Download PDF
Planta Med 2016; 82(03): 238-243
DOI: 10.1055/s-0035-1558158
Natural Product Chemistry & Analytical Studies
Original Papers
Georg Thieme Verlag KG Stuttgart · New York

Sulfation of 6-Gingerol by the Human Cytosolic Sulfotransferases: A Systematic Analysis

Lijun Luo
1   Department of Pharmacology, College of Pharmacy and Pharmaceutical Sciences, University of Toledo Health Science Campus, Toledo, Ohio, USA
2   School of Pharmacy, North Sichuan Medical College, Nanchong, Sichuan, China
,
Xue Mei
1   Department of Pharmacology, College of Pharmacy and Pharmaceutical Sciences, University of Toledo Health Science Campus, Toledo, Ohio, USA
2   School of Pharmacy, North Sichuan Medical College, Nanchong, Sichuan, China
,
Yuecheng Xi
1   Department of Pharmacology, College of Pharmacy and Pharmaceutical Sciences, University of Toledo Health Science Campus, Toledo, Ohio, USA
,
Chunyang Zhou
1   Department of Pharmacology, College of Pharmacy and Pharmaceutical Sciences, University of Toledo Health Science Campus, Toledo, Ohio, USA
2   School of Pharmacy, North Sichuan Medical College, Nanchong, Sichuan, China
,
Ying Hui
1   Department of Pharmacology, College of Pharmacy and Pharmaceutical Sciences, University of Toledo Health Science Campus, Toledo, Ohio, USA
3   Department of Obstetrics and Gynecology, Beijing Hospital, Beijing, China
,
Katsuhisa Kurogi
4   Biochemistry and Applied Biosciences, University of Miyazaki, Miyazaki, Japan
,
Yoichi Sakakibara
4   Biochemistry and Applied Biosciences, University of Miyazaki, Miyazaki, Japan
,
Masahito Suiko
4   Biochemistry and Applied Biosciences, University of Miyazaki, Miyazaki, Japan
,
Ming-Cheh Liu
1   Department of Pharmacology, College of Pharmacy and Pharmaceutical Sciences, University of Toledo Health Science Campus, Toledo, Ohio, USA
› Author Affiliations
Further Information

Publication History

received 20 June 2015
revised 12 September 2015

accepted 16 September 2015

Publication Date:
06 November 2015 (online)

    Permissions and Reprints

Abstract

Previous studies have demonstrated the presence of the sulfated form of 6-gingerol, a major pharmacologically active component of ginger, in plasma samples of normal human subjects who were administered 6-gingerol. The current study was designed to systematically identify the major human cytosolic sulfotransferase enzyme(s) capable of mediating the sulfation of 6-gingerol. Of the 13 known human cytosolic sulfotransferases examined, six (SULT1A1, SULT1A2, SULT1A3, SULT1B1, SULT1C4, SULT1E1) displayed significant sulfating activity toward 6-gingerol. Kinetic parameters of SULT1A1, SULT1A3, SULT1C4, and SULT1E1 that showed stronger 6-gingerol-sulfating activity were determined. Of the four human organ samples tested, small intestine and liver cytosols displayed considerably higher 6-gingerol-sulfating activity than those of the lung and kidney. Moreover, sulfation of 6-gingerol was shown to occur in HepG2 human hepatoma cells and Caco-2 human colon adenocarcinoma cells under the metabolic setting. Collectively, these results provided useful information relevant to the metabolism of 6-gingerol through sulfation both in vitro and in vivo.

