Digestion of Stevioside, a Natural Sweetener, by Various Digestive Enzymes.

Hutapea, Albert M.; Toskulkao, Chaivat; Buddhasukh, Duang; Wilairat, Prapin; Glinsukon, Thirayudh

doi:10.3164/jcbn.23.177

Cited by 102 publications

(90 citation statements)

References 19 publications

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“…Although steviol glycosides share a common metabolic fate in both rats and humans (Wingard et al, 1980;Hutapea et al, 1997;Gardana et al, 2003;Koyama et al, 2003a;Geuns et al, 2007;Roberts and Renwick, 2008;Wheeler et al, 2008;Nikiforov et al, 2013;Purkayastha et al, 2014Purkayastha et al, , 2015Purkayastha et al, , 2016, some differences in pharmacokinetics have been noted. As evaluated by JECFA at their sixty-ninth meeting (JECFA, 2009), studies comparing the pharmacokinetics of steviol and steviol glucuronide following oral administration of steviol glycosides demonstrated substantial differences in the concentration of circulating plasma steviol and steviol glucuronide between rats and humans (Roberts and Renwick, 2008;Wheeler et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

“…Steviol glycosides pass undigested through the upper gastrointestinal tract to the colon where they are hydrolyzed to steviol by sequential removal of one sugar moiety at a time, prior to absorption of steviol (Wingard et al, 1980;Hutapea et al, 1997;Gardana et al, 2003;Koyama et al, 2003a,b;Geuns et al, 2003Geuns et al, , 2007Renwick and Tarka, 2008;Purkayastha et al, 2015). In rats (Roberts and Renwick, 2008), pigs (Geuns et al, 2003) and humans Wheeler et al, 2008) exposures to the parent steviol glycosides are negligible following oral exposure.…”

Section: Introductionmentioning

confidence: 99%

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Chemical-specific adjustment factors (inter-species toxicokinetics) to establish the ADI for steviol glycosides

Roberts

Lynch

Rogerson

et al. 2016

Regulatory Toxicology and Pharmacology

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Abbreviations: λz, terminal elimination constant; ADI, acceptable daily intake; AUC0-last, area under the curve from time zero until the last sampling time point; AE, adverse events; AUC, area under the plasma concentration-time curve; AUC-0.75-inf, AUC from time zero to infinity; AUClast, AUC to the last quantifiable observation; BLQ, below the limit of quantification; BMI, body mass index; bw, body weight; Cmax, concentration maximum; CSAF, chemical-specific adjustment factor; EE, efficacy evaluable population; EKG, electrocardiogram; HBsAg, hepatitis B surface antigen; IQR, interquartile range; IRB, Institutional Review Board; JECFA, Joint FAO/WHO Expert Committee on Food Additives; LC-MS/MS, liquid chromatography-tandem mass spectrometry; LLOQ, lower limit of quantification, LOQ, limit of quantification; NOAEL, noobserved-adverse-effect level; PP, per protocol population; SD, standard deviation; T1/2, half-life; Tmax, time to maximum concentration; WHO, World Health Organization * Corresponding author: Tel: +1-905-542-2900 E-mail address: ashley.roberts@intertek.com AbstractThe acceptable daily intake (ADI) of commercially available steviol glycosides is currently 4 mg/kg body weight (bw)/day, based on application of a 100-fold uncertainty factor to a noobserved-adverse-effect-level value from a chronic rat study. Within the 100-fold uncertainty factor is a 10-fold uncertainty factor to account for inter-species differences in toxicokinetics (4-fold) and toxicodynamics (2.5-fold). Single dose pharmacokinetics of stevioside were studied in rats (40 and 1,000 mg/kg bw) and in male human subjects (40 mg/kg bw) to generate a chemical-specific, inter-species toxicokinetic adjustment factor. Tmax values for steviol were at ~8 and ~20 hours after administration in rats and humans, respectively. Peak concentrations of steviol were similar in rats and humans, while steviol glucuronide concentrations were significantly higher in humans. Glucuronidation in rats was not saturated over the dose range 40-1,000 mg/kg bw. The AUC0-last for steviol was approximately 2.8-fold greater in humans compared to rats. Chemical-specific adjustment factors for extrapolating toxicokinetics from rat to human of 1 and 2.8 were established based on Cmax and AUC0-last data respectively. Because these factors are lower than the default value of 4.0, a higher ADI for steviol glycosides of between 6 to 16 mg/kg bw/d is justified.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Chemical-specific adjustment factors (inter-species toxicokinetics) to establish the ADI for steviol glycosides

Roberts

Lynch

Rogerson

et al. 2016

Regulatory Toxicology and Pharmacology

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“…Alternatively, stevioside is degraded by the bacterial flora of the caecum or colon producing free steviol which is further converted into its glucuronide derivative in the liver and excreted from the body through urine (Geuns et al 2007). An in vitro method of digesting steviosides by various digestive enzymes was studied by Hutapea et al (1997) and it was found that none of the enzymes digested the stevioside but the microflora present in the intestinal tract hydrolysed the stevioside to further compounds steviol and steviol-16,17alpha-epoxide. Eventually, steviol-16,17alpha-epoxide was then completely transformed back into steviol and excreted as steviol glucuronide from the body in urine (Chatsudthipong & Muanprasat 2009).…”

Section: Biotransformationmentioning

confidence: 99%

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

Gupta¹,

Purwar²,

Sundaram³

et al. 2016

Czech J. Food Sci.

