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Yuichi Yokoyama, Yoshifumi Sasaki, Natsuko Terasaki, Taku Kawataki, Koji Takekawa, Yumiko Iwase, Toshinobu Shimizu, Seigo Sanoh, Shigeru Ohta
Differentiated HepaRG cells maintain liver-specific functions such as drug-metabolizing enzymes. In this study, the feasibility of HepaRG cells as a human hepatocyte model for in vitro toxicity assessment was examined using selected hepatotoxic compounds. First, basal drug-metabolizing enzyme activities (CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4, uridine 5'-diphospho-glucuronosyltransferase [UGT], and sulfotransferases [SULT]) were measured in HepaRG, human hepatocytes, and HepG2 cells. Enzyme activities in differentiated HepaRG cells were comparable to those in human hepatocytes and much higher than those in HepG2 cells, except for SULT activity...
February 14, 2018: Biological & Pharmaceutical Bulletin
William Davies
Steroid hormones can exist in functionally-dissociable sulfated and non-sulfated (free) forms and can exert profound effects on numerous aspects of mammalian physiology; the ratio of free to sulfated steroids is governed by the antagonistic actions of steroid sulfatase (STS) and sulfotransferase (SULT) enzymes. Here, I examine evidence from human and animal model studies which suggests that STS and its major substrate (dehydroepiandrosterone sulfate, DHEAS) and product (DHEA) can influence brain function, behavior and mental health, before summarising how the activity of this axis varies throughout mammalian pregnancy and the postpartum period...
February 13, 2018: Journal of Molecular Endocrinology
Muhamad Ashraf Rostam, Aravindra Shajimoon, Danielle Kamato, Partha Mitra, Terrence Piva, Robel Getachew, Yingnan Cao, Wenhua Zheng, Narin Osman, Peter James Little
Transforming Growth Factor (TGF) β is a pleiotropic growth factor implicated in the development of atherosclerosis for its role in mediating glycosaminoglycan (GAG) chain hyperelongation on the proteoglycan biglycan, a phenomenon that leads to increased binding of atherogenic lipoproteins in the wall of blood vessels. TGF-β signalling pathway components leading to the modification of GAG chains on biglcyan are therefore potential targets for the treatment of atherosclerosis. Phosphorylation of the transcription factor Smad has emerged as a critical step in the signalling pathways that control the synthesis of biglycan, both the core protein and the GAG chains...
February 9, 2018: Journal of Pharmacology and Experimental Therapeutics
Husna Yetti, Hisao Naito, Yuan Yuan, Xiaofang Jia, Yumi Hayashi, Hazuki Tamada, Kazuya Kitamori, Katsumi Ikeda, Yukio Yamori, Tamie Nakajima
During middle age, women are less susceptible to nonalcoholic steatohepatitis (NASH) than men. Thus, we investigated the underlying molecular mechanisms behind these sexual differences using an established rat model of NASH. Mature female and male stroke-prone spontaneously hypertensive 5/Dmcr rats were fed control or high-fat-cholesterol (HFC) diets for 2, 8, and 14 weeks. Although HFC-induced hepatic fibrosis was markedly less severe in females than in males, only minor gender differences were observed in expression levels of cytochrome P450 enzymes (CYP)7A1, CYP8B1 CYP27A1, and CYP7B1, and multidrug resistance-associated protein 3, and bile salt export pump, which are involved in fibrosis-related bile acid (BA) kinetics...
2018: PloS One
Yuki Asai, Yukiko Sakakibara, Miyabi Kondo, Masayuki Nadai, Miki Katoh
1. Sulfotransferase (SULT) has been found in the brain; however, the details of its function remain unclear. The present study aimed to elucidate the regional differences in the expression of SULT1 and SULT2 mRNA and SULT activities in the eight functional regions of the rat brain (cerebellum, cortex, hippocampus, medulla oblongata, midbrain, olfactory bulb, striatum, and thalamus). 2. All SULT1 isoforms were detected in the medulla oblongata and thalamus. SULT2A1 mRNA was not observed in any of the eight regions, whereas SULT2B1a and SULT2B1b were found in all regions...