Key words

6-gingerol - sulfation - cytosolic sulfotransferase - SULT
 

  • References

  • 1 Aggarwal BB, Kunnumakkara AB, Harikumar KB, Tharakan ST, Sung B, Anand P. Potential of spice-derived phytochemicals for cancer prevention. Planta Med 2008; 74: 1560-1569
    Article in Thieme ConnectPubMedGoogle Scholar
  • 2 Wang S, Zhang C, Yang G, Yang Y. Biological properties of 6-gingerol: a brief review. Nat Prod Commun 2014; 9: 1027-1030
    PubMedGoogle Scholar
  • 3 Young HY, Luo YL, Cheng HY, Hsieh WC, Liao JC, Peng WH. Analgesic and anti-inflammatory activities of [6]-gingerol. J Ethnopharmacol 2005; 96: 207-210
    CrossrefPubMedGoogle Scholar
  • 4 Abdel-Aziz H, Nahrstedt A, Petereit F, Windeck T, Ploch M, Verspohl EJ. 5-HT3 receptor blocking activity of arylalkanes isolated from the rhizome of Zingiber officinale . Planta Med 2005; 71: 609-616
    Article in Thieme ConnectPubMedGoogle Scholar
  • 5 Jeong CH, Bode AM, Pugliese A, Cho YY, Kim HG, Shim JH, Jeon YJ, Li H, Jiang H, Dong Z. [6]-Gingerol suppresses colon cancer growth by targeting leukotriene A4 hydrolase. Cancer Res 2009; 69: 5584-5591
    CrossrefPubMedGoogle Scholar
  • 6 Lee HS, Seo EY, Kang NE, Kim WK. [6]-Gingerol inhibits metastasis of MDA-MB-231 human breast cancer cells. J Nutr Biochem 2008; 19: 313-319
    CrossrefPubMedGoogle Scholar
  • 7 Lee E, Surh YJ. Induction of apoptosis in HL-60 cells by pungent vanilloids, [6]-gingerol and [6]-paradol. Cancer Lett 1998; 134: 163-168
    CrossrefPubMedGoogle Scholar
  • 8 Ishiguro K, Ando T, Maeda O, Ohmiya N, Niwa Y, Kadomatsu K, Goto H. Ginger ingredients reduce viability of gastric cancer cells via distinct mechanisms. Biochem Biophys Res Commun 2007; 362: 218-223
    CrossrefPubMedGoogle Scholar
  • 9 Nonn L, Duong D, Peehl DM. Chemopreventive anti-inflammatory activities of curcumin and other phytochemicals mediated by MAP kinase phosphatase-5 in prostate cells. Carcinogenesis 2007; 28: 1188-1196
    CrossrefPubMedGoogle Scholar
  • 10 Rhode J, Fogoros S, Zick S, Wahl H, Griffith KA, Huang J, Liu JR. Ginger inhibits cell growth and modulates angiogenic factors in ovarian cancer cells. BMC Complement Altern Med 2007; 7: 44
    CrossrefPubMedGoogle Scholar
  • 11 Wang G, Li X, Huang F, Zhao J, Ding H, Cunningham C, Coad JE, Flynn DC, Reed E, Li QQ. Antitumor effect of h-elemene in nonsmall-cell lung cancer cells is mediated via induction of cell cycle arrest and apoptotic cell death. Cell Mol Life Sci 2005; 62: 881-893
    CrossrefPubMedGoogle Scholar
  • 12 Ghayur MN, Gilani AH, Afridi MB, Houghton PJ. Cardiovascular effects of ginger aqueous extract and its phenolic constituents are mediated through multiple pathways. Vascul Pharmacol 2005; 43: 234-241
    CrossrefPubMedGoogle Scholar
  • 13 Liu Q, Liu J, Guo H, Sun S, Wang S, Zhang Y, Li S, Qiao Y. [6]-Gingerol: a novel AT1 antagonist for the treatment of cardiovascular disease. Planta Med 2013; 79: 322-326
    Article in Thieme ConnectPubMedGoogle Scholar
  • 14 Li Y, Aggarwal VH, Duke CC, Roufogalis BD. Gingerols of Zingiber officinale enhance glucose uptake by increasing cell surface GLUT4 in cultured L6 myotubes. Planta Med 2012; 78: 1549-1555
    Article in Thieme ConnectPubMedGoogle Scholar
  • 15 Yu Y, Zick S, Li X, Zou P, Wright B, Sun D. Examination of the pharmacokinetics of active ingredients of ginger in humans. AAPS J 2011; 13: 417-426
    CrossrefPubMedGoogle Scholar
  • 16 Zick SM, Djuric Z, Ruffin MT, Litzinger AJ, Normolle DP, Alrawi S, Feng MR, Brenner DE. Pharmacokinetics of 6-gingerol, 8-gingerol, 10-gingerol, and 6-shogaol and conjugate metabolites in healthy human subjects. Cancer Epidemiol Biomarkers Prev 2008; 17: 1930-1936
    CrossrefPubMedGoogle Scholar
