The Clinical Effects of Synsepalum dulcificum : A Review

Abstract

Synsepalum dulcificum or the “miracle fruit” is well known for its taste-modifying ability. The aim of this review was to assess the published medically beneficial as well as potential characteristics of this fruit. A search in three databases, including PubMed, ScienceDirect, and Google Scholar, was made with appropriate keywords. The resulting articles were screened in different stages based on the title, abstract, and content. A total of nine articles were included in this review. This review summarized the findings of previously published studies on the effects of miracle fruit. The main studied characteristic of the fruit was its effect on the taste receptors, resulting in the sweet sensation when substances with acidic content were ingested. This effect was shown to be related to a glycoprotein called “miraculin.” Other beneficial characteristics of this fruit were its antioxidant and anticancer abilities that are due to the various amides existing in the miracle fruit. Apart from the above, the other observed effect of this fruit was its antidiabetic effect that was tested in rats. Further studies should be conducted to establish the findings. The miracle fruit can be a healthy additive due to its unique characteristics, including sour taste sensation modification as well as its antioxidant and antidiabetic effects.

Introduction

The Synsepalum dulcificum also known as Richardella dulcificum is the indigenous fruit of tropical West Africa.¹ Other local names of this fruit include miracle fruit or miracle berry, Pokok Ajaib in Malay language, and agbayun taami asaa and ledidi in West African languages.^2,3 This shrub grows either on the edge of virgin forests or in the farm and bushes. The edible pulp of the small, ellipsoid, bright red berry-like fruits of this plant was shown to have a wonderful ability to convert the sour taste into sweet taste by affecting the taste buds of the tongue.^1,4 Based on this characteristic, the fruit is also known as the “miracle fruit”.^1,4

Miracle fruit is rich in terpenoids (74.4%). The edible pulp surrounding the seed contains phenolic compounds (15.8%), flavonoids (11.9%), and an antioxidant activity (18.9%), while the skin contains higher amounts of phenolic compounds (36.7%), flavonoids (51.9%), and therefore, a higher antioxidant activity (22.6%) than the pulp.^5,6 The high content of flavonoids in the skin and pulp of the miracle fruit has led to the historical use of this fruit as a traditional remedy for diarrhea in humans and animals in Africa.^7,8 This fruit can also be served as a good source of antioxidants and was shown to reduce malignant cell proliferation in vitro.^6,9 The other special component of this fruit is a protein called miraculin.¹⁰ Miraculin is known to be responsible for the strange property of this fruit for altering the sour taste perception into a sweet one.¹⁰ This extraordinary property of the miracle fruit has long been known to the African tribes as well as the scientific community.¹¹ Some Western African tribes used miracle fruit in the process of flavoring beers as well as improving the palatability of sour sources of food.¹¹ Although this fruit has been traditionally used in its indigenous lands, it was neglected by the industrialized world.¹¹

Miracle fruit was considered as a potential food colorant due to the production of an orange-red color when added to carbonated water and sugar solutions.¹² Being accepted as an additive by the food and drug administration (FDA) facilitated further research on the miracle fruit.¹³ As the artificial sweeteners were found to be associated with plenty of side effects, the miracle fruit attracted the attention of the manufacturers of the sweeteners.^14,15 Miraculin was extracted and its gene has been transferred to other plants such as tomato and lettuce to facilitate mass production of this protein.^14,16 Thus, the miracle fruit was identified as a source of natural sweetener.^14,15 Unlike the studies on the sweetening effect of the miracle fruit, less work has been done on other clinical and medical properties of this fruit. The aim of this review was to identify the current properties of miracle fruit as well as its possible clinical values that need to be investigated.

Materials and Methods

To conduct this review, three scientific websites, including PubMed, Google Scholar, and ScienceDirect, were searched for relevant articles and reviews. The keywords that were used for the search included Synsepalum dulcificum, Richardella dulcificum, effects, human, and rat. The websites were primarily searched using the keywords and the search results were screened for relevancy to the research questions based on their title and abstract. The inclusion criteria for selecting articles were cross-sectional and randomized trials. Systematic reviews and meta-analyses that were published in the English language were also included in this review. Articles were excluded if they did not contain the complete instruction of the use of fruit extract or whole fruit in the methodology or did not report the observed effects of miracle fruit as a separate finding in studies that compared the effect of miracle fruit with other agents. The selected articles were finally investigated based on the methodology and analysis, the results were ranked based on the review criteria, and the key findings were used for the final conclusion of the review.