February 13, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
Caleb K Y Yip, Sumit Bansal, Siew Ying Wong, Aik Jiang Lau
Galeterone and abiraterone acetate are anti-androgens developed for the treatment of metastatic castration-resistant prostate cancer. In the present study, we investigated the effect of these drugs on dehydroepiandrosterone (DHEA) sulfonation catalyzed by human liver and intestinal cytosols and human recombinant sulfotransferase enzymes (SULT2A1, SULT2B1b, and SULT2E1), and compared their effects to those of other anti-androgens (cyproterone acetate, spironolactone, and danazol). Each of these chemicals (10 μM) inhibited DHEA sulfonation catalyzed by human liver and intestinal cytosols...
February 7, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Victoria S Parker, Edwin J Squirewell, Hans-Joachim Lehmler, Larry W Robertson, Michael W Duffel
Polychlorinated biphenyls (PCBs) are ubiquitous environmental contaminants that are associated with varied adverse health effects. Lower chlorinated PCBs are prevalent in indoor and outdoor air and can be metabolized to their hydroxylated derivatives (OH-PCBs) followed by sulfation to form PCB sulfates. Sulfation is also a means of signal termination for steroid hormones. The human estrogen sulfotransferase (SULT1E1) and alcohol/hydroxysteroid sulfotransferase (SULT2A1) catalyze the formation of steroid sulfates that are inactive at steroid hormone receptors...
January 31, 2018: Environmental Toxicology and Pharmacology
Srividyameena Haridoss, Mladen I Yovchev, Hannah Schweizer, Sabreen Megherhi, Maria Beecher, Joseph Locker, Michael Oertel
Activin A, a multifunctional cytokine, plays an important role in hepatocyte growth suppression and is involved in liver size control. The present study was aimed to determine the cell location of activin A in the normal rat liver microenvironment and the contribution of activin A signaling to the hepatocyte phenotype to obtain insight into molecular mechanisms. Immunohistochemical and in situ hybridization analyses identified hepatocytes as the major activin A-positive cell population in normal liver and identified mast cells as an additional activin A source...
November 2017: Hepatology Communications
Isaac V Cohen, Elizabeth T Cirulli, Matthew W Mitchell, Thomas J Jonsson, James Yu, Naisha Shah, Tim D Spector, Lining Guo, J Craig Venter, Amalio Telenti
BACKGROUND: Acetaminophen (paracetamol) is one of the most common medications used for management of pain in the world. There is lack of consensus about the mechanism of action, and concern about the possibility of adverse effects on reproductive health. METHODS: We first established the metabolome profile that characterizes use of acetaminophen, and we subsequently trained and tested a model that identified metabolomic differences across samples from 455 individuals with and without acetaminophen use...
February 1, 2018: EBioMedicine
Ethan Miller, Munaf H Zalzala, Maryam S Abunnaja, Katsuhisa Kurogi, Yoichi Sakakibara, Masahito Suiko, Ming-Cheh Liu
BACKGROUND AND OBJECTIVES: Previous studies have demonstrated the metabolism of tibolone through sulfation, with the cytosolic sulfotransferase (SULT) SULT2A1 as the major responsible enzyme. The current study aimed to investigate how SULT2A1 genetic polymorphisms may affect the dehydroepiandrosterone (DHEA)- and tibolone-sulfating activity of SULT2A1. METHODS: Site-directed mutagenesis was employed to generate cDNAs encoding ten different SULT2A1 allozymes. Recombinant SULT2A1 allozymes were expressed in BL21 E...
February 1, 2018: European Journal of Drug Metabolism and Pharmacokinetics
Yalong Lu, Wenfeng Li, Xingbin Yang
This study was designed to probe the promoting effects of soybean soluble polysaccharide (SSPS) on bioavailability of genistein in mice and the underlying molecular mechanism. Male Kunming mice (n=8) were administered intragastrically with either saline, SSPS (5mg/kgbw), genistein (100mg/kgbw), or SSPS (5 or 50mg/kgbw) together with genistein (100mg/kgbw) for consecutive 28days. UPLC-qTOF/MS analysis showed that co-administration of SSPS and genistein in mice caused significant elevation in the urinary levels of genistein and its metabolites (p<0...
