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Home , Betalain, Opuntia matudae, Vulgaxanthin

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Betalains: Chemistry and Biological Functions Armando Carrillo-López,1∗ Elhadi M. Yahia2

1Posgrado en Ciencia y Tecnología de Alimentos, Universidad Autónoma de Sinaloa, Blvd de las Américas y Josefa Ortiz de Domínguez, Ciudad Universitaria, , Culiacán, Sinaloa, CP 80013, Mexico 2Facultad de Ciencias Naturales, Universidad Autónoma de Querétaro, Avenida de las Ciencias S/N, Juriquilla, Querétaro, 76230 Qro., Mexico

17.1 Introduction activity of , which has been associated with protection against degenerative diseases. Currently, there Fruits and vegetables are an important part of the human is general consensus (at least in theory) that diseases, such diet, and a source of energy, minerals, vitamins, and as cancer, that originate in or are aggravated by oxidative . Diets rich in such products reduce incidence stress, may be mitigated by compounds found and mortality by cancer, cardiovascular disorders, and in the diet (Yahia, 2010). In addition, a role for betalains chronic diseases caused by oxidative stress (Yahia, 2010). pigments in chemoprevention against lung and skin The protection of human health is attributed mainly to cancers has been documented (Kapadia et al., 1996). It the presence of different nutritional and functional com- has been reported that natural food colors such as ponents, such as vitamins C and E, and pigments can inhibit the proliferation of a variety of human tumor such as , , , and cells (Reddy et al., 2005). This review synthesizes the betalains. Although, over the centuries, plant pigments published literature on the basic chemistry of betalains have been utilized in the prevention and treatment of a and their sources, chemical stability, and functional variety of human diseases, only in the past few years have properties. the potential health benefits received renewed attention by the scientific community. This is largely due to the recent findings that pigments act as natural antioxidants, 17.1.1 Definition exhibiting powerful free radical scavenging properties with potentials for prevention and cure of a variety of Betalains are compounds derived from via beta- diseases associated with oxidative stress. It has been lamic acid. They include betacyanins (reddish to violet proven that different sources of betalains such as prickly pigments) and betaxanthins (yellow to orange pigments) pear, , Amaranthus tricolor, and red have and are found in the order of and properties related to anticarcinogenic, antioxidative, some basidiomycetes (Guaadaoui et al., 2014). They are hypoglycemic, and immunomodulatory effects, all of natural water-soluble, -containing pigments which could be directly relevant for health benefits. whose chemical structure is based on the immonium Betalains are natural pigments from plants that are of conjugates of betalamic acid with cyclo-DOPA and amino growing interest as substitutes for synthetic dyes in the acids or amines. Their core structure is represented by the food and pharmaceutical industry, and they will increase protonated 1,2,4,4,7-pentasubstituted 1,7-diazaheptame- their value if they possess additional positive effects on thin system which is responsible for their chroma (Strack health. Betalains are water-soluble, nitrogen-containing et al., 2003). pigments composed of two structural groups: the red- violet betacyanins and the yellow-orange betaxanthins. Several reports have demonstrated the potent antioxidant 17.1.2 Classification

Betalains classification is commonly based on their chem- ∗ Corresponding author. ical structure and characteristics, and depends on the

Fruit and Vegetable : Chemistry and Human Health, Volume I, Second Edition. Edited by Elhadi M. Yahia. © 2017 John Wiley & Sons Ltd. Published 2017 by John Wiley & Sons Ltd. C17 06/07/2017 3:55:54 Page 384

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substitution of the 1,7-diazaheptamethin moiety. Accord- Beetroot Prickly pear ing to this, there are two categories of betalains: betacya- nins and betaxanthins. The former include the red-purple pigments, whereas the latter include the yellow pigments. Betacyanin structures exhibit variations in the acyl groups and sugar moieties, while betaxanthin structures exhibit the same dihydropyridine moiety but show conjugation with several amines and amino acids (Delgado-Vargas et al., 2000).

