Subscribe to RSS
DOI: 10.1055/a-1351-0618
Sulfation of Quercitrin, Epicatechin and Rutin by Human Cytosolic Sulfotransferases (SULTs): Differential Effects of SULT Genetic Polymorphisms
Supported by: China Scholarship Council 18SXHZ0250![](https://www.thieme-connect.de/media/plantamedica/202106/lookinside/thumbnails/10-1055-a-1351-0618_pme0726-1.jpg)
Abstract
Radix Bupleuri is one of the most widely used herbal medicines in China for the treatment of fever, pain, and/or chronic inflammation. Quercitrin, epicatechin, and rutin, the flavonoids present in Radix Bupleuri, have been reported to display anti-inflammatory, antitumor, and antioxidant biological activities among others. Sulfation has been reported to play an important role in the metabolism of flavonoids. In this study, we aimed to systematically identify the human cytosolic sulfotransferase enzymes that are capable of catalyzing the sulfation of quercitrin, epicatechin, and rutin. Of the thirteen known human cytosolic sulfotransferases, three (cytosolic sulfotransferase 1A1, cytosolic sulfotransferase 1C2, and cytosolic sulfotransferase 1C4) displayed sulfating activity toward quercitrin, three (cytosolic sulfotransferase 1A1, cytosolic sulfotransferase 1A3, and cytosolic sulfotransferase 1C4) displayed sulfating activity toward epicatechin, and six (cytosolic sulfotransferase 1A1, cytosolic sulfotransferase 1A2, cytosolic sulfotransferase 1A3, cytosolic sulfotransferase 1B1, cytosolic sulfotransferase 1C4, and cytosolic sulfotransferase 1E1) displayed sulfating activity toward rutin. The kinetic parameters of the cytosolic sulfotransferases that showed the strongest sulfating activities were determined. To investigate the effects of genetic polymorphisms on the sulfation of quercitrin, epicatechin, and rutin, individual panels of cytosolic sulfotransferase allozymes previously prepared were analyzed and shown to display differential sulfating activities toward each of the three flavonoids. Taken together, these results provided a biochemical basis underlying the metabolism of quercitrin, epicatechin, and rutin through sulfation in humans.
Key words
Bupleurum scorzonerifolium - Apiaceae - quercitrin - epicatechin - rutin - sulfation - cytosolic sulfotransferase - SULT - single nucleotide polymorphism - SNPPublication History
Received: 08 July 2020
Accepted after revision: 01 January 2021
Article published online:
11 February 2021
© 2021. Thieme. All rights reserved.
Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany
-
References
- 1 Editorial Committee of Chinese Pharmacopoeia. Traditional Chinese medicinal Crops and Prepared Slices. In: Editorial Committee of Chinese Pharmacopoeia. ed. Chinese Pharmacopoeia Part One. Beijing: Medical Science and Technology Press; 2015: 280-281
- 2 Van Wyk BE, Wink M. An illustrated scientific Guide to important medicinal Plants and their Uses. In: Van Wyk BE, Wink M. eds. Medicinal Plants of the World. Vol. 58. Portland: Timber Press; 2004: 58
- 3 Ashour ML, Wink M. Genus Bupleurum: a review of its phytochemistry, pharmacology and modes of action. J Pharm Pharmacol 2011; 63: 305-321
- 4 Yang F, Dong X, Yin X, Wang W, You L, Ni J. Radix Bupleuri: A review of traditional uses, botany, phytochemistry, pharmacology, and toxicology. Biomed Res Int 2017; 2017: 1-22
- 5 Yoshie F, Iizuka A, Komatsu Y, Matsumoto A, Itakura H, Kondo K. Effects of Dai-saiko-to (Da-Chai-Hu-Tang) on plasma lipids and atherosclerotic lesions in female heterozygous heritable Kurosawa and Kusanagi-hypercholesterolemic (KHC) rabbits. Pharmacol Res 2004; 50: 223-230
