Czech J. Food Sci., 2016, 34(4):281-299 | DOI: 10.17221/335/2015-CJFS

Stevioside and rebaudioside A - predominant ent-kaurene diterpene glycosides of therapeutic potential: a reviewReview

Ena GUPTA1, Shalini PURWAR1, Shanthy SUNDARAM1, Prashasti TRIPATHI2, Gyanendra RAI1,2
1 Centre for Biotechnology and
2 Centre of Food Technology, University of Allahabad, Uttar Pradesh, India

Stevia rebaudiana (Bertoni) is a Paraguayan perennial herb of the family Asteraceae. The leaves contain a great amount of secondary metabolites with a wide range of important biological activities commonly known as steviol glycosides which differ in their molecular configuration, power of sweetness and their taste profile. Out of various steviol glycosides, the main compounds of interest are diterpenoid glycosides of ent-kaurene type extracted from the leaves of this plant as non-toxic, thermally stable, low-calorie natural sweeteners stevioside and rebaudioside A. These glycosides are a high-quality sugar substitute or dietary supplement with diverse applications in the medicinal world along with the food and beverage industry. This review article is aimed at the chemistry of stevioside and rebaudioside A, possible biosynthetic pathways, their metabolism and acceptable daily intake along with a broad spectrum of pharmacological and therapeutic applications.

Keywords: Stevia rebaudiana; secondary metabolites, therapeutic applications; sweetener

Published: August 31, 2016  Show citation

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GUPTA E, PURWAR S, SUNDARAM S, TRIPATHI P, RAI G. Stevioside and rebaudioside A - predominant ent-kaurene diterpene glycosides of therapeutic potential: a review. Czech J. Food Sci. 2016;34(4):281-299. doi: 10.17221/335/2015-CJFS.
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    References

    1. Abudula R., Matchkov V.V., Jeppesen P.B., Nilsson H., Aalkjaer C., Hermansen K. (2008): Rebaudioside A directly stimulates insulin secretion from pancreatic beta cells: a glucose dependent action via inhibition of ATP-sensitive K + -channels. Diabetes, Obesity and Metabolism, 10: 1074-1085. Go to original source... Go to PubMed...
    2. Ahmed B., Hossain M., Islam R., Kumar Saha A., Mandal A. (2011): A review on natural sweetener plant - stevia having medicinal and commercial importance. Agronomski glasnik, 73: 75-91.
    3. Atteh J., Onagbesan O., Tona K., Decuypere E., Geuns J., BuyseJ. (2008): Evaluation of supplementary Stevia (Stevia rebaudiana Bertoni) leaves and stevioside in broiler diets: Effects on feed intake, nutrient metabolism, blood parameters and growth performance. Journal of Animal Physiology and Animal Nutrition, 92: 640-649. Go to original source... Go to PubMed...
    4. Awney H.A., Massoud M.I., El-Maghrabi S. (2011): Longterm feeding effect of stevioside sweetener on some toxicological parameters of growing male rats. Journal of Applied Toxicology, 31: 431-438. Go to original source... Go to PubMed...
    5. Aze Y., Toyoda K., Imaida K., Hayashi S., Imazawa T., Hayashi Y., Takahashi M. (1991): Subchronic oral toxicity study of stevioside in F344 rats. Eisei Shikenjo Hokoku. Bulletin of National Institute of Hygienic Sciences, 109: 48-54. (in Japanese)
    6. Barriocanal L.A., Palacios M., Benitez G., Benitez S., Jimenez J.T., Jimenez N. (2008): Apparent lack of pharmacological effect of steviol glycosides used as sweeteners in humans. A pilot study of repeated exposures in some normotensive and hypotensive individuals and in Type 1 and Type 2 diabetics. Regulatory Toxicology and Pharmacology, 51: 37-41. Go to original source... Go to PubMed...
    7. Bergs D., Burghoff B., Joehnck M., Martin G., Schembecker G. (2012): Fast and isocratic HPLC-method for steviol glycosides analysis from Stevia rebaudiana leaves. Journal für Verbraucherschutz und Lebensmittelsicherheit, 7: 147-154. Go to original source...
    8. Bertoni M.S. (1918): La Stevia rebaudiana Bertoni. Anales Cientificos Paraguayos. Serie II, 2: 129-134.
    9. Bertoni M. (1905): Le kaa He-e-Sa nature et ses proprieties. Anales Cientificos Paraguayos. Serie I, 5: 1-14.
    10. Brandle B.E., Telmer P.G. (2007): Steviol glycoside biosynthesis. Phytochemistry, 68: 1855-1863. Go to original source... Go to PubMed...