Betalains from beetroot Betalains most abundantly found in prickly pear 17.1.3 Sources

Betalains are present in the order Caryophyllales of higher Betalains: Betalains: plants and some genera of fungi. Mabry et al. (1963) - Betanin - Betanin reported that 10 families of Caryophyllales (Aizoaceae, - Isobetanin - Isobetanin , Basellaceae, Cactaceae, Chenopodia- - Betanidin - Betanidin ceae, Didiereaceae, Halophytaceae, Nyctaginaceae, Phy- - Gomphrenin I tolaccaceae, and Portulacaceae) have been shown to Betaxanthins: Betaxanthins: produce betalains. Khan and Giridhar (2015) mentioned - I - that about 75 betalains have been structurally identified - Vulgaxanthin II - Muscaaurin from plants of about 17 out of the 34 families within the order Caryophyllales. In fungi, betalains have also been shown to be present in the genera Amanita, Hygrocybe, Figure 17.1 Betalains from beetroot () and prickly pear fi and Hygrophorus (Steglich and Strack, 1990; Strack et al., fruit ( cus-indica)(Sources: beetroot, Chethana et al., 2007; prickly pear, Castellanos-Santiago and Yahia, 2008). 1993). Betalains are accumulated in cell , mainly in epidermal and subepidermal tissues in a variety of plant structures such as flowers of Portulacaceae plants, fruits of Opuntia spp., roots of Beta vulgaris, bracts of Bougain- 17.2 Chemistry and Biochemistry villea spp., seeds of Amaranthus spp., and leaves and stems of Teloxys spp. (Delgado-Vargas et al., 2000). The 17.2.1 Isolation main known edible sources of betalains are red beet (Kanner et al., 2001; Stintzing and Carle, 2004), prickly Betalains can be extracted from macerated raw material pear (Butera et al., 2002; Stintzing et al., 2001), with pure water (cold or at room temperature), but (Kugler et al., 2004), grains or leaves (Cai et al., methanol and ethanol solutions at 20–50% v/v improved 2005), pitaya (Hylocereus spp.) (Vaillant et al., 2005; the extraction (Piatelli, 1981). The addition of ascorbic Herbach et al., 2006), ulluco tubers ( tuberosus) acid (c. 50 mM) to aqueous methanol as extraction (Svenson et al., 2008), djulis (Chenopodium formosanum), medium has been recommended (Schliemann et al., a cereal native to Taiwan (Tsai et al., 2010, 2011), and 1999) in order to stabilize the betacyanin molecules garambullo (Myrtillocactus geometrizans), a plant with a slightly acidic pH, but also to inhibit the potential endemic to and widely consumed in Mexico (Moreno betacyanin oxidation by polyphenoloxidases and to avoid et al., 2008; González-Nava, 2010). González-Nava (2010) high tyrosinase activities when betaxanthins are present reported for garambullo a level of 233 mg/kg fruit pulp of (Steiner et al., 1999). In the case of materials rich in free total betalains, which is higher than those for Opuntia sugars, aerobic juice fermentation with Saccharomyces cultivars ‘Red’ and ‘Orange’ at 114.1 and 90.6 mg/kg, cerevisiae is needed in order to deplete the free sugars and respectively; however, it is less than that for ‘Purple’ at to obtain a higher yield in the extraction process (Pourrat 431.6 mg/kg, as reported by Stintzing et al. (2005). Cas- et al., 1988). The purification of betalains can be done tellanos-Santiago and Yahia (2008) studied 10 Mexican using conventional anion-exchange column chromatog- cultivars of prickly pear and quantified 8.1 mg/g dw of raphy (Gandía-Herrero et al., 2006) or size-exclusion total betalains in prickly pear ‘Camuesa’ (Opuntia robusta chromatography prior to NMR identification (Khan Wendl.), a result comparable to the 8.6 mg/g dw they and Giridhar, 2015). Dark conditions and low tempera- found in red beet ‘Pablo’ (Beta vulgaris L.). Figure 17.1 ture in the laboratory are recommended during the shows specific betalains found in Beta vulgaris and Opun- isolation process of betalains in order to avoid pigment tia ficus-indica. degradation (Delgado-Vargas et al., 2000). C17 06/07/2017 3:55:54 Page 385