January 2018: Food Research International
Yuhan Bi, Xiongjie Shi, Junjie Zhu, Xiudong Guan, Wojciech G Garbacz, Yixian Huang, Li Gao, Jiong Yan, Meishu Xu, Songrong Ren, Shunlin Ren, Yulan Liu, Xiaochao Ma, Song Li, Wen Xie
The cholesterol sulfotransferase SULT2B1b converses cholesterol to cholesterol sulfate (CS). We previously reported that SULT2B1b inhibits hepatic gluconeogenesis by antagonizing the gluconeogenic activity of hepatocyte nuclear factor 4α (HNF4α). In this study, we showed that the SULT2B1b gene is a transcriptional target of HNF4α, which led to our hypothesis that the induction of SULT2B1b by HNF4α represents a negative feedback to limit the gluconeogenic activity of HNF4α. Indeed, down-regulation of Sult2B1b enhanced the gluconeogenic activity of HNF4α, which may have been accounted for by the increased acetylation of HNF4α as a result of decreased expression of the HNF4α deacetylase Sirt1...
January 29, 2018: Molecular and Cellular Biology
Shulin Low, Jotaro Hirakawa, Hitomi Hoshino, Kenji Uchimura, Hiroto Kawashima, Motohiro Kobayashi
Ulcerative colitis (UC) is a chronic inflammatory disease histologically characterized by diffuse mononuclear cell infiltrates in colonic mucosa. These inflammatory cells are considered to be recruited via high endothelial venule (HEV)-like vessels displaying mucosal addressin cell adhesion molecule 1 (MAdCAM-1), the ligand for α4β7 integrin, and/or peripheral lymph node addressin (PNAd), an L-selectin ligand. 6- O-sulfation of N-acetylglucosamine in the carbohydrate moiety of PNAd is catalyzed exclusively by N-acetylglucosamine-6- O-sulfotransferase 1 (GlcNAc6ST-1) and GlcNAc6ST-2...
January 1, 2018: Journal of Histochemistry and Cytochemistry: Official Journal of the Histochemistry Society
Timothy Wong, Zhican Wang, Brian D Chapron, Mizuki Suzuki, Katrina G Claw, Chunying Gao, Robert S Foti, Bhagwat Prasad, Alenka Chapron, Justina Calamia, Amarjit Chaudhry, Erin G Schuetz, Ronald L Horst, Qingcheng Mao, Ian H de Boer, Timothy A Thornton, Kenneth E Thummel
Metabolism of 25-hydroxyvitamin D3 (25OHD3) plays a central role in regulating the biological effects of vitamin D in the body. Although cytochrome P450-dependent hydroxylation of 25OHD3 has been extensively investigated, limited information is available on the conjugation of 25OHD3. In the present study, we report that 25OHD3 is selectively conjugated to 25OHD3-3-O-sulfate by human sulfotransferase 2A1 (SULT2A1) and that the liver is a primary site of metabolite formation. At a low (50 nM) concentration of 25OHD3, 25OHD3-3-O-sulfate was the most abundant metabolite, with an intrinsic clearance approximately 8-fold higher than the next most efficient metabolic route...
January 17, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Chengcheng Ren, Jelleke Dokter-Fokkens, Susana Figueroa Lozano, Qiuxiang Zhang, Bart J de Haan, Hao Zhang, Marijke M Faas, Paul de Vos
SCOPE: Lactic acid bacteria (LAB) are recognized to promote gastrointestinal health by mechanisms that are not fully understood. LABs might modulate the mucus and thereby enhance intestinal barrier function. Herein, we investigated effects of different LAB strains and species on goblet cell genes involved in mucus synthesis. METHODS AND RESULTS: Gene expression profiles of goblet cell-associated products (mucin MUC2, trefoil factor 3, resistin-like molecule β, carbohydrate sulfotransferase 5, and galactose-3-O-sulfotransferase 2) induced by LAB or their derived conditioned medium in human goblet cell line LS174T were studied...
