Human Sulfotransferases Enhance the Cytotoxicity of Tolvaptan

Fang, Jia‐Long; Wu, Yuanfeng; Costa, Gonçalo Gamboa da; Chen, Si; Chitranshi, Priyanka; Beland, Frederick A.

doi:10.1093/toxsci/kfv311

Cited by 12 publications

(3 citation statements)

References 24 publications

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“…Furthermore, SULT2A1 is involved in the individual genetic disposition, species differences, and organotropisms for toxicological effects of chemicals 40 . The activity modulation of SULT2A1 with the aid of selective inhibitor may prove to be preventive or therapeutic method for metabolic activation mediated toxicological effects 41 , 42 , 43 . Therefore, a specific activity-based probe for SULT2A1 is a valuable tool for measuring the function level of SULT2A1 and searching for the novel therapeutic agent that targeted to SULT2A1.…”

Section: Discussionmentioning

confidence: 99%

Arenobufagin is a novel isoform-specific probe for sensing human sulfotransferase 2A1

Tian

Wang

Dong

et al. 2018

Acta Pharmaceutica Sinica B

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Human cytosolic sulfotransferase 2A1 (SULT2A1) is an important phase II metabolic enzyme. The detection of SULT2A1 is helpful for the functional characterization of SULT2A1 and diagnosis of its related diseases. However, due to the overlapping substrate specificity among members of the sulfotransferase family, it is difficult to develop a probe substrate for selective detection of SULT2A1. In the present study, through characterization of the sulfation of series of bufadienolides, arenobufagin (AB) was proved as a potential probe substrate for SULT2A1 with high sensitivity and specificity. Subsequently, the sulfation of AB was characterized by experimental and molecular docking studies. The sulfate-conjugated metabolite was identified as AB-3-sulfate. The sulfation of AB displayed a high selectivity for SULT2A1 which was confirmed by in vitro reaction phenotyping assays. The sulfation of AB by human liver cytosols and recombinant SULT2A1 both obeyed Michaelis-Menten kinetics, with similar kinetic parameters. Molecular docking was performed to understand the interaction between AB and SULT2A1, in which the lack of interaction with Met-137 and Tyr-238 of SULT2A1 made it possible to eliminate substrate inhibition of AB sulfation. Finally, the probe was successfully used to determine the activity of SULT2A1 and its isoenzymes in tissue preparations of human and laboratory animals.

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Section: Discussionmentioning

confidence: 99%

Arenobufagin is a novel isoform-specific probe for sensing human sulfotransferase 2A1

Tian

Wang

Dong

et al. 2018

Acta Pharmaceutica Sinica B

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“…Studies to evaluate SULT1C3 (isoform d) activity have indicated that this enzyme can sulfonate large benzylic alcohols, including metabolites of polycyclic aromatic hydrocarbons, and the steroid-related compounds a-zearalenol and lithocholic acid (Allali-Hassani et al, 2007;Meinl et al, 2008a). Also, a recent study reported that SULT1C3 had the lowest K m and highest V max of 12 human SULTs tested for sulfonation of tolvaptan, which is a selective vasopressin V 2 -receptor antagonist that possesses a benzylic hydroxy group (Fang et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Transcriptional Regulation of Human Cytosolic Sulfotransferase 1C3 by Peroxisome Proliferator-Activated Receptor γ in LS180 Human Colorectal Adenocarcinoma Cells