    11. Brandle J.E., Richman A., Swanson A.K., Chapman B.P. (2002): Leaf ESTs from Stevia rebaudiana: a resource for gene discovery in diterpene synthesis. Plant Molecular Biology, 50: 613-622. Go to original source... Go to PubMed...
    12. Brusick D. (2008): A critical review of the genotoxicity of steviol and steviol glycosides. Food and Chemical Toxicology, 7: S83-S91. Go to original source... Go to PubMed...
    13. Carakostas M.C., Curry L.L., Boilea A.C., Brusick D. (2008): Overview: the history, technical function and safety of rebaudioside A, a naturally occurring steviol glycoside, for use in food and beverages. Food and Chemical Toxicology, 46: S1-S10. Go to original source... Go to PubMed...
    14. Chan P., Tomlinson B., Chen Y.J., Liu J.C., Hsieh M.H., Cheng J.T. (2000): A double-blind placebo-controlled study of the effectiveness and tolerability of oral stevioside in human hypertension. British Journal of Clinical Pharmacology, 50: 215-220. Go to original source... Go to PubMed...
    15. Chatsudthipong V., Muanprasat C. (2009): Stevioside and related compounds: therapeutic benefits beyond sweetness. Pharmacology and Therapeutics, 121: 41-54. Go to original source... Go to PubMed...
    16. Chatsudthipong V., Thongouppakarn P. (1995): Effect and mechanism of stevioside on rat renal function. The FASEB Journal, 9: A917-A917.
    17. Chaturvedula V.S.P., Prakash I. (2011): Diterpene glycosides from Stevia rebaudiana. Journal of Medicinal Plants Research, 5: 4838-4842.
    18. Chen T.H., Chen S.C., Chan P., Chu Y.L., Yang H.Y., Cheng J.T. (2005): Mechanism of the hypoglycemic effect of stevioside, a glycoside of Stevia rebaudiana. Planta Medica, 71: 108-113. Go to original source... Go to PubMed...
    19. Chester K., Tamboli E., Singh M., Ahmad S. (2012): Simultaneous quantification of stevioside and rebaudioside A in different samples collected from the Indian subcontinent. Journal of Pharmacy and Bioallied Sciences, 4: 276-281. Go to original source... Go to PubMed...
    20. Curry L., Roberts A., Brown N. (2008): Rebaudioside A: two-generation reproductive toxicity study in rats. Food and Chemical Toxicology, 46: S21-S30. Go to original source... Go to PubMed...
    21. Dacome A.S., Da Silva C.C., Da Costa C.E.M., Fontana J.D., Adelmann J., Da Costa S.C. (2005): Sweet diterpenic glycosides balance of a new cultivar of Stevia rebaudiana (Bert.) Bertoni: Isolation and quantitative distribution by chromatographic, spectroscopic, and electrophoretic methods. Process Biochemistry, 40: 3587-3594. Go to original source...
    22. Das A., Gantait S., Mandal N. (2011): Micropropagation of an elite medicinal plant: Stevia rebaudiana Bert. International Journal of Agricultural Research, 6: 40-48. Go to original source...
    23. Das S., Das A.K., Murphy R.A., Punwani I.C., Nasution M.P., Kinghorn A.D. (1992): Evaluation of the cariogenic potential of the intense natural sweeteners stevioside and rebaudioside A. Caries Research, 26: 363-366. Go to original source... Go to PubMed...
    24. Deshmukh S.R., Kedari V.R. (2014): Isolation, purification and characterization of sweetners from Stevia rebaudiana (Bertoni) for their anticancerous activity against colon cancer. World Journal of Pharmacy and Pharmaceutical Sciences, 3: 1394-1410.
    25. Felippe G.M., Lucas N.M.C. (1971): Estudo da viabilidade dos frutos de Stevia rebaudiana Bert. Hoehnea 1: 95-105. (in Portuguese, English abstract)
    26. FDA (2007): Letter Department of Health and Human Services. Food and Drug Administration to Hain Celestial Group Inc., Washington, DC. Aug 17, 2007. Available at www.fda.gov/foi/warning_letters/s6500c.htm
    27. Gardana C., Scaglianti M., Simonetti P. (2010): Evaluation of steviol and its glycosides in Stevia rebaudiana leaves and commercial sweetener by ultra high performance liquid chromatography-mass spectrometry. Journal of Chromatography A, 1217: 1463-1470. Go to original source... Go to PubMed...
    28. Geeraert B., Crombe F., Hulsmans M., Benhabiles N., Geuns J.M., Holvoet P. (2010): Stevioside inhibits atherosclerosis by improving insulin signaling and antioxidant defense in obese insulin-resistant mice. International Journal of Obesity, 34: 569-577. Go to original source... Go to PubMed...