- 6 Tung NH, Uto T, Morinaga O, Shoyama Y. Chemical constituents from the aerial parts of Bupleurum falcatum L. and biological evidences. Nat Prod Sci 2015; 21: 71-75
- 7 Romero M, Vera B, Galisteo M, Toral M, Gálvez J, Perez-Vizcaino F, Duarte J. Protective vascular effects of quercitrin in acute TNBS-colitis in rats: the role of nitric oxide. Food Funct 2017; 8: 2702-2711
- 8 Morrison M, van der Heijden R, Heeringa P, Kaijzel E, Verschuren L, Blomhoff R, Kooistra T, Kleemann R. Epicatechin attenuates atherosclerosis and exerts anti-inflammatory effects on diet-induced human-CRP and NFκB in vivo . Atherosclerosis 2014; 233: 149-156
- 9 Bahia PK, Rattray M, Williams RJ. Dietary flavonoid (−) epicatechin stimulates phosphatidylinositol 3-kinase-dependent anti-oxidant response element activity and up-regulates glutathione in cortical astrocytes. J Neurochem 2008; 106: 2194-2204
- 10 Guardia T, Rotelli AE, Juarez AO, Pelzer LE. Anti-inflammatory properties of plant flavonoids. Effects of rutin, quercetin and hesperidin on adjuvant arthritis in rat. Farmaco 2001; 56: 683-687
- 11 Lin JP, Yang JS, Lin JJ, Lai KC, Lu HF, Ma CY, Sai-Chuen Wu R, Wu KC, Chueh FS, Gibson Wood W. Rutin inhibits human leukemia tumor growth in a murine xenograft model in vivo . Environ Toxicol 2012; 27: 480-484
- 12 Zhi K, Li M, Bai J, Wu Y, Zhou S, Zhang X, Qu L. Quercitrin treatment protects endothelial progenitor cells from oxidative damage via inducing autophagy through extracellular signal-regulated kinase. Angiogenesis 2016; 19: 311-324
- 13 Li W, Li H, Zhang M, Wang M, Zhong Y, Wu H, Yang Y, Morel L, Wei Q. Quercitrin ameliorates the development of systemic lupus erythematosus-like disease in a chronic graft-versus-host murine model. Am J Physiol Renal Physiol 2016; 311: F217-F226
- 14 Villarreal F. Epicatechin as a therapeutic strategy to mitigate the development of cardiac remodeling and fibrosis. San Diego La Jolla United States: University of California; 2018. Accessed January 28, 2021 at: https://apps.dtic.mil/sti/pdfs/AD1093340.pdf
- 15 Singh A, Demont A, Actis-Goretta L, Holvoet S, Lévêques A, Lepage M, Nutten S, Mercenier A. Identification of epicatechin as one of the key bioactive constituents of polyphenol-enriched extracts that demonstrate an anti-allergic effect in a murine model of food allergy. Br J Nutr 2014; 112: 358-368
- 16 Habtemariam S. Rutin as a natural therapy for alzheimerʼs disease: insights into its mechanisms of action. Curr Med Chem 2016; 23: 860-873
- 17 Habtemariam S, Belai A. Natural therapies of the inflammatory bowel disease: the case of rutin and its aglycone, quercetin. Mini Rev Med Chem 2018; 18: 234-243
- 18 Sak K. Anticancer Action of sulfated Flavonoids as Phase II Metabolites. In: Grumezescu AM, Holban AM. eds. Food Bioconversion. London: Andre Gerhard Wolff; 2017: 207-236
- 19 Huang C, Chen Y, Zhou T, Chen G. Sulfation of dietary flavonoids by human sulfotransferases. Xenobiotica 2009; 39: 312-322
- 20 Coughtrie MW. Function and organization of the human cytosolic sulfotransferase (SULT) family. Chem Biol Interact 2016; 259: 2-7
- 21 Klaassen CD, Boles JW. Sulfation and sulfotransferases 5: the importance of 3′-phosphoadenosine 5′-phosphosulfate (PAPS) in the regulation of sulfation. FASEB J 1997; 11: 404-418
- 22 Gamage N, Barnett A, Hempel N, Duggleby RG, Windmill KF, Martin JL, McManus ME. Human sulfotransferases and their role in chemical metabolism. Toxicol Sci 2006; 90: 5-22
