of rat hepatic SULT2A enzyme activity (Fang et al, 2005a). The expression of rodent and human hepatic SULT2A is regulated by the Pregnane X Receptor (PXR) (Liu and Klaassen, 1996;Runge-Morris and Kocarek, 2005;Fang et al, 2005a;2005b;Duanmu et al, 2002). Dexamethasone administration produced significant increases in rat hepatic SULT2A mRNA and protein contents, relative to control (Fang et al, 2005a).…”

Section: Discussionmentioning

confidence: 99%

“…Dexamethasone administration produced significant increases in rat hepatic SULT2A mRNA and protein contents, relative to control (Fang et al, 2005a). Treatment of human hepatocyte cultures with PXRactivating concentrations of dexamethasone and rifampicin both produced concentration-dependent increases in human SULT2A1 mRNA and protein contents (Fang et al, 2005a;2005b;Duanmu et al, 2002). In addition, more and more recent data suggest that hepatic SULT gene expression is regulated by the same transcription factor networks that also control the expression of the Cytochrome P450s (CYP), such as the Aryl hydrocarbon (Ah) receptor and members of the nuclear receptor superfamily, such as PXR, CAR and PPARα, although the co-regulation between the SULT and CYP gene families doesn't always occur in a coordinate direction (Runge-Morris, 1998;Runge-Morris and Kocarek, 2005;Jain et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Methamphetamine Regulation of Sulfotransferases in Rat Liver and Brain

Zhou¹

2010

American Journal of Pharmacology and Toxicology

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Problem statement: Sulfotransferases (SULTs) are important phase II drug metabolizing enzymes. They also regulate the biological activities of various hormones. To the best of our knowledge, psychostimulants regulation of SULTs is basically not studied except one article reported that Methamphetamine (METH) treatment induced rat amygdale rSULT1A1 mRNA 4.3 fold by using microarray method to identify a series of candidate genes after single-dose METH treatment. The psychostimulant METH is used to treat disorders such as attention deficit, narcolepsy and obesity. It is also a highly addictive drug that causes serious social problems. The abuse of this drug leads to the damage of monoaminergic systems in the mammalian brain. It is important to understand how SULT expressions are regulated by psychostimulants. Approach: This study was performed to evaluate the effect of METH on SULT gene expressions in rat liver and brain. METH (0, 1, 5, 20 mg kg −1 day −1 ) was used to treat male and female rats for 7 days by oral administration. Rat livers and brains were collected 24 h after the final drug treatment. Western blot and real-time RT-PCR were used to investigate the effect of METH on SULT protein and mRNA expression, respectively, in rat liver and brain. Results: Proteins and mRNAs of rSULT1A1, rSULT2A1 and rSULT1E1 were induced in liver and brain of both male and female rats following METH treatment. rSULT1E1 was induced at much higher level compared to that of rSULT1A1 and rSULT2A1. Brain inductions were found to be much higher than those found in liver. Conclusion: These data suggest an important role of the central dopaminergic system in the regulation of liver and brain rSULT expressions.

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“…This inducing effect is controlled, in part, by the bile acid-activated FXR (Song et al 2001). Similarly, human SULT2A1 has been shown to be induced in response to various ligands for the PXR (Kliewer et al 1998, Duanmu et al 2002, Echchgadda et al 2004). More recently, it has been determined that the CAR is also potentially involved in rodent SULT2A1 regulation (Saini et al 2004).…”

Section: Figurementioning

confidence: 99%

“…A number of studies reported single nucleotide polymorphisms (SNPs) within the human Sult2A1 gene (Igaz et al 2002), some of which have resulted in reduced levels of both enzyme activity and protein (Thomae et al 2002). Furthermore, research in both human and rodent SULT2A1 regulation has revealed that this gene may be controlled by various nuclear receptors including the constitutive androstane receptor (CAR) (Saini et al 2004), the pregnane X receptor (PXR) (Kliewer et al 1998, Duanmu et al 2002, Echchgadda et al 2004, and the farnesoid X receptor (FXR) (Makishima et al 1999, Song et al 2001. However, the involvement of nuclear receptors in the regulation of porcine SULT2A1 has not been determined.…”

mentioning

confidence: 99%

Molecular cloning and regulation of porcine SULT2A1: relationship between SULT2A1 expression and sulfoconjugation of androstenone

Sinclair

Gilmore²,

Lin³

et al. 2006

Journal of Molecular Endocrinology

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Hydroxysteroid sulfotransferase (SULT2A1) is a key enzyme in the testicular and hepatic metabolism of 5 -androstenone, which is a major component of the off-odor and off-flavor in pork known as boar taint. The goals of this study were to determine the role of testicular and hepatic SULT2A1 activity on plasma 5 -androstenone sulfate levels, the accumulation of 5 -androstenone in adipose tissue, and to gain insight into the regulatory control of SULT2A1. Testicular SULT2A1 activity was negatively correlated (r= −0·57; P,0·01) with 5 -androstenone concentrations in fat. The differences observed in SULT2A1 activity warranted investigation into potential genetic variation within porcine SULT2A1. The cDNA sequence of porcine Sult2A1 was determined to be .82% homologous to the human, mouse, and rat Sult2A1 genes. A single nucleotide polymorphism was detected within the coding region of the Sult2A1 from individual testes and liver samples; however, this did not affect the amino acid sequence of the enzyme. Western blot analysis determined that animals with high concentrations of 5 -androstenone in fat and low SULT2A1 activity had corresponding low levels of SULT2A1 protein compared with animals with low levels of 5 -androstenone in fat. Real-time PCR analysis indicated that Sult2A1 mRNA was increased 2·8-fold in animals with high levels of the protein relative to animals with low levels of the protein. Furthermore, we demonstrated the positive role of the nuclear receptors constitutive androstane receptor and pregnane X receptor, as well as the possible role of farnesoid X receptor in the regulation of testicular SULT2A1 activity. Together, the results of this study suggest that differences in SULT2A1 expression can influence 5 -androstenone accumulation in fat.

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Effects of Dexamethasone on Aryl (SULT1A1)- and Hydroxysteroid (SULT2A1)-Sulfotransferase Gene Expression in Primary Cultured Human Hepatocytes

Cited by 76 publications

References 35 publications

Dexamethasone protects primary cultured hepatocytes from death receptor-mediated apoptosis by upregulation of cFLIP

Dexamethasone protects primary cultured hepatocytes from death receptor-mediated apoptosis by upregulation of cFLIP

Methamphetamine Regulation of Sulfotransferases in Rat Liver and Brain

Molecular cloning and regulation of porcine SULT2A1: relationship between SULT2A1 expression and sulfoconjugation of androstenone

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