Dehydroepiandrosterone Sulfotransferase Is a Target for Transcriptional Induction by the Vitamin D Receptor

Echchgadda, Ibtissam; Song, Chenchen; Roy, Arun K.; Chatterjee, Bandana

doi:10.1124/mol.65.3.720

Cited by 150 publications

(117 citation statements)

References 37 publications

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“…Total bilirubin, as well as bile acid levels, can be reduced as a consequence of higher conjugation rates and excretion via bile when hepatic enzyme-inducing chemicals are administered (Boiteux-antoine et al 1989;Echchgadda et al 2004;Gógl et al 1979). An increase in plasma bilirubin levels is generally not seen following liver enzyme induction, but is usually indicative of impaired hepatic bile flow, accelerated red blood cell destruction, or decreased bilirubin metabolism (Boone et al 2005;Jonker, Liddleb, and Downes 2011).…”

Section: Bilirubin/bile Acidsmentioning

confidence: 99%

Liver Hypertrophy

Elcombe²,

et al. 2012

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Preclinical toxicity studies have demonstrated that exposure of laboratory animals to liver enzyme inducers during preclinical safety assessment results in a signature of toxicological changes characterized by an increase in liver weight, hepatocellular hypertrophy, cell proliferation, and, frequently in long-term (life-time) studies, hepatocarcinogenesis. Recent advances over the last decade have revealed that for many xenobiotics, these changes may be induced through a common mechanism of action involving activation of the nuclear hormone receptors CAR, PXR, or PPARa. The generation of genetically engineered mice that express altered versions of these nuclear hormone receptors, together with other avenues of investigation, have now demonstrated that sensitivity to many of these effects is rodent-specific. These data are consistent with the available epidemiological and empirical human evidence and lend support to the scientific opinion that these changes have little relevance to man. The ESTP therefore convened an international panel of experts to debate the evidence in order to more clearly define for toxicologic pathologists what is considered adverse in the context of hepatocellular hypertrophy. The results of this workshop concluded that hepatomegaly as a consequence of hepatocellular hypertrophy without histologic or clinical pathology alterations indicative of liver toxicity was considered an adaptive and a non-adverse reaction. This conclusion should normally be reached by an integrative weight of evidence approach.

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Section: Bilirubin/bile Acidsmentioning

confidence: 99%

Liver Hypertrophy

Elcombe²,

et al. 2012

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“…3A). The mRNA induction is due to promoter activation since we had shown earlier that in PXR cotransfected HepG2 cells, luciferase expression driven by the mouse Sult2A1 promoter increased several fold by the activated PXR, and this induction was mediated through the IR0 enhancer (Echchgadda et al, 2004b). The IR0's activity to recruit PXR and its heterodimer partner RXR-α in young and old mice was investigated using chromatin IP (Fig.…”

Section: Xenobiotic-mediated Induction Of the Sult2a1 Genementioning

confidence: 99%

“…Total liver RNAs, isolated by Trizol (Invitrogen), were analyzed semi-quantitatively for Sult2A1 mRNAs using reverse transcriptionpolymerase chain reaction (RT-PCR). Reverse transcription of RNAs and PCR amplification of the reverse transcribed cDNAs were as described (Echchgadda et al, 2004b). PCR primers were selected from the N-terminal end of the mouse Sult2A1 cDNA in order to avoid cross reactivity with any other SULT family members.…”

Section: Hormone and Drug Injections Semi-quantitative Rt-pcr Pcr Pmentioning

confidence: 99%

“…Multiple nuclear receptors including PXR, CAR and VDR can induce SULT2A1 in cultured cells and in vivo in the mouse liver (Song et al, 2001;Sonoda et al, 2002;Echchgadda et al, 2004a;Assem et al, 2004;Maglich et al, 2004;Fang et al, 2005;Seeley et al, 2005;Chatterjee et al, 2005;Song et al, 2006). We had shown earlier that the vitamin D 3 -and xenobiotic-mediated induction of the mouse Sult2A1 promoter in transfected liver and intestinal cells is dependent upon binding of the corresponding receptors to a 21-base pair inverted repeat (IR0) enhancer (Echchgadda et al, 2004b). Chromatin immunoprecipitation (ChIP) assay showed that the IR0 in the Sult2A1 chromatin was enriched for VDR in the livers of vitamin D 3 -injected mice, thus validating the enhancer's role in a tissue context (Song et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

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Xenobiotic- and vitamin D-responsive induction of the steroid/bile acid-sulfotransferase Sult2A1 in young and old mice: The role of a gene enhancer in the liver chromatin