    29. Geuns J.M.C., Buyse J., Vankeirsbilck A., Temme E.H.M. (2007): Metabolism of stevioside by healthy subjects. Experimental Biology and Medicine, 232: 164-173.
    30. Gregersen S., Jeppesen P.B., Holst J.J., Hermansen K. (2004): Antihyperglycemic effects of stevioside in type 2 diabetic subjects. Metabolism-Clinical and Experimental, 53: 73-76. Go to original source... Go to PubMed...
    31. Gupta E., Purwar S., Sundaram S., Rai G.K. (2013): Nutritional and therapeutic values of Stevia rebaudiana: a review. Journal of Medicinal Plants Research, 7: 3343-3353.
    32. Hagiwara A., Fukushima S., Kitaori M., Shibata M., Ito N. (1984): Effects of the three sweeteners on rats urinary bladder carcinogenesis initiated by N-butyl-N-(4hydroxybutyl)-nitrosamine. Gann Japanese Journal of Cancer Research, 75: 763-768.
    33. Hanson J.R., White A.F. (1968): Studies in terpenoid biosynthesis. II: The biosynthesis of steviol. Phytochemistry, 7: 595-597. Go to original source...
    34. Hashemi S.A., Allameh A., Daraei B., Peynevandi K.M., Pashazadeh R. (2014): The effect of rebadioside A on attenuation of oxidative stress in kidney of mice under acetaminophen toxicity. Iranian Journal of Toxicology, 7: 944-951.
    35. Hearn L.K., Subedi P.P. (2009): Determining levels of steviol glycosides in the leaves of Stevia rebaudiana by near infrared reflectance spectroscopy. Journal of Food Composition and Analysis, 22: 165-168. Go to original source...
    36. Helliwell C.A., Poole A., Peacock W.J., Dennis E.S. (1999): Arabidopsis ent-kaurene oxidase catalyzes three steps of gibberellin biosynthesis. Plant Physiology, 119: 507-510. Go to original source... Go to PubMed...
    37. Holvoet P., Rull A., Heredia A.G., López-Sanromà S., Geeraert B., Joven J., Camps J. (2015): Stevia-derived compounds attenuate the toxic effects of ectopic lipid accumulation in the liver of obese mice: A transcriptomic and metabolomics study. Food and Chemical Toxicology, 77: 22-33. Go to original source... Go to PubMed...
    38. Hong J., Chen L., Jeppesen P.B., Nordentoft I., Hermansen K. (2006): Stevioside counteracts the α-cell hypersecretion caused by long-term palmitate exposure. American Journal of Physiology - Endocrinology and Metabolism, 290: E416-E422. Go to original source... Go to PubMed...
    39. Hsieh M.H., Chan P., Sue Y.M., Liu J.C., Liang T.H., Huang T.Y., Tomlinson B., Chow M.S., Kao P.F., Chen Y.J. (2003): Efficacy and tolerability of oral stevioside in patients with mild essential hypertension, a two-year, randomized, placebo-controlled study. Clinical Therapeutics, 25: 2797-2808. Go to original source... Go to PubMed...
    40. Humbolt G., Boech E.M. (1977): Efeito do edulcorante natural (stevioside) e sinte'tico (sacarina) sobre oritmo cardiac em ratos. Arquios Brasileirosde Cardiologia, 30: 257-277.
    41. Humphrey T.V., Richman A.S., Menassa R., Brandle J.E. (2006): Spatial organisation of four enzymes from Stevia rebaudiana that are involved in steviol glycoside synthesis. Plant Molecular Biology, 61: 47-62. Go to original source... Go to PubMed...
    42. Hutapea A.M., Toskulkao C.H., Buddhasukh D., Wilairat P., Glinsukon T.H. (1997): Digestion of stevioside, a natural sweetener, by various digestive enzymes. Journal of Clinical Biochemistry and Nutrition, 23: 177-186. Go to original source...
    43. Jackson A.U., Tata A., Wu C., Perry R.H., Haas G., West L., Cooks R.G. (2009): Direct analysis of Stevia leaves for diterpene glycosides by desorption electrospray ionisation mass spectrometry. Analyst, 134: 867-874. Go to original source... Go to PubMed...