A total of 145 articles were found based on the search terms. This number reduced to 75 articles after excluding repeated works in the search results. Screening and evaluating the articles based on the content resulted in excluding 66 articles. The final articles used in this review were 9 articles, among which 1 was a review and 8 articles were original research works.

Results

The findings of the studies are categorized into three aspects, including the taste modification properties, antioxidant and anticancer effects, and antidiabetic effects, based on the main findings of the studies reviewed. The main findings of each study are shown in Table 1.

Table 1.

Summary of the Findings of the Studies

Author/year	Type of study	Part of the plant used	Findings
Bartoshuk/1974	Cross sectional	Whole fruit	Taste modification using hydrochloric and citric acids
Theerasilp/1989	Cross sectional	Whole fruit	Taste modification using different acids
			Duration of the effect was 30 min
Wong/2011	Randomized crossover trial	Fruit as additive to dessert	Improved acceptability of dessert
			Nondifferentiable taste from regular sweet dessert
Kurihara/1968	Cross sectional	Whole fruit	Extracted miraculin protein
			Identified chemical characteristics of the miraculin
Theerasilp/1989	Cross sectional	Whole fruit	Amino acid sequence of miraculin
Brouwer/1983	Cross sectional	Miraculin	Physiologic assessment of the mechanism of action of miraculin in monkeys
Chen/2009	Cross sectional	Pulp extract	Identified taste-modifying properties of miraculin
			Identified antioxidant and antityrosinase activity of the pulp extract
Kant/2005	Review	—	Molecular mechanism of action of miraculin in human
Wang/2011	Cross sectional	Stem of the plant	Identified amides content of miracle fruit
			Identified antioxidant and antityrosinase activity of the stem extract against human melanoma cells
Chen/2006	Cross sectional	Whole fruit in powder form	Reduced insulin resistance in rats fed with fructose-rich chow

Bartoshuk et al. were among the first to describe the taste-modifying effects of the miracle fruit.¹⁷ Although they were unable to describe the main component responsible for this effect, they could well identify the properties of the substance in taste modification.¹⁷ They reported the sour taste of the hydrochloric and citric acids, while this sensation was neutralized and tasted sour when Gymnema sylvestre was applied as antisweet.¹⁷ They could also find that the sweet taste sensation of different acids was different after consuming the miracle fruit.¹⁷ The same taste-modifying properties of the miracle fruit were reported in a later study by Theerasilp et al. ¹⁸ They reported that the taste-modifying effect of miracle fruit is effective on all acids and that the effect lasts for 30 min before it vanishes gradually.¹⁸

In a study by Wong and Kern, the sour taste-modifying effect of the miracle fruit was assessed in 13 subjects.¹⁹ In this randomized crossover trial, subjects were given a standard breakfast and lunch followed by four types of desserts, including lemon juice based normal or sucrose-sweetened popsicles and low sugar (named as DIET) version of popsicle with or without miracle fruit.¹⁹ Subjects were asked to rate the acceptability of popsicles using a hedonic scale, while sweetness and fullness were assessed using visual analogue scales.¹⁹ Wong and Kern reported that although there was no significant difference between the four types of desserts in terms of acceptability, subjects were unable to differentiate the regular popsicle from the DIET version mixed with miracle fruit.¹⁹ The substance related to the taste-modifying property of the miracle fruit was first separated and purified by Kurihara and Beidler.²⁰ The protein was identified as a 44-kDa basic glycoprotein.²⁰ The protein was named miraculin after the name of the miracle fruit.²⁰

The amino acid sequence of miraculin was determined by Theerasilp et al. ¹⁸ Miraculin was found to be a single polypeptide that consists of 192 amino acids.¹⁸ The mechanism of action of miraculin was assessed on monkeys by Brouwer et al. ¹⁰ They conducted their study with five different acids and found that the acceptability of the acids was increased when monkeys were pretreated with 0.3–0.5 mg miraculin.¹⁰ They also reported that the nerve response to acid was doubled, while the response to sucrose was reduced by 10% after the pretreatment with miraculin.¹⁰ This effect lasted for an hour and diminished within 20 min.¹⁰ Based on these findings, they suggested that the miraculin should have increased the sensitivity of the sweet-sensing cells to acids.¹⁰