  • 17 Wu Z, Liu H, Wu B. Regioselective glucuronidation of gingerols by human liver microsomes and expressed UDP-glucuronosyltransferase enzymes: reaction kinetics and activity correlation analyses for UGT1A9 and UGT2B7. J Pharm Pharmacol 2015; 67: 583-596
    CrossrefPubMedGoogle Scholar
  • 18 Falany CN, Roth JA. Properties of human cytosolic sulfotransferases involved in the drug metabolism. In: Jeffery HE, editor Human drug metabolism: from molecular biology to man. Boca Raton: CRC-Press; 1993: 101-115
    Google Scholar
  • 19 Mulder GJ, Jakoby WB. Sulfation. In: Mulder GJ, editor Conjugation reactions in drug metabolism. London: Taylor & Francis; 1990: 107-161
    Google Scholar
  • 20 Weinshilboum RM, Otterness DM. Sulfotransferase enzymes. In: Kaufman FC, editor Conjugation-deconjugation reactions in drug metabolism and toxicity. Berlin: Springer-Verlag; 1994: 45-78
    CrossrefGoogle Scholar
  • 21 Lipmann F. Biological sulfate activation and transfer. Science 1958; 128: 575-580
    CrossrefPubMedGoogle Scholar
  • 22 Veronese ME, Burgess W, Zhu X, McManus ME. Functional characterization of two human sulphotransferase cDNAs that encode monoamine- and phenol-sulphating forms of phenol sulphotransferase: substrate kinetics, thermal-stability and inhibitor-sensitivity studies. Biochem J 1994; 302: 497-502
    CrossrefPubMedGoogle Scholar
  • 23 Wilborn TW, Comer KA, Dooley TP, Reardon IM, Heinrikson RL, Falany CN. Sequence analysis and expression of the cDNA for the phenol-sulfating form of human liver phenol sulfotransferase. Mol Pharmacol 1993; 43: 70-77
    PubMedGoogle Scholar
  • 24 Wood TC, Aksoy IA, Aksoy S, Weinshilboum RM. Human liver thermolabile phenol sulfotransferase: cDNA cloning, expression and characterization. Biochem Biophys Res Commun 1994; 198: 1119-1127
    CrossrefPubMedGoogle Scholar
  • 25 Wang J, Falany JL, Falany CN. Expression and characterization of a novel thyroid hormone-sulfating form of cytosolic sulfotransferase from human liver. Mol Pharmacol 1998; 53: 274-282
    PubMedGoogle Scholar
  • 26 Her C, Kaur GP, Athwal RS, Weinshilboum RM. Human sulfotransferase SULT1C1: cDNA cloning, tissue-specific expression, and chromosomal localization. Genomics 1997; 41: 467-470
    CrossrefPubMedGoogle Scholar
  • 27 Sakakibara Y, Yanagisawa K, Katafuchi J, Ringer DP, Takami Y, Nakayama T, Suiko M, Liu MC. Molecular cloning, expression, and characterization of novel mouse sulfotransferase that catalyze the sulfonation of N-hydroxy-2-acetylaminofluorene. J Biol Chem 1998; 273: 33929-33935
    CrossrefPubMedGoogle Scholar
  • 28 Aksoy IA, Wood TC, Weinshilboum RM. Human liver estrogen sulfotransferase: identification by cDNA cloning and expression. Biochem Biophys Res Commun 1994; 200: 1621-1629
    CrossrefPubMedGoogle Scholar
  • 29 Falany CN, Vazquez ME, Kalb JM. Purification and characterization of human liver dehydroepiandrosterone sulphotransferase. Biochem J 1989; 260: 641-646
    CrossrefPubMedGoogle Scholar
  • 30 Otterness DM, Wieben ED, Wood TC, Watson WG, Madden BJ, McCormick DJ, Weinshilboum RM. Human liver dehydroepiandrosterone sulfotransferase: molecular cloning and expression of cDNA. Mol Pharmacol 1992; 41: 865-872
    PubMedGoogle Scholar
  • 31 Fuda H, Lee YC, Shimizu C, Javitt NB, Strott CA. Mutational analysis of human hydroxysteroid sulfotransferase SULT2B1 isoforms reveals that exon 1B of the SULT2B1 gene produces cholesterol sulfotransferase, whereas exon 1 A yields pregnenolone sulfotransferase. J Biol Chem 2002; 277: 36161-36166
    CrossrefPubMedGoogle Scholar
  • 32 Her C, Wood TC, Eichler EE, Mohrenweiser HW, Ramagli LS, Siciliano MJ, Weinshilboum RM. Human hydroxysteroid sulfotransferase SULT2B1: two enzymes encoded by a single chromosome 19 gene. Genomics 1998; 53: 284-295
    CrossrefPubMedGoogle Scholar
  • 33 Falany CN, Xie X, Wang J, Ferrer J, Falany JL. Molecular cloning and expression of novel sulphotransferase-like cDNAs from human and rat brain. Biochem J 2000; 346: 857-864