    44. JECFA (1999): Sweetening agent: stevioside. In: 51st Meeting Joint FAO/WHO Expert Committee on Food Additives (JECFA). World Health Organization, Geneva, Switzerland. WHO Food Additive Series, 42: 119-143. Available at http://www.inchem.org/documents/jecfa/ jecmono
    45. JECFA (2005): Steviol glycosides. In: 63 rd Meeting of the Joint FAO/WHO Expert Committee on Food Additives, Geneva: World Health Organization (WHO), Geneva, Switzerland, WHO Technical Report Series 928: 34- 39 and 138. Available at http://whqlibdoc.who.int/trs/WHO_TRS_928.pdf
    46. JECFA (2007) Evaluation of Certain Food Additives and Contaminants. 68th Report of the Joint FAO/WHO Expert Committee on Food Additives. World Health Organization (WHO), Geneva, Switzerland. WHO Technical Report Series No. 947: 50-54. Available at http://whqlibdoc.who.int/trs/WHO_TRS_947.pdf
    47. JECFA (2010): Steviol glycosides. Compendium of Food Additive Specifications FAO JECFA Monographs 10. General Specifications for Enzymes Analytical Methods. Vol. 4. Rome, Food and Agriculture Organization of the United Nations (FAO), Joint FAO/WHO Expert Committee on Food Additives (JECFA), Geneva. Available at http://www. fao. org/ag(agnj ecfa-additive s/vec s/ monograph 1 Wadditive-44 2-m 1 0.pdf
    48. Jeppesen P.B., Gregersen S., Poulsen C.R., Hermansen K. (2000): Stevioside acts directly on pancreatic β-cells to secrete insulin; Actions independent of cyclic adenosine monophosphate and adenosine triphosphate-sensitive K+-channel activity. Metabolism - Clinical and Experimental, 49: 208-214. Go to original source... Go to PubMed...
    49. Jeppesen P.B., Gregersen S., Alstrup K.K., Hermansen K. (2002): Stevioside induces antihyperglycaemic, insulinotropic and glucagonostatic effects in vivo: studies in the diabetic Goto-Kakizaki (GK) rats. Phytomedicine, 9: 9-14. Go to original source... Go to PubMed...
    50. Jeppesen P.B., Gregersen S., Rolfsen S.E., Jepsen M., Colombo M., Agger A., Xiao J., Kruhøffer M., Orntoft T., Hermansen K. (2003): Antihyperglycemic and blood pressure-reducing effects of stevioside in the diabetic Goto-Kakizaki rat. Metabolism - Clinical and Experimental, 52: 372-378. Go to original source... Go to PubMed...
    51. Joint FAO/WHO Expert Committee on Food Additives (1999): Toxicological evaluation of certain food additives. Geneva, WHO Food Additives Series, No. 10: 119-143.
    52. Jutabha P., Toskulkao C., Chatsudthipong V. (2000): Effect of stevioside on PAH transport by isolated perfused rabbit renal proximal tubule. Canadian Journal of Physiology and Pharmacology, 78: 737-744. Go to original source...
    53. Kim K.K., Sawa Y., Shibata H. (1996): Hydroxylation of entkaurenoic acid to steviol in Stevia rebaudiana Bertoni - purification and partial characterization of the enzyme. Archives of Biochemistry and Biophysics, 332: 223-230. Go to original source... Go to PubMed...
    54. Kinghorn A.D., Soejarto D.D. (1985): Current status of stevioside as a sweetening agent for human use. In: Wagner H., Hikino H., Farnsworth N.R. (eds): Economics and Medicinal Plant Research. Vol. 1. London, Academic Press: 1-52.
    55. Klongpanichpak S., Temcharoen P., Toskulkao C., Apibal S., Glinsukon T. (1997): Lack of mutagenicity of stevioside and steviol in Salmonella typhimurium TA 98 and TA 100. Journal of Medical Association of Thailand, 80 (Supplement 1): S121-S128.
    56. Konoshima T., Takasaki M. (2002): Cancer-chemopreventive effects of natural sweeteners and related compounds. Pure and Applied Chemistry, 74: 1309-1316. Go to original source...
    57. Koubaa M., Roselló-Soto E., ®labur J.S., Jambrak A.R., Brnčić M., Grimi N., Boussetta N., Barba F.J. (2015): Current and new insights in the sustainable and green recovery of nutritionally valuable compounds from Stevia rebaudiana Bertoni. Journal of Agricultural and Food Chemistry, 63: 6835-6846. Go to original source... Go to PubMed...
    58. Koyama E., Kitazawa K., Ohori Y., Izawa O., Kakegawa K., Fujino A., Ui M. (2003): In vitro metabolism of the glycosidic sweeteners, Stevia mixture and enzymatically modified Stevia in human intestinal microflora. Food and Chemical Toxicology, 41: 359-374. Go to original source... Go to PubMed...