Seo

Chung

Kim

et al. 2007

Gene

Self Cite

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The xenobiotic-activated nuclear receptors PXR (pregnane X receptor) and CAR (constitutive androstane receptor) and the vitamin D 3 -activated nuclear receptor VDR regulate steroid and xenobiotic metabolism by inducing the phase I cytochrome P450 monooxygenases, phase II conjugating transferases, and the phase III transporters, which mediate the efflux of water-soluble lipid metabolites from cells. Metabolic stress due to the deviant expression of steroid-and xenobioticmetabolizing enzymes is known to have severe health consequences including accelerated aging, and increased expression of these enzymes is associated with extended longevity (Gachon et al, 2006;McElwee et al, 2004). Information on the similarities and dissimilarities in drug metabolism between the young and old, as may be uncovered by studying aging regulation of the genes relevant to steroid and xenobiotic metabolism, is likely to have clinical significance. In this report, we examined the VDR-and PXR-mediated gene induction of the phase II sulfotransferase Sult2A1 in the livers of 4-month and 20-month old mice. Sult2A1 converts bile acids, steroids and a number of drugs to the corresponding sulfated metabolites, which are readily eliminated from the body due to increased water solubility. In RT-PCR assay, aging did not change the induction of Sult2A1 mRNAs by the hormonally active vitamin D 3 and the catatoxic synthetic steroid PCN (pregnenolone-16α-carbonitrile). Chromatin immunoprecipitation (ChIP) from liver nuclei showed that aging had no effect on the activity of an IR0 enhancer in the Sult2A1 chromatin to recruit VDR, RXR-α (retinoid X receptor) and PXR in mice injected with D 3 or PCN. Thus, mice in late life are as competent as those in early life in responding to the hormonal and xenobiotic signaling for Sult2A1 induction. This is the first report describing the role of aging in the functional response of an enhancer in the liver chromatin to the nuclear receptor-dependent signaling.

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“…A study on the suppression of mSULT2A1 during the acute phase response also suggested that PXR and FXR are responsible for the induction of mSULT2A1 (Kim et al, 2004). It was reported that SULT2A1 is a target for transcriptional activation by vitamin D3 mediated through vitamin D receptor (VDR) in rats and mice (Echchgadda et al, 2004b). FXR and PXR inhibited the vitamin D3 induction of SULT2A1.…”

Section: Introductionmentioning

confidence: 99%

Human constitutive androstane receptor mediated methotrexate induction of human dehydroepiandrosterone sulfotransferase (hSULT2A1)☆

et al. 2007

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Sulfotransferases (SULTs) catalyzed sulfation is important in the regulation of biological activities of hormones and neurotransmitters, the metabolism of drugs, and the detoxification of xenobiotic toxicants. Sulfation also leads to the bioactivation of procarcinogens. Human dehydroepiandrosterone sulfotransferase (hSULT2A1) is a major SULT catalyzing the sulfation of hydroxysteroids and xenobiotic alcohols. Our previous studies had shown that the anti-folate drug methotrexate (MTX) can up-regulate several major isoforms of human SULTs. To determine the mechanisms controlling the regulation of hSULT2A1, the 5′-flanking region of hSULT2A1 was constructed into the pGL3-Basic luciferase reporter vector. The transcriptional regulation mechanism of hSULT2A1 promoter was studied using Caco-2 cell line based on the reporter gene assay. Nuclear receptor co-transfection results indicated that human constitutive androstane receptor (hCAR) and human retinoid X receptor α (hRXRα) were involved in the transcriptional regulation of hSULT2A1. RNA interference experiments further proved the role of hCAR in hSULT2A1 regulation. Progressive promoter deletion, DNA sequence alignment, and site directed promoter mutation results suggested that an imperfect inverted repeat DNA motif, IR2 (-186AGCTCAGATGACCC-173), within the hSULT2A1 promoter region mediated the hSULT2A1 induction by MTX. Furthermore, electrophoretic mobility shift assay and super shift assay were employed to characterize the interactions of hCAR and hRXRα with the IR2 element. In summary, we identified an IR2 DNA cis-element located at -186/-173 of hSULT2A1 promoter region; the IR2 element mediates the MTX induction of hSULT2A1 through interacting with hCAR and hRXRα.

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Dehydroepiandrosterone Sulfotransferase Is a Target for Transcriptional Induction by the Vitamin D Receptor

Cited by 150 publications

References 37 publications

Liver Hypertrophy

Liver Hypertrophy

Xenobiotic- and vitamin D-responsive induction of the steroid/bile acid-sulfotransferase Sult2A1 in young and old mice: The role of a gene enhancer in the liver chromatin

Human constitutive androstane receptor mediated methotrexate induction of human dehydroepiandrosterone sulfotransferase (hSULT2A1)☆

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