- 23 Hempel N, Barnett A, Gamage N, Duggleby RG, Windmill KF, Martin JL, McManus ME. 10 Human SULT1A SULTs. In: Pacifici GM, Coughtrie MWH. eds. Human cytosolic sulfotransferases. New York: Taylor & Francis Group; 2005: 181-189
- 24 Lu LY, Hsu YC, Yang YS. Spectrofluorometric assay for monoamine-preferring phenol sulfotransferase (SULT1A3). Anal Biochem 2010; 404: 241-243
- 25 Runge-Morris M, Kocarek T. Expression of the sulfotransferase 1C family: implications for xenobiotic toxicity. Drug Metab Rev 2013; 45: 450-459
- 26 Wood TC, Her C, Aksoy I, Otterness DM, Weinshilboum RM. Human dehydroepiandrosterone sulfotransferase pharmacogenetics: quantitative western analysis and gene sequence polymorphisms. J Steroid Biochem Mol Biol 1996; 59: 467-478
- 27 Raftogianis RB, Wood TC, Otterness DM, Van Loon JA, Weinshilboum RM. Phenol sulfotransferase pharmacogenetics in humans: association of common SULT1A1 alleles with TS PST phenotype. Biochem Biophys Res Commun 1997; 239: 298-304
- 28 Raftogianis RB, Wood TC, Weinshilboum RM. Human phenol sulfotransferases SULT1A2 and SULT1A1: genetic polymorphisms, allozyme properties, and human liver genotype-phenotype correlations. Biochem Pharmacol 1999; 58: 605-616
- 29 Thomae BA, Rifki OF, Theobald MA, Eckloff BW, Wieben ED, Weinshilboum RM. Human catecholamine sulfotransferase (SULT1A3) pharmacogenetics: functional genetic polymorphism. J Neurochem 2003; 87: 809-819
- 30 Freimuth RR, Eckloff B, Wieben ED, Weinshilboum RM. Human sulfotransferase SULT1C1 pharmacogenetics: gene resequencing and functional genomic studies. Pharmacogenet Genomics 2001; 11: 747-756
- 31 Adjei AA, Thomae BA, Prondzinski JL, Eckloff BW, Wieben ED, Weinshilboum RM. Human estrogen sulfotransferase (SULT1E1) pharmacogenomics: gene resequencing and functional genomics. Br J Pharmacol 2003; 139: 1373-1382
- 32 Hui Y, Liu MC. Sulfation of ritodrine by the human cytosolic sulfotransferases (SULTs): effects of SULT1A3 genetic polymorphism. Eur J Pharmacol 2015; 761: 125-129
- 33 Pai TG, Sugahara T, Suiko M, Sakakibara Y, Xu F, Liu MC. Differential xenoestrogen-sulfating activities of the human cytosolic sulfotransferases: molecular cloning, expression, and purification of human SULT2B1a and SULT2B1b sulfotransferases. Biochim Biophys Acta Gen Subj 2002; 1573: 165-170
- 34 Sakakibara Y, Suiko M, Pai TG, Nakayama T, Takami Y, Katafuchi J, Liu MC. Highly conserved mouse and human brain sulfotransferases: molecular cloning, expression, and functional characterization. Gene 2002; 285: 39-47
- 35 Suiko M, Sakakibara Y, Liu MC. Sulfation of environmental estrogen-like chemicals by human cytosolic sulfotransferases. Biochem Biophys Res Commun 2000; 267: 80-84
- 36 Rasool MI, Bairam AF, Gohal SA, El Daibani AA, Alherz FA, Abunnaja MS, Alatwi ES, Kurogi K, Liu MC. Effects of the human SULT1A1 polymorphisms on the sulfation of acetaminophen, O-desmethylnaproxen, and tapentadol. Pharmacol Rep 2019; 71: 257-265
- 37 Petrotchenko EV, Pedersen LC, Borchers CH, Tomer KB, Negishi M. The dimerization motif of cytosolic sulfotransferases. FEBS Lett 2001; 490: 39-43
- 38 Fernando PHP, Karakawa A, Sakakibara Y, Ibuki H, Nakajima H, Liu MC, Suiko M. Preparation of 3′-phosphoadenosine 5′-phospho35S-sulfate using ATP sulfurylase and APS kinase from Bacillus stearothermophilus: enzymatic synthesis and purification. Biosci Biotechnol Biochem 1993; 57: 1974-1975
- 39 Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 1976; 72: 248-254
- 40 Alherz FA, Almarghalani DA, Hussein NA, Kurogi K, Liu MC. A reappraisal of the 6-O-desmethylnaproxen-sulfating activity of the human cytosolic sulfotransferases. Can J Physiol Pharmacol 2017; 95: 647-651