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17.2.2 Structure Tyrosine

Hydroxylation and oxidation Chemical structures of betalains are based on the immo- Tyrosine hydrolase nium conjugates of betalamic acid with cyclo-DOPA and amino acids or amines (Strack et al., 2003). The betala- L-DOPA mic acid is the chromophore of all the pigments, Oxidation and DOPA dioxygenase and the nature of the residue (cyclo-DOPA or amino- O2-dependent cleavage acid/amine) that is condensed to betalamic acid deter- mines the type of betalain, i.e. betacyanin or betaxanthin 4,5-seco-DOPA (Azeredo, 2009). In betacyanins the betalamic acid con- denses with cyclo-DOPA (cyclo-3,4-dihydroxyphenyla- Spontaneous cyclization lanine residue), while in betaxanthins the betalamic acid condenses with an amino-acid/amine or derivatives Betalamic Cyclo-DOPA + + Amino acid/amine (Strack et al., 2003). Betalains may be considered to acid be amphiphilic-like compounds, since this property derived from their chemical nature could explain the observed charge-related interaction with polar head groups of membrane constituents. Betanin and indicax- Betacyanin Betaxanthin anthin have shown antioxidant activity in biological lipid environments in vitro, for example, in human low- Figure 17.2 General biosynthetic pathway of betalains (adapted density lipoproteins and cell membranes (Kanner from Khan and Giridhar, 2015; reproduced with permission of et al., 2001; Tesoriere et al., 2003, 2005). The interaction Elsevier). of the betalain molecules with the lipid structures has been considered to be the basis of such an activity. Betanin and indicaxanthin can bind to biological mem- pH Huang and von Elbe (1987) reported that the hue branes, and to either dipalmitoyl-phosphatidylcholine or color parameter from betalains is unaffected in the pH large unilamellar soybean phosphatidylcholine lipo- range 3.5 to 7. This is an acidic range within which most somes (Kanner et al., 2001; Tesoriere et al., 2006). foods are included. In particular, betanin showed that its stability is pH dependent, and in this case Huang and von Elbe (1987) showed that the pH for maximum betanin 17.2.3 Biosynthesis stability ranges from 5.5 to 5.8 when oxygen is present. On the other hand, red beet solutions showed their maximum Betalain synthesis has as first step the simultaneous stability at pH 5.5, which is the normal pH for beets. Also, hydroxylation and oxidation of tyrosine by tyrosine vulgaxanthin-I was most stable between pH 5.0 to 6.0, hydroxylase to form DOPA (L-3,4-dihydroxiphenylala- being more stable in juice than in purified extracts, nine) and the subsequent oxidation and cleavage of the whereas reconstituted powders showed optimal pigment aromatic ring of DOPA by DOPA-dioxygenase to pro- stability at pH 5.7 (Singer and von Elbe, 1980). duce 4,5-seco-DOPA, which exhibits a spontaneous cycli- zation and becomes betalamic acid (Khan and Giridhar, Temperature According to Drdák and Vallová (1990), 2015). Tyrosine hydroxylase is a bifunctional enzyme that temperature has showed a clear effect on betalain stability. hydrolyzes and oxidizes tyrosine, whereas DOPA-dioxy- Heating of betanin solutions produces a gradual reduc- genase performs an O2-dependent cleavage of the aro- tion of red color, and eventually the appearance of a light matic ring of DOPA. From betalamic acid, various brown color (Delgado-Vargas et al., 2000). A first-order spontaneous cyclization, molecule condensation, and reaction kinetics for betanin degradation by heating was glycosylation steps are carried out in order to complete observed by von Elbe et al. (1974). the formation of betalains. Figure 17.2 shows a general schematic pathway of betalains biosynthesis. Light Von Elbe et al. (1974) found that the rate of betanin degradation increased 15.6% after the exposure of pig- ment to daylight at 15 °C, following a first-order kinetic 17.2.4 Stability reaction. Furthermore, the degradation was higher at pH 3.0 (k = 0.35/day) than at pH 5.0 (k = 0.11/day) when Several factors have been recognized to affect the stability betacyanins were exposed to fluorescent light. However, of these pigments, including pH, temperature, light, oxy- betacyanins were most stable (k = 0.07/day) in dark con- gen, and water activity. ditions (Sapers and Hornstein, 1979). C17 06/07/2017 3:55:54 Page 386