January 15, 2018: Molecular Nutrition & Food Research
Christopher P Leonetti, Craig M Butt, Heather M Stapleton
Brominated flame retardants (BFRs) have been shown to disrupt thyroid hormone (TH) homeostasis through multiple mechanisms, including inhibition of enzymes that regulate intracellular levels of THs, such as sulfotransferases (SULTs). The placenta plays a critical role in helping to maintain TH levels during fetal development and expresses SULTs. This is concerning given that disruption of TH regulation within the placenta could potentially harm the developing fetus. In this study, we investigated the effects of two polybrominated diphenyl ethers (PBDEs), two hydroxylated PBDEs, and 2,4,6-tribromophenol (2,4,6-TBP) on TH SULT activity in a choriocarcinoma placenta cell line (BeWo)...
December 28, 2017: Chemosphere
Ditmer T Talsma, Kirankumar Katta, Marieke A B Ettema, Berna Kel, Marion Kusche-Gullberg, Moh R Daha, Coen A Stegeman, Jacob van den Born, Lianchun Wang
Inflammation plays a vital role in the development of diabetic nephropathy, but the underlying regulatory mechanisms are only partially understood. Our previous studies demonstrated that, during acute inflammation, endothelial heparan sulfate (HS) contributes to the adhesion and transendothelial migration of leukocytes into perivascular tissues by direct interaction with L-selectin and the presentation of bound chemokines. In the current study, we aimed to assess the role of endothelial HS on chronic renal inflammation and fibrosis in a diabetic nephropathy mouse model...
January 12, 2018: Laboratory Investigation; a Journal of Technical Methods and Pathology
J Chris Vos, Shalenie P den Braver-Sewradj, Michiel W den Braver, Marc van Dijk, Yongjie Zhang, Stefan J Dekker, Lukas Wijaya, Nico P E Vermeulen, Lysiane Richert, Jan N M Commandeur
BACKGROUND: Inter-individual variability in hepatic drug metabolizing enzyme (DME) activity is a major contributor to heterogeneity in drug clearance and safety. Accurate data on expression levels and activities of DMEs is an important prerequisite for in vitro-in vivo extrapolation and in silico based predictions. Characterization and assessment of inter-correlations of the major DMEs cytochrome P450s (CYPs) and UDP-glucuronosyltransferases (UGTs) have been extensively documented, but simultaneous quantification including other major DMEs has been lacking...
January 8, 2018: Current Drug Metabolism
Thomas Wong, Richard J Bloomer, Rodney L Benjamin, Randal K Buddington
The principal dietary sources of sulfur, the amino acids methionine and cysteine, may not always be consumed in adequate amounts to meet sulfur requirements. The naturally occurring organosulfur compound, methylsulfonylmethane (MSM), is available as a dietary supplement and has been associated with multiple health benefits. Absorption of MSM by the small intestine and accumulation of the associated sulfur moiety in selected tissues with chronic (8 days) administration were evaluated using juvenile male mice...
December 25, 2017: Nutrients
Shohana S Islam, Diana M Mate, Ronny Martínez, Felix Jakob, Ulrich Schwaneberg
Bacterial aryl sulfotransferases (AST) utilize p-nitrophenylsulfate (pNPS) as a phenolic donor to sulfurylate typically a phenolic acceptor. Interest in aryl sulfotransferases is growing because of their broad variety of acceptors and cost-effective sulfuryl-donors. For instance, aryl sulfotransferase A (ASTA) from Desulfitobacterium hafniense was recently reported to sulfurylate D-glucose. In this study, a directed evolution protocol was developed and validated for aryl sulfotransferase B (ASTB). Thereby the well-known pNPS quantification system was advanced to operate efficiently as a continuous screening system in 96-well MTP format with a true coefficient of variation of 14...
December 30, 2017: Biotechnology and Bioengineering
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