    59. Kujur R.S., Singh V., Ram M., Yadava H.N., Singh K.K., Kumari S., Roy B.K. (2010): Antidiabetic activity and phytochemical screening of crude extract of Stevia rebaudiana in alloxan-induced diabetic rats. Pharmacognosy Research, 2: 258-263. Go to original source... Go to PubMed...
    60. Lailerd N., Saengsirisuwan V., Sloniger J.A., Toskulkao C., Henriksen E.J. (2004): Effects of stevioside on glucose transport activity in insulin-sensitive and insulinresistant rat skeletal muscle. Metabolism-Clinical and Experimental, 53: 101-107. Go to original source... Go to PubMed...
    61. Lee C.N., Wong K.L., Liu J.C., Chen Y.J., Cheng J.T., Chan P. (2001): Inhibitory effect of stevioside on calcium influx to produce antihypertension. Planta Medica, 67: 796-799. Go to original source... Go to PubMed...
    62. Lemus-Mondaca R., Vega-Galvez A., Zura-Bravo L., AhHen K. (2012): Stevia rebaudiana Bertoni, source of a high-potency natural sweetener: a comprehensive review on the biochemical, nutritional and functional aspects. Food Chemistry, 132: 1121-1132. Go to original source... Go to PubMed...
    63. Londhe S.V., Nanaware S.M. (2013): HPTLC method for simultaneous analysis of stevioside and rebaudioside-A in Stevia rebaudiana. Journal of AOAC International, 96: 24-26. Go to original source... Go to PubMed...
    64. Maki K.C., Curry L.L., Carakostas M.C., Tarka S.M., Reeves M.S., Farmer M.V., McKenney J.M., Toth P.D., Schwartz S.L., Lubin B.C., Dicklin M.R., Boileau A.C., Bisognano J.D. (2008): The hemodynamic effects of rebaudioside A in healthy adults with normal and low-normal blood pressure. Food and Chemical Toxicology, 46: S40-S46. Go to original source... Go to PubMed...
    65. Matsui M., Matsui K., Kawasaki Y., Oda Y., Nogushi T., Kitagawa Y., Sawada M., Hayashi M., Nohmi T., Yoshihira K., Ishidate J.R.M., Sofuni T. (1996): Evaluation of the genotoxicity of stevioside and steviol using six in vitro and one in vivo mutagenicity assays. Mutagenesis, 11: 573-579. Go to original source... Go to PubMed...
    66. Mauri P., Catalano G., Gardana C., Pietta P. (1996): Analysis of Stevia glycosides by capillary electrophoresis. Electrophoresis, 17: 367-371. Go to original source... Go to PubMed...
    67. Medon P.J., Pezzuto J.M., Havanec-Brown J.M., Nanayakkara N.P., Soejarto D.D., Kamath S.K. (1982): Safety assessment of some Stevia rebaudiana sweet principles. In: Abstracts of Papers 66th Annual Meeting, New Orleans, Louisiana Federation Proceedings, 41: 1568.
    68. Melis M.S. (1992): Stevioside effect on renal function of normal and hypertensive rats. Journal of Ethnopharmacology, 36: 213-217. Go to original source... Go to PubMed...
    69. Melis M.S., Maciel R.E., Sainati A.R. (1985): Effects of indomethacin on the action of stevioside on mean arterial pressure and renal function in rats. IRCS Medical Science-Biochemistry, 13: 1230-1231.
    70. Melis M.S., Sainati A.R. (1991): Effect of calcium and verapamil on renal function of rats during treatment with stevioside. Journal of Ethnopharmacology, 33: 257-262. Go to original source... Go to PubMed...
    71. Mizushina Y., Akihisa T., Ukiya M., Hamasaki Y., MurakamiNakai C., Kuriyama I., Takeuchi T., Sugawara F., Yoshida H. (2005): Structural analysis of isosteviol and related compounds as DNA polymerase and DNA topoisomerase inhibitors. Life Sciences, 77: 2127-2140. Go to original source... Go to PubMed...
    72. Monteiro R. (1980): Taxonomia e biologia da reproducao da Stevia rebaudiana Bert. [PhD. Thesis.] Universidate Estadual de Campinas, Brazil.
    73. Mori N., Sakanoue M., Takeuchi M., Shimpo K., Tanabe T. (1981): Effects of stevioside on fertility in rats. Journal of the Food Hygienic Society of Japan, 22: 409-414. Go to original source...
    74. Mosetting E., Beglinger U., Dolder F., Lichti H., Quilt P., Waters J.A. (1963): Absolute configuration of steviol and isosteviol. Journal of the American Chemical Society, 85: 2305-2305. Go to original source...