et al. 2016

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Cytosolic sulfotransferase 1C3 (SULT1C3) is the least characterized of the three human SULT1C subfamily members. Originally identified as an orphan SULT by computational analysis of the human genome, we recently reported that SULT1C3 is expressed in human intestine and LS180 colorectal adenocarcinoma cells and is upregulated by agonists of peroxisome proliferator-activated receptor (PPAR) α and γ To determine the mechanism responsible for PPAR-mediated upregulation, we prepared reporter plasmids containing fragments of the SULT1C3 5'-flanking region. During initial attempts to amplify a 2.8-kb fragment from different sources of human genomic DNA, a 1.9-kb fragment was sometimes coamplified with the expected 2.8-kb fragment. Comparison of the 1.9-kb fragment sequence to the published SULT1C3 5'-flanking sequence revealed an 863-nt deletion (nt -146 to -1008 relative to the transcription start site). Transfection analysis in LS180 cells demonstrated that PPARα, δ, and γ agonist treatments induced luciferase expression from a reporter plasmid containing the 2.8-kb but not the 1.9-kb fragment. The PPAR agonists also activated a 1-kb reporter containing the 863-nt deletion region. Computational analysis identified three peroxisome proliferator response elements (PPREs) within the 863-nt region and serial deletions and site-directed mutations indicated that the most distal PPRE (at nt -769) was essential for obtaining PPAR-mediated transcriptional activation. Although agonists of all three PPARs could activate SULT1C3 transcription, RNA interference analysis indicated the predominance of PPARγ These data demonstrate that the PPARγ regulatory network includes SULT1C3 and imply that this enzyme contributes to the control of such PPARγ-regulated intestinal processes as growth, differentiation, and metabolism.

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“…Sulfation often results in the inactivation of the substrates or reduced potency of ligands (Strott, 2002;Bjerregaard-Olesen et al, 2015) but with some exceptions. Their abundance in the liver and wide range of substrates suggest SULTs may act as important mediators for the development of liver diseases, such as hepatocellular carcinoma (Xie et al, 2017;Zou et al, 2017), liver fibrosis (Hardwick et al, 2013;Krattinger et al, 2016;Yetti et al, 2018), and drug-induced liver injury (Fang et al, 2016). Therefore, in this review we focus on the roles of the human and rodent SULTs in liver diseases.…”

Section: Introductionmentioning

confidence: 99%

The Role of Sulfotransferases in Liver Diseases

Xie

2020

Drug Metab Dispos

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The cytosolic sulfotransferases (SULTs) are phase II conjugating enzymes that catalyze the transfer of a sulfonate group from the universal sulfate donor 39-phosphoadenosine-59-phosphosulfate to a nucleophilic group of their substrates to generate hydrophilic products. Sulfation has a major effect on the chemical and functional homeostasis of substrate chemicals. SULTs are widely expressed in metabolically active or hormonally responsive tissues, including the liver and many extrahepatic tissues. The expression of SULTs exhibits isoform-, tissue-, sex-, and development-specific regulations. SULTs display a broad range of substrates including xenobiotics and endobiotics. The expression of SULTs has been shown to be transcriptionally regulated by members of the nuclear receptor superfamily, such as the peroxisome proliferator-activated receptors, pregnane X receptor, constitutive androstane receptor, vitamin D receptor, liver X receptors, farnesoid X receptor, retinoid-related orphan receptors, estrogen-related receptors, and hepatocyte nuclear factor 4a. These nuclear receptors can be activated by numerous xenobiotics and endobiotics, such as fatty acids, bile acids, and oxysterols, many of which are substrates of SULTs. Due to their metabolism of xenobiotics and endobiotics, SULTs and their regulations are implicated in the pathogenesis of many diseases. This review is aimed to summarize the central role of major SULTs, including the SULT1 and SULT2 subfamilies, in the pathophysiology of liver and liver-related diseases. SIGNIFICANCE STATEMENTSulfotransferases (SULTs) are indispensable in the homeostasis of xenobiotics and endobiotics. Knowing SULTs and their regulations are implicated in human diseases, it is hoped that genetic or pharmacological manipulations of the expression and/or activity of SULTs can be used to affect the clinical outcome of diseases.

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Human Sulfotransferases Enhance the Cytotoxicity of Tolvaptan

Cited by 12 publications

References 24 publications

Arenobufagin is a novel isoform-specific probe for sensing human sulfotransferase 2A1

Arenobufagin is a novel isoform-specific probe for sensing human sulfotransferase 2A1

Transcriptional Regulation of Human Cytosolic Sulfotransferase 1C3 by Peroxisome Proliferator-Activated Receptor γ in LS180 Human Colorectal Adenocarcinoma Cells

The Role of Sulfotransferases in Liver Diseases

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