Chen et al. reported the taste-modifying ability of miraculin with the application of the protein before testing the taste perception with citric acid, ascorbic acid, acetic acid, and hydrochloric acid, all of which produce a sour taste in humans.²¹ The molecular mechanism of action for miraculin was described by Kant.¹⁵ The main taste receptors (TRs) that are affected by miraculin are suggested to be the taste receptor type 1 member 2 and taste receptor type 1 member 3 (T1R2-T1R3).¹⁵ It was shown that the effect of miraculin along with other sweet proteins is made through shifting the equilibrium between the two forms of the T1R2-T1R3 toward the free form II.¹⁵

In a study by Chen et al., the antityrosinase activity was reported for the methanol solution extract of the fruit as well as the chloroform extract of the pulp of the miracle fruit.²¹ The antityrosinase effects were assessed basing on the hydroxylation of L-tyrosine to L-dopa according to the in vitro mushroom tyrosinase assay.²¹ The antioxidant activity of the extracts was assessed using the scavenging of 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical in vitro.²¹ Chen et al. revealed the antioxidant and anti-tyrosine effect for the two extracts of the miracle fruit.²¹

On the other hand, moderate in vitro radical scavenging and antioxidant activity, as well as tyrosinase inhibition effects were also reported for the extracted amides from the stem of the S. dulcificum.⁹ The scavenging and antioxidant effects of the amides derived from the plant were investigated by scavenging of DPPH free radicals mainly due to the amides derived from the stem of the S. dulcificum.⁹ These amides include dihydro-feruloyl-5-methoxytyramine, (+)-syringaresinol, (+)-epi-syringaresinol, 4-acetonyl-3,5-dimethoxy-p-quinol, cis-p-coumaric acid, trans-p-coumaric acid, p-hydroxybenzoic acid, syringic acid, vanillic acid, veratric acid, N-cis-feruloyltyramine, N-trans-feruloyltyramine, and N-cis-caffeoyltyramine.⁹ Moreover, the antityrosinase effects of (+)-syringaresinol and (+)-epi-syringaresinol were significant on human melanoma cells when assessed using the hydroxylation of L-tyrosine to L-dopa according to the in vitro mushroom tyrosinase assay.⁹

Only one study was found suggesting that the miracle fruit may improve the insulin resistance in rats.²² The insulin resistance was induced in rats by the administration of fructose-rich chow for 4 weeks.²² It was found that a single dose of 0.02, 0.04, and 0.2 mg/kg of miracle fruit powder resulted in reduced plasma glucose for 150 min.²² This effect was found to be dose related.²² Oral administration of 0.2 mg/kg of miracle fruit thrice daily for 3 days was found to reduce the raised value of the glucose–insulin index.²² Oral administration of the miracle fruit resulted in a delay in the loss of the plasma glucose-lowering response of tolbutamide (10.0 mg/kg) in fructose-rich chow-fed rats. After induction of diabetes in rats using the streptozocin (STZ), the glucose-lowering effects of miracle fruit administration were achieved to a higher extent and faster compared with the controls treated with metformin.²²

Discussion

S. dulcificum was first known for its taste-modifying property that made it a useful source in traditional food processing in the tropical regions of West Africa.^1,7,8,11 This fruit was known as an additive and food colorant in the developed world, but its taste-modifying character made it the subject of new research.¹² Due to the industrial need for artificial sweeteners, a great body of research was conducted on the sweetening properties of the miracle fruit.^15,16,19,21 Moreover, based on its chemical properties, this fruit is also hypothesized to be beneficial in other clinical and medical conditions.^6,9 This review summarized the findings of previously published articles on the effects and properties of the miracle fruit, as well as the possible properties of this fruit that should be investigated.