    75. Murashige T., Skoog F. (1962): A revised medium of rapid growth and essays within tobacco tissue culture. Physiologia Plantarum, 15: 473-497. Go to original source...
    76. Murch S.J., Krishna R.S., Saxena P.K. (2000): Tryptophan as a precursor for melatonin and serotonin biosynthesis in in-vitro regenerated St. John's ort (Hypericum perforatum cv. Anthos) plants. Plant Cell Reports, 19: 698-704. Go to original source... Go to PubMed...
    77. Nakajima (2000a): Chromosome aberration assay of Rebaudioside A in cultured mammalian cells. Test Number 5001 (079-085). Unpublished report of a study conducted at the Biosafety Research Center, Japan. Submitted to WHO by Ministry of Health and Welfare, Japan. Cited in: JECFA 2005.
    78. Nakajima (2000b): Micronucleus test of Rebaudioside A in mice. Test Number 5002 (079-086). Unpublished report of a study conducted at the Biosafety Research Center, Japan. Submitted to WHO by Ministry of Health and Welfare, Japan. Cited in: JECFA 2005.
    79. Nakamura Y., Sakiyama S., Takenaga K. (1995): Suppression of syntheses of high molecular weight nonmuscle tropomyosins in macrophages. Cell Motility and the Cytoskeleton, 31: 273-282. Go to original source... Go to PubMed...
    80. Paul S., Sengupta S., Bandyopadhyay T.K., Bhattacharyya A. (2012): Stevioside induced ROS-mediated apoptosis through mitochondrial pathway in human breast cancer cell line MCF-7. Nutrition and Cancer, 64: 1087-1094. Go to original source... Go to PubMed...
    81. Pezzuto J.M., Compadre C.M., Swanson S.M., Nanayakkara N.P.D., Kinghorn A.D. (1985): Metabolically activated steviol, the aglycone of stevioside, is mutagenic. Proceedings of the National Academy of Sciences of the United States of America, 82: 2478-2482. Go to original source... Go to PubMed...
    82. Pichersky E., Gershenzon J. (2002): The formation and function of plant volatiles: perfumes for pollinator attraction and defense. Current Opinion in Plant Biology, 5: 237-243. Go to original source... Go to PubMed...
    83. Planas G.M., Kuc J. (1968): Contraceptive properties of Stevia rebaudiana. Science, 162: 1007. Go to original source... Go to PubMed...
    84. Pól J., Hohnová B., Hyötyläinen T. (2007): Characterization of Stevia rebaudiana by comprehensive two-dimensional liquid chromatography time-of-flight mass spectrometry. Journal of Chromatography A, 1150: 85-92. Go to original source... Go to PubMed...
    85. Potzel A., Brouns F. (2012): Stevia: a natural opportunity. 38 The World of Food Ingredients, February 2012: 38-40.
    86. Renwick A.G., Tarka S.M. (2008): Microbial hydrolysis of steviol glycosides. Food and Chemical Toxicology, 46: S70-S74. Go to original source... Go to PubMed...
    87. Richman A.S., Gijzen M., Starratt A.N., Yang Z., Brandle J.E. (1999): Diterpene synthesis in Stevia rebaudiana: recruitment and up-regulation of key enzymes from the gibberellin biosynthetic pathway. Plant Journal, 19: 411-421. Go to original source... Go to PubMed...
    88. Roberts A., Renwick A.G. (2008): Comparative toxicokinetics and metabolism of rebaudioside A, stevioside, and steviol in rats. Food and Chemical Toxicology, 46: S31-S39. Go to original source... Go to PubMed...
    89. Sakaguchi M., Kan T. (1982): Japanese researches on Stevia rebaudiana (Bert.) Bertoni and stevioside. Ci Cult, 34: 235-248.
    90. Salvador R.R., Sotelo M.H., Paucar L.M. (2014): Study of Stevia (Stevia rebaudiana Bertoni) as a natural sweetener and its use in health benefit. Scientia Agropecuaria, 5: 157-163. Go to original source...
    91. Saravanan R., Ramachandran V. (2013): Modulating efficacy of Rebaudioside A, a diterpenoid on antioxidant and circulatory lipids in experimental diabetic rats. Environmental Toxicology and Pharmacology, 36: 472-483. Go to original source... Go to PubMed...
