Sweetness and Sweeteners - American Chemical Society

Chapter 38

Stevioside: A Safe Sweetener and Possible New Drug for the Treatment of the Metabolic Syndrome

Downloaded by UNIV OF PITTSBURGH on October 28, 2015 | http://pubs.acs.org Publication Date: March 4, 2008 | doi: 10.1021/bk-2008-0979.ch038

Jan M. C. Geuns Laboratory Functional Biology, K U Leuven, 3001 Leuven, Belgium

Steviol glycosides used in low amounts for sweetening purposes are safe. Their absorption by the intestines is very low. They are degraded to steviol by bacteria of the colon. Part of this steviol is absorbed and transformed into steviol glucuronide that is excreted in the urine. No accumulation in the body seems to exist. N o harmful effects of steviol glycosides have been published in the scientific litterature. A D I values have been suggested by calculations made from published results. High doses of steviol glycosides (750 1500 mg/day) may have beneficial pharmacological effects as lowering the blood pressure of hypertensive patients, lowering the blood glucose in diabetes type 2. In animal models, they have anti-carcinogenic effects. It is not proven that they have similar effects in man, as the intake as a sweetener will be very low.

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© 2008 American Chemical Society

In Sweetness and Sweeteners; Weerasinghe, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2008.

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Stevioside and rebaudioside A are the main sweeteners extracted from Stevia rebaudiana (Bertoni) Bertoni, although many other compounds with varying degrees of sweetness are present in the mixture extracted (/). As all the sweeteners are degraded to steviol by bacteria of the colon, the mixture of sweeteners should be called steviol glycosides. Stevioside and rebaudioside A taste about 300 times sweeter than sucrose (0.4% solution). Their structure is given in Figure 1. Rebaudioside A has one β-glucose unit more than stevioside.

Figure 1. Structures of stevioside and rebaudioside A

The incidence of diabetes type 2, obesitas and hypertension is sharply increasing, due to too much sugar, fat and salt intake and the addition of taste enhancers (eg. glutamates). A U this is accompanied by a lack of physical exercise. The yearly costs of these diseases were estimated to be 5 billion euro in Belgium and over 230 billion euro in Europe and the costs are probably about the same in the U S A (Geuns, unpublished). This sum includes the money for drugs, for hospitalisation, amputations, eye diseases going to blindness, treatment of heart and blood circulation problems, special diets, dental care, costs of the medical staff and so on. This estimation of the yearly costs does not include social aspects (e.g. inability to work) and human suffering. Stevioside is a good substitute for table sugar. From the beginning, a clear-cut distinction should be made between low doses of steviol glycosides for sweetening purposes, and high doses in which case beneficial pharmacological effects might occur, but that should be administered preferably under medical surveyance.


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This chapter will deal with the following points. •

Steviol glycosides used as a sweetener, in L O W doses (maximum 200-300 mg/day).

•

Stevioside used in H I G H doses for its pharmacological effects. Here we will discuss effects on blood pressure, diabetes type 2 and anticarcinogenic effects.

•

Steviol glucuronide will be suggested as the active principle provoking the pharmacological effects of high doses.

Steviol glycosides as a sweetener There are several advantages in using Stevia or steviol glycosides as a sweetener. It is a completely natural product; steviol glycosides contain no calories; the leaves of Stevia can be used in their natural state; thanks to the enormous sweetening power of steviol glycosides, only small quantities need to be used; the plant is non-toxic; the leaves as well as the steviol glycosides can be cooked; they have a little bit a licorice-like aftertaste; they are stable when heated up to 200 °C; they are non fermentative and flavour enhancing, they were clinically tested and used in several countries without negative effect; they are an ideal, non-addictive sweetener for children. Several toxicological studies have been performed as well as metabolism studies that will shortly be discussed in this chapter, as well as the ADI.

Uptake and metabolism studies It has been shown that oral stevioside and rebaudioside A were not taken up by the human body or the uptake was extremely low (2-4) and none of the digestive enzymes from the gastro-intestinal tract of different animals and man were able to degrade stevioside into steviol, the aglycone of stevioside (2,5). Nevertheless, in feeding experiments with rats and hamsters stevioside was metabolized to steviol by the bacterial flora of the caecum. Free steviol was found in the blood of the animals with the maximum concentration occurring after 8 hours (6,7). Studies with roosters (8) and chickens (laying hens and broilers) (9) indicated that stevioside was rapidly eliminated from the body, largely untransformed. Bacteria isolated from the human colon were able to transform stevioside into steviol in vitro (5,7,10). In vivo stevioside degradation to steviol occurred by bacterial action in the colon of pigs (5) and humans (7775). Among the selected intestinal groups, bacteroidaceae were the most efficient in hydrolyzing Stevia sweeteners to steviol (70). Steviol was the only metabolite in the feces (3, 77-75). Stevioside or free steviol were not detected in blood plasma, but steviol glucuronide was found in a maximum concentration of 67


599 μ§/πιΙ. (21.3 μg steviol equivalents/mL) (72,75). In urine, no stevioside or free steviol were present, but steviol glucuronide was found in amounts up to 318 mg/24 h urine (205 mg steviol equivalents/24 h). No other steviol derivatives were detected (72,75).


ADI Many toxicological studies have proven that steviol glycosides are safe (for review see 14). N o effects were found of steviol glycosides or steviol on carcinogenicity, on reproduction/fertility or reproductive organs. There were no teratogenic effects or effects on the embryo, as also evidenced by recent work with chicken embryo's (75). Steviol formed in the colon is easily excreted in urine as SV glucuronide. There is no accumulation in the body. No other harmful metabolites are formed (72,75). Moreover, many plant gibberellins, a group of plant hormones, are very similar to steviol and also possess a 16-methylene group and 13-hydroxyl function as also found in steviol (Figure 2). This combination is suspected of induction of mutagenic effects of steviol in S. typhimurium TM677 (7).

GAI

GA3

Figure 2. Examples of the structures ofgibberellines (GAI, GA3) with a 16-methylene group and a 13-OH function.

No effects of steviol glycosides could be found on bio-availability of nutrients from the diet. Stevioside used as a sweetener is safe for diabetics (type 2), phenylketonuria patients (PKU) as well as for Candida patients. It is beneficial for persons with hypertension, is not carcinogenic, not cariogenic and no allergenicity problems are known, nor are they expected as the compounds resemble the plant gibberellins that are daily eaten by the whole world population! There is a safe use in Japan, U S A , South Korea, Brazil, Paraguay, Israel and still other countries. We summarised suggested values for the Allowable Daily


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Table I. Suggested A D I (mg/kg B W ) and N O A E L (mg/kg B W ) . The duration of the experiments is given in months. ADI (mg/kg BW) 7.938* 25 25 25 25 6.25** 5.5* « 12.5*** 25*** K

5(2mgSVeq)

Organism Wistar rat rat rat rat rat hamster rat F344 man man man

NOAEL (mg/kg) 794 2500 2500 2500 2500 250** 550 = 12.5 «25

Duration (in months) 24 3 3 3 # generations 22

Sweetness and Sweeteners - American Chemical Society

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