The taste-modifying properties of the miracle fruit is well established.^10,15,21 This effect is due to miraculin, a 44-kDa glycoprotein in the pulp of the fruit.^10,21 Miraculin categorizes a group of proteins that convey the sweet taste.¹⁵ These proteins include Brazzein, Thaumatin, Monelin, Curculin, Mabinlin, Miraculin, and Pentadin.¹⁵ The sweet receptors in the taste buds are parts of the TR family, among which the T1R2+T1R3 are responsible for the sweet taste.¹⁵ These receptors are composed of two heteromeric complexes that are coupled with G-protein receptors.¹⁵ The hypothetical mechanism of interaction between taste-modifying proteins and these receptors is different from that of small sweet molecules.^15,23,24 These receptors have two free forms; form I (open-open-R) that has two open sites for the binding ligand and free form II that has only one open site for a ligand to bind.^15,23,24 These forms are normally in equilibrium.^15,23,24 To activate the receptor, this equilibrium should be altered.^15,23,24 While the short sweetener molecules bind with an open site in form I, larger sweetener molecules such as the miraculin ligand with form II prevent it from reverting to form I.^15,23,24 Although much is known about the possible taste-modifying mechanism of sweet proteins, many aspects of their effect have still remained unknown.¹⁵ In summary, miraculin sensitizes the TRs to acids, thus inducing sweet sensation when sour acids are consumed.^10,15 The clinical benefits of the taste-modifying effect of miracle fruits have been studied in two fields, including the management of changes in taste perception in cancer patients who undergo chemotherapy as well as reducing the calorie intake of obese subjects in a low-calorie diet.^19,25,26 It was shown that the miracle fruit could improve the palatability of foods in cancer patients undergoing chemotherapy, although no changes in weight were observed.^25,26 These studies were small (4–12 subjects) and performed for a short duration (2 weeks) and therefore their results may not be strong enough to draw a conclusion. In contrast, the taste-modifying effect of the miracle fruit was successfully used to improve the palatability of low-calorie diets.¹⁹ Regarding the findings of the mentioned studies, it can be inferred that the use of miracle fruit in the diet may increase the palatability, but reduce the calorie intake at the same time, which makes it more difficult to make a suggestion for including this fruit or derivatives in the diet of chemotherapy patients. More studies are required to assess the pros and cons of the supplementation of miracle fruit to the diet of these patients.

The antioxidant effects of the fruit, stem, and seeds of the S. dulcificum have been hypothesized due to their high antioxidant content.^5,6,9,21 The antioxidant effects related to the consumption of this fruit are mainly related to its content of terpenoids and amides.^5,6,9 By scavenging free radicals, these components can produce an acceptable antioxidant and cancer protective effects.^5,6,9 Although the antioxidant capacity of the components of the miracle fruit is known, scarcity of supportive data from the laboratory and clinical experiments prevent us from identifying the actual antioxidant capacity of the fruit, seed, or stem of the S. dulcificum.^5,6

The miracle fruit has not yet been investigated for antidiabetic effects. The only study found was performed by Chen et al., where a glucose-lowering effect was observed by the administration of miracle fruit extract powder to fructose-rich chow-fed rats.²² The glucose-lowering property of the miracle fruit was hypothesized to be due to its ability to induce the sensitivity to endogenous insulin and thus delay the process of insulin resistance in rats.²² The fast glucose reduction effect of miracle fruit in comparison with metformin might result in hypoglycemia, which is identified with polyphagia in rats.²³ The study revealed an elevated body weight in rats after the period of study (213.2 g/rat in rats that received miracle fruit compared with 182.4 g/rat in the control group).²² More studies are needed to identify the substance responsible for this effect as well as the safety of this component in terms of hypoglycemia.

Conclusions

This study revealed that the miracle fruit can be used as an additive and sweetener with potential anticancer and antidiabetic effects. More research should be performed to ensure the efficacy of this fruit in higher primates and humans.

Footnotes

Acknowledgment

I am really bound to extend my immense respects and thanks to (1) Dato Prof. Dr. Alias Bin Daud, former Vice Chancellor for UniSZA, Kuala Terengganu, Malaysia; (2) Dato Prof. Dr. Khairul Anuar, Vice Chancellor, MAHSA University, Kuala Lumpur; (3) Dato Prof. Dr. Ahmad Zubaidi Bin A. Latif, Director, Hospitals, Kula Terengganu, Malaysia; (4) Prof. Dr. R.S. Rao, Professor and Head, Department of Biological Anthropology, Andhra University, India; and (5) Prof. Dr. Srijit Das, Professor of Anatomy, UKM, Kula Lumpur, Malaysia for their continuous encouragement, constant support, and unforgettable concern, which together kept me up in heights in my academic positions.

Author Disclosure Statement

No competing financial interests exist.

References

Opeke

: Tropical Tree Crops. Spectrum Books Ltd, Ibadan, 1992, pp. 312–313.

Wiersema

: Handbook of World Economic Plants: A Standard Reference. CRC Press, Boca Raton, 1999, pp. 661–662.

Hanelt

, Büttner

: Mansfeld's Encyclopedia of Agricultural and Horticultural Crops: (Except Ornamentals), Vol. 1. Springer, New York, NY, 2001, pp. 1660–1661.

Ogunsola

, Ilori

: In vitro propagation of miracle berry (Synsepalum dulcificu Daniel) through embryo and nodal cultures. Afr J Biotechnol, 2008; 7:244–248.