    92. SCF (1985): Reports of the Scientific Committee on Food (SCF) Concerning Sweeteners, 16 th Series (Opinion Expressed 14 September 1984). In: Food Science and Techniques. Commission of the European Communities (EEC), Health and Consumer Protection DirectorateGeneral, Brussels, Belgium. Available at http://www.europa.eu.int/comm/food/fs/sc/scf/reports/scf_reports_16.pdf
    93. SCF (1999a): Opinion on Stevioside as a Sweetener (Adopted on 17/6/99), Scientific Committee on Food (SCF). European Commission, Health and Consumer Protection Directorate-General, Brussels, Belgium. Available at http://www.europa.eu.int/comm/food/fs/sc/scf/out34_en.pdf
    94. SCF (1999b): Opinion on Stevia rebaudina Bertoni Plant and Leaves (Adopted on 17/6/ 99), Scientific Committee on Food (SCF). European Commission, Health and Consumer Protection Directorate-General, Brussels, Belgium, CS/NF/STEV/3 Final. Available at http://www.europa.eu.int/comm/food/fs/sc/scf/out36_en.pdf
    95. Sekihashi K., Saitoh H., Sasaki Y.F. (2002): Genotoxicity studies of stevia extract and steviol by the comet assay. The Journal of Toxicological Sciences, 27: 1-8.
    96. Shibata H., Sonoke S., Ochiai H., Nishihashi H., Yamada M. (1991): Glucosylation of steviol and steviol-glycosides in extracts from Stevia rebaudiana Bertoni. Plant Physiology, 95: 152-156. Go to original source... Go to PubMed...
    97. Shibata H., Sawa Y., Oka T., Sonoke S., Kim K.K., Yoshioka M. (1995): Steviol and steviol-glycosides: glucosyltranferase activities in Stevia rebaudiana Bertoni: Purification and partial characterization. Archives of Biochemistry and Biophysics, 321: 390-396. Go to original source... Go to PubMed...
    98. Sloter E.D. (2008): Oral (Gavage) Study of Chrysanta ® 99-P on Embryo/Fetal Development in Rats. WIL Research Laboratories, LLC. [Unpublished Report.] Study Number WIL-568004.
    99. Solecki R.S. (1975): Shanidar IV, a Neanderthal flower burial in northern Iraq. Science, 190: 880-881. Go to original source...
    100. Steinmetz W.E., Lin A. (2009): NMR studies of the conformation of the natural sweetener rebaudioside A. Carbohydrate Research, 344: 2533-2538. Go to original source... Go to PubMed...
    101. Stoyanova S., Geuns J., Hideg E., Van den Ende W. (2011): The food additives inulin and stevioside counteract oxidative stress. International Journal of Food Sciences and Nutrition, 62: 207-214. Go to original source... Go to PubMed...
    102. Suttajit M., Vinitketkaumnuen U., Meevatee U., Buddhasukh D. (1993): Mutagenicity and human chromosomal effect of stevioside, a sweetener from stevia rebaudiana Bertoni. Environmental Health Perspectives (Supplement), 101: S53-S56. Go to original source...
    103. Tada A., Ishozuki K., Iwamura J., Mikami H., Hirao Y., Fujita I., Yamazaki T., Akiyama H., Kawamura Y. (2013): Improvement of the assay method for steviol glycosides in the JECFA specification. American Journal of Analytical Chemistry, 4: 190-196. Go to original source...
    104. Takahashi K., Sun Y., Yanagiuchi I., Hosokawa T., Saito T., Komori M., Okino T., Kurasaki M. (2012): Stevioside enhances apoptosis induced by serum deprivation in PC12 cells. Toxicology Mechanisms and Methods, 22: 243-249. Go to original source... Go to PubMed...
    105. Takanaka T., Kawashima K., Usami M., Sakami K. (1991): A teratological study of stevioside administered orally to rats. Unpublished report from Department of Pharmacology, Biological Safety Research Center, National Institute of Hygienic Sciences, Japan. Submitted to WHO by Ministry of Health and Welfare, Food Chemistry Division, Japan.
    106. Takasaki M., Konoshima T., Kozuka M., Tokunda H., Takayasu J., Nishino H., Miyakoshi M., Mizutani K., Lee K.H. (2009): Cancer preventive agents. Part 8: Chemopreventive effects of stevioside and related compounds. Bioorganic and Medicinal Chemistry, 17: 600-605. Go to original source... Go to PubMed...
    107. Tirapelli C.R., Dos Anjos Neto Filho M., Bonaventura D., Melo M.C., Ambrosio S.R., De Oliveira A.M., Bendhack L.M., Da Costa F.B. (2008): Pimaradienoic acid inhibits vascular contraction and induces hypotension in normotensive rats. Journal of Pharmacy and Pharmacology, 60: 453-459. Go to original source... Go to PubMed...
    108. Tirapelli C.R., Ambrosio S.R., De Oliveira A.M., Tostes R.C. (2010): Hypotensive action of naturally occurring diterpenes: A therapeutic promise for the treatment of hypertension. Fitoterapia, 81: 690-702. Go to original source... Go to PubMed...