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Gupta E., Purwar S., Sundaram S., Tripathi P., Rai G. (2016): Stevioside and rebaudioside A -predominant ent-kaurene diterpene glycosides of therapeutic potential -a review. Czech J. Food Sci., 34: 281-299.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.

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“…The metabolism of stevioside (purity not reported) was studied by using various digestive enzymes or 8 fluids like salivary α-amylase, pancreatic α-amylase, saliva, pepsin, gastric secretion, pancreatin and 9 intestinal brush border membrane enzymes of rodents as well as by the intestinal microflora of various 10 species including humans (Hutapea et al, 1997). None of these enzymes digested stevioside.…”

Section: Efsa Ans Panel Evaluation:mentioning

confidence: 99%

Scientific Opinion on Flavouring Group Evaluation 310 (FGE.310): Rebaudioside A from chemical group 30

Flavourings¹

2011

EFS2

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The Panel on Food Contact Materials, Enzymes, Flavourings and Processing Aids of the European Food Safety Authority was requested to evaluate rebaudioside A .113], a steviol glycoside. The substance was not considered to have genotoxic potential. Since a comprehensive and adequate toxicological database, including human studies, is available for steviol glycosides, the Panel based its evaluation of rebaudioside A on a comparison of the ADI of 4 mg/kg bw, expressed as steviol, established by EFSA, with the estimated dietary exposure figures based on the MSDI and mTAMDI approaches. The Panel concluded that rebaudioside A would not give rise to safety concerns at the estimated level of intake arising from its use as flavouring substance. It has been reported that the flavouring substance occurs naturally in Stevia rebaudiana, up to 16200 -72700 mg/kg, depending on plant species.The flavouring substance is included in the specifications for the food additive (sweetener) steviol glycosides which has recently been evaluated by both the JECFA (JECFA, 2009a) and EFSA (EFSA, 2010k). The flavouring substance rebaudioside A ] is closely related structurally to stevioside. Both compounds contain the same aglycon steviol, the only difference being that rebaudioside A contains an extra glucose molecule in the glycoside moiety. Steviol glycosides are chemically defined mixtures that comprise not less than 95 % stevioside and/or rebaudioside A. Both the JECFA and EFSA established an ADI for steviol glycosides (including rebaudioside A), expressed as steviol equivalents, of 4 mg/kg bw/day.In its evaluation, the Panel as a default used the "Maximised Survey-derived Daily Intake" (MSDI) approach to estimate the per capita intakes of the flavouring substances in Europe. However, when the Panel examined the information provided by the European Flavouring Industry on the use levels in various foods, it appeared obvious that the MSDI approach in a number of cases would grossly underestimate the intake by regular consumers of products flavoured at the use level reported by the Industry, especially in those cases where the annual production values were reported to be small. In consequence, the Panel had reservations about the data on use and use levels provided and the intake estimates obtained by the MSDI approach.In the absence of more precise information that would enable the Panel to make a more realistic estimate of the intakes of the flavouring substances, the Panel has decided also to perform an estimate of the daily intakes per person using a "modified Theoretical Added Maximum Daily Intake" (mTAMDI) approach based on the normal use levels reported by Industry. In those cases where the mTAMDI approach indicated that the intake of a flavouring substance might exceed its corresponding threshold of concern, the Panel decided not to carry out a formal safety assessment using the Procedure. In these cases the Panel requires more precise data on use and use levels. According to the default MSDI approach, the substance has a ...

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Digestion of Stevioside, a Natural Sweetener, by Various Digestive Enzymes.

Abstract: which hydrolyzed it to both steviol and steviol-16,17ƒ¿-epoxide. Steviol-16,17ƒ¿-epoxide was then completely converted back into steviol. These results suggest that steviol might be the only metabolite produced by the intestinal microflora from various animal species and humans.

Cited by 102 publications

References 19 publications

Chemical-specific adjustment factors (inter-species toxicokinetics) to establish the ADI for steviol glycosides

Chemical-specific adjustment factors (inter-species toxicokinetics) to establish the ADI for steviol glycosides

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

Scientific Opinion on Flavouring Group Evaluation 310 (FGE.310): Rebaudioside A from chemical group 30

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