Ntie-Kang

, Lifongo

, Mbaze

, et al.: Cameroonian medicinal plants: a bioactivity versus ethnobotanical survey and chemotaxonomic classification. BMC Complement Altern Med, 2013; 13:147–165.

Inglett

, Chen

: Contents of phenolics and flavonoids and antioxidant activities in skin, pulp, and seeds of miracle fruit. J Food Sci, 2011; 76:479–482.

Offiah

, Makama

, Elisha

, et al.: Ethnobotanical survey of medicinal plants used in the treatment of animal diarrhoea in Plateau State, Nigeria. BMC Vet Res, 2011; 7:36.

Buckmire

, Francis

: Anthocyanins and flavonols of miracle fruit, Synsepalum dulcificum, Schum. J Food Sci, 1976; 41:1363–1365.

Wang

, Chou

, Hong

, et al.: Bioconstituents from stems of Synsepalum dulcificum Daniell (Sapotaceae) inhibit human melanoma proliferation, reduce mushroom tyrosinase activity and have antioxidant properties. J Taiwan Inst Chem Eng, 2011; 42:204–211.

10.

Brouwer

, Glaser

, Hard

, Seqerstad

, et al.: The sweetness-inducing effect of miraculin; behavioural and neurophysiological experiments in the rhesus monkey Macaca mulatta. J Physiol, 1983; 337:221–240.

11.

Inglett

, Dowling

, Albecht

, Hoglan

: Taste modifiers, taste-modifying properties of miracle fruit (Synsepalum dulcificum). J Agric Food Chem, 1965; 13:284–287.

12.

Buckmire

, Francis

: Pigments of miracle fruit, Synsepalum dulcificum, Schum, as potential food colorants. J Food Sci, 1978; 43:908–911.

13.

Small

, Catling

: Blossoming treasures of biodiversity: 20. Miracle tree—will wonders never cease!. Biodiversity, 2006; 7:21–26.

14.

Hiwasa-Tanase

, Hirai

, Duhita

, Ezura

: From miracle fruit to transgenic tomato: mass production of the taste-modifying protein miraculin in transgenic plants. Plant Cell Rep, 2012; 31:513–525.

15.

Kant

: Sweet proteins—potential replacement for artificial low calorie sweeteners. Nutr J, 2005; 4:1–6.

16.

Sun

, Cui

, Ma

, Ezura

: Functional expression of the taste-modifying protein, miraculin, in transgenic lettuce. FEBS lett, 2006; 580:620–626.

17.

Bartoshuk

, Gentile

, Molkowitz

, Melselman

: Sweet taste induced by miracle fruit (Synsepalum dulcificum). Physiol Behav, 1974; 12:449–456.

18.

Theerasilp

, Hititsuya

, Nakio

, et al.: Complete amino acid sequence and structure characterization of the taste-modifying protein, miraculin. J Biol Chem, 1989; 264:6655–6659.

19.

Wong

, Kern

: Miracle fruit improves sweetness of a low-calorie dessert without promoting subsequent energy compensation. Appetite, 2011; 56:163–166.

20.

Kurihara

, Beidler

: Taste-modifying protein from miracle fruit. Science, 1968; 161:1241–1243.

21.

Chen

, Wu

, Huang

, et al.: The sour taste-modifying protein (Miraculin), tyrosinase inhibitors and antioxidants from synsepalum dulcificum . Curr Nutr Food Sci, 2009; 5:172–179.

22.

Chen

, Liu

, Cheng

: Improvement of insulin resistance by miracle fruit (Synsepalum dulcificum) in fructose-rich chow-fed rats. Phytother Res, 2006; 20:987–992.

23.

Temussi

: Why are sweet proteins sweet? Interaction of brazzein, monellin and thaumatin with the T1R2-T1R3 receptor. FEBS Lett, 2002; 526:1–4.

24.

Kunishima

, Shimada

, Tsuji

, et al.: Structural basis of glutamate recognition by a dimeric metabotropic glutamate receptor. Nature, 2000; 407:971–977.

25.

Wilken

, Satiroff

: Pilot study of miracle fruit to improve food palatability for patients receiving chemotherapy. Clin J Oncol Nurs, 2012; 16:E173–E177.

26.

Soares

, Cusnir

, Schwartz

, et al.: Treatment of taste alterations in chemotherapy patients using the miracle fruit: preliminary analysis of a pilot study. J Clin Oncol (Meeting Abstracts), 2010; 28:e19523.