    109. Toffler F., Orio O.A. (1981): Acceni sulla pinata tropicale 'Kaa-he-e' o 'erba dulce'. Rivista della Societa Italiana di Scienza dell'Alimentazione, 10: 225-230.
    110. Toskulkao C., Deechakawan W., Temcharoen P., Buddhasukh D., Glinsukon T. (1994): Nephrotoxic effects of stevioside and steviol in rat renal cortical slices. Journal of Clinical Biochemistry and Nutrition, 16: 123-131. Go to original source...
    111. Toyoda K., Matsui H., Shoda T., Uneyama C., Takada K., Takahashi M. (1997): Assessment of the carcinogenicity of stevioside in F344 rats. Food and Chemical Toxicology, 35: 597-603. Go to original source... Go to PubMed...
    112. Urban J.D., Carakostas M.C., Brusick D.J. (2013): Steviol glycoside safety: Is the genotoxicity database sufficient? Food and Chemical Toxicology, 51: 386-390. Go to original source... Go to PubMed...
    113. Usami M., Sakemi K., Kawashima K., Tsuda M., Ohno Y. (1995): Teratogenicity study of stevioside in rats. Eisei Shikenjo Hokoku - Bulletin of National Institute of Hygienic Sciences, 113: 31-35.
    114. Wang L., Goh B., Fan L., Lee H. (2004): Sensitive highperformance liquid chromatography/mass spectrometry method for determination of steviol in rat plasma. Rapid Communications in Mass Spectrometry, 18: 83-86. Go to original source... Go to PubMed...
    115. Wanke M., Tudek K.S., Swiezewska E. (2001): Isoprenoid biosynthesis via 1-deoxy-d-xylulose 5-phosphate/2-Cmethyl-d-erythritol 4-phosphate (DOXP/MEP) pathway. Acta Biochimca Polonica, 48: 663-672. Go to original source...
    116. Williams L.D., Burdock G.A. (2009): Genotoxicity studies on a high purity rebaudioside A preparation. Food and Chemical Toxicology, 47: 1831-1836. Go to original source... Go to PubMed...
    117. Wingard R., Brown J., Enderlin F., Dale J., Hale R., Seitz C. (1980): Intestinal degradation and absorption of the glycosidic sweeteners stevioside and rebaudioside A. Experientia, 36: 519-520. Go to original source... Go to PubMed...
    118. Woelwer-Rieck U., Lankes C., Wawrzun A., Wüst M. (2010): Improved HPLC method for the evaluation of the major steviol glycosides in leaves of Stevia rebaudiana. European Food Research and Technology, 231: 581-588. Go to original source...
    119. Xili L., Chengjiany B., Eryi X., Reiming S., Yuengming W., Haodong S., Zhiyan H. (1992): Chronic oral toxicity and carcinogenicity study of stevioside in rats. Food and Chemical Toxicology, 30: 957-965. Go to original source... Go to PubMed...
    120. Yadav S.K., Guleria P. (2012): Steviol glycosides from Stevia: biosynthesis pathway review and their application in foods and medicine. Critical Reviews in Food Science and Nutrition, 52: 988-998. Go to original source... Go to PubMed...
    121. Yamada A., Ohgaki S., Noda T., Shimizu M. (1985): Chronic toxicity study of dietary Stevia extracts in F344 rats. Journal of the Food Hygienic Society of Japan, 26: 169-183. Go to original source...
    122. Yasukawa K., Kitanaka S., Seo S. (2002): Inhibitory effect of stevioside on tumor promotion by 12-O-tetradecanoylphorbol-13-acetate in two-stage carcinogenesis in mouse skin. Biological and Pharmaceutical Bulletin, 25: 1488-1490. Go to original source... Go to PubMed...
    123. Yilmaz M., Turkdemir H., Kilic M.A., Bayram E., Cicek A., Mete A., Ulug B. (2011): Biosynthesis of silver nanoparticles using leaves of Stevia rebaudiana. Materials Chemistry and Physics, 130: 1195-1202. Go to original source...
    124. Yodyingyuad V., Bunyawong S. (1991): Effect of stevioside on growth and reproduction. Human Reproduction, 6: 158-165. Go to original source... Go to PubMed...
    125. ®labur J.S., Voća S., Dobričević N., Brnčić M., Dujmić F., Brnčić S.R. (2015): Optimization of ultrasound assisted extraction of functional ingredients from Stevia rebaudiana Bertoni leaves. International Agrophysics, 29: 231-237. Go to original source...

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