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 35 Jiang H, Somogyi A, Timmermann BN, Gang DR. Instrument dependence of electrospray ionization and tandem mass spectrometric fragmentation of the gingerols. Rapid Commun Mass Spectrom 2006; 20: 3089-3100
    CrossrefPubMedGoogle Scholar
  • 36 Tao Y, Li W, Liang W, Van Breemen RB. Identification and quantification of gingerols and related compounds in ginger dietary supplements using high-performance liquid chromatography-tandem mass spectrometry. J Agric Food Chem 2009; 57: 10014-10021
    CrossrefPubMedGoogle Scholar
  • 37 Riches Z, Stanley EL, Bloomer JC, Coughtrie MW. Quantitative evaluation of the expression and activity of five major sulfotransferases (SULTs) in human tissues: the SULT “pie”. Drug Metab Dispos 2009; 37: 2255-2261
    CrossrefPubMedGoogle Scholar
  • 38 Shwed JA, Walle UK, Walle T. HepG2 cell line as a human model for sulphate conjugation of drugs. Xenobiotica 1992; 22: 973-982
    CrossrefPubMedGoogle Scholar
  • 39 Chen X, Baker SM, Chen G. Methotrexate induction of human sulfotransferases in HepG2 and Caco-2 cells. J Appl Toxicol 2005; 25: 354-360
    CrossrefPubMedGoogle Scholar
  • 40 Miyano J, Yamamoto S, Hanioka N, Narimatsu S, Ishikawa T, Ogura K, Watabe T, Nishimura M, Ueda N, Naito S. Involvement of SULT1A3 in elevated sulfation of 4-hydroxypropranolol in HepG2 cells pretreated with beta-naphthoflavone. Biochem Pharmacol 2005; 69: 941-950
    CrossrefPubMedGoogle Scholar
  • 41 Westerink WM, Schoonen WG. Phase II enzyme levels in HepG2 cells and cryopreserved primary human hepatocytes and their induction in HepG2 cells. Toxicol In Vitro 2007; 21: 1592-1602
    CrossrefPubMedGoogle Scholar
  • 42 Li X, Pandak WM, Erickson SK, Ma Y, Yin L, Hylemon P, Ren S. Biosynthesis of the regulatory oxysterol, 5-cholesten-3beta, 25-diol 3-sulfate, in hepatocytes. J Lipid Res 2007; 48: 2587-2596
    CrossrefPubMedGoogle Scholar
  • 43 Dooley TP, Haldeman-Cahill R, Joiner J, Wilborn TW. Expression profiling of human sulfotransferase and sulfatase gene superfamilies in epithelial tissues and cultured cells. Biochem Biophys Res Commun 2000; 277: 236-245
    CrossrefPubMedGoogle Scholar
  • 44 Stanley EL, Hume R, Coughtrie MW. Expression profiling of human fetal cytosolic sulfotransferase involved in steroid and thyroid hormone metabolism and in detoxification. Mol Cell Endocrinol 2005; 240: 32-42
    CrossrefPubMedGoogle Scholar
  • 45 Teubner W, Meinl W, Florian S, Kretzschmar M, Glatt H. Identification and localization of soluble sulfotransferases in the human gastrointestinal tract. Biochem J 2007; 404: 207-215
    CrossrefPubMedGoogle Scholar
  • 46 Chen Y, Zhang C, Zhang M, Fu X. Assay of 6-gingerol in CO2 supercritical fluid extracts of ginger and evaluation of its sustained release from a transdermal delivery system across rat skin. Pharmazie 2014; 69: 506-511
    PubMedGoogle Scholar
  • 47 Yanagisawa K, Sakakibara Y, Suiko M, Takami Y, Nakayama T, Nakajima H, Takayanagi K, Natori Y, Liu MC. cDNA cloning, expression, and characterization of the human bifunctional ATP sulfurylase/adenosine 5′-phosphosulfate kinase enzyme. Biosci Biotechnol Biochem 1998; 62: 1037-1040
    CrossrefPubMedGoogle Scholar
  • 48 Sakakibara Y, Takami Y, Nakayama T, Suiko M, Liu MC. Localization and functional analysis of the substrate specificity/catalytic domains of human M-form and P-form phenol sulfotransferases. J Biol Chem 1998; 273: 6242-6247
    CrossrefPubMedGoogle Scholar
  • 49 Suiko M, Sakakibara Y, Liu MC. Sulfation of environmental estrogen-like chemicals by human cytosolic sulfotransferases. Biochem Biophys Res Commun 2002; 267: 80-88
    PubMedGoogle Scholar
  • 50 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 2002; 1573: 165-170
    CrossrefPubMedGoogle Scholar