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Oxygen Betanin reacts with molecular oxygen, produc- 17.4.2 Anti-inflammatory Response ing pigment degradation in air-saturated solutions (Attoe and von Elbe, 1985). It was observed by von Elbe et al. Inactivation of COX-2 is of relevance in the modulation of (1974) that color degradation increased up to 15% due to the inflammatory response due to its effect in the synthe- air conditions when betanin buffered solutions at neutral sis of prostaglandins and related molecules (Hata and pH were stored under an atmosphere of air and nitrogen Breyer, 2004). Vidal et al. (2014) explored the possible for 6 days at 15 °C. inactivation of the key enzymes involved in the inflam- matory response (LOX and COX) by natural pure beta- Water Activity It has been established that water activity lains. They obtained pure betalains from natural plant aw has a pronounced exponential effect on pigment products, betanin from roots of Beta vulgaris, dopaxan- stability, which decreased by one order of magnitude thin from yellow flowers of Lampranthus productus, and fl when aw was increased from 0.32 to 0.75 (Cohen and betanidin from violet owers also of Lampranthus pro- Saguy, 1983). Water activity has been included among the ductus. Natural betalains inhibited the activity of the primary factors affecting betalain stability and/or the enzymes LOX and COX which are involved in the inflam- color of food products containing these pigments (von matory response. Increasing concentrations of betanidin Elbe, 1987). The greatest stability of betalains has been provoked a significant reduction in the activity of LOX in reported in foods or model systems with low moisture and a dose-dependent manner (0 to 350 μM). Betanidin and aw (Cohen and Saguy, 1983). The increase in stability of dopaxanthin, which are dihydroxylated betalains, dem- betanin with decreasing aw may be attributed to reduced onstrated a considerable reduction in the LOX activity at mobility of reactants or limited oxygen solubility. both tested pH values (6 and 9), with a total lack of activity observed for betanidin at pH 9.0. On the other hand, betanin showed a significant reduction in COX-2 activity 17.3 Physiological Properties in after 30 min of incubation at 125 μM. Molecular docking Plants studies revealed that betalains interact with specific amino acid residues in the active site of COX and with 17.3.1 Interaction with Biotic and Abiotic Factors relevant amino acids in the surface of LOX responsible for substrate binding. The interaction of betalains with them Betalains accumulate in different parts of plants such as might cause the decrease in the enzyme activities meas- flowers, fruits, roots, bracts, seeds, leaves, and stems ured after incubation (Vidal et al., 2014). Since a correla- (Delgado-Vargas et al., 2000; Strack et al., 2003; Nemzer tion between inflammatory response and tumor et al., 2011), where they play important physiological formation has been described, and the inhibition of roles. Betacyanin synthesis in red beet (Beta vulgaris) LOX and COX by anti-inflammatory drugs reduced the leaves is induced by wounding and bacterial infiltration, prevalence of certain types of cancer (Schneider and as a protective response by the plant against the damage Pozzi, 2011), betalains may also reduce this prevalence. caused by mechanical injury or UV radiation, but beta- In this sense, betalains have been reported to significantly lains also act as attractive pigments that favor pollination reduce the formation of tumors in vivo (Lechner et al., and seed dispersal (Sepúlveda-Jiménez et al., 2004). 2010).

17.4.3 Antioxidant Activity and Action against Oxidative 17.4 Functional Properties and Benefits Stress to Human Health An interesting study carried out by Cai et al. (2005) 17.4.1 Bioavailability showed that betalain pigments from Amaranthaceae exhibited strong antioxidant activity when evaluated by Betanin bioavailability in humans was demonstrated with the DPPH (1,1-diphenyl-2-picrylhydrazyl) method. The four volunteers who consumed 300 mL of red beet juice, strongest antioxidant activity was shown by gomphre- containing 120 mg of the antioxidant. The betacyanins nin-type betacyanins (EC50 3.7 μM) and betaxanthins were absorbed from the gut and identified in urine after (EC50 4.2 μM), the activity being threefold to fourfold 2–4 h. The calculated amount of betacyanins found in the stronger than ascorbic acid (EC50 13.9 μM) and also urine was 0.5–0.9% of that ingested. Because of their stronger than rutin (EC50 6.1 μM) and (EC50 bioavailability, red beet products used regularly in the 7.2 μM).Caietal.(2005)orderedthelevelsofantiox- diet may provide protection against certain oxidative idant activity of the tested betalains from high to low as stress-related disorders in humans (Kanner et al., 2001). follows: simple gomphrenins > acylated gomphrenins C17 06/07/2017 3:55:54 Page 387

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> dopamine-betaxanthin > (S)--betaxanthin IC50 of 40 μM. The pigment was able to enter the K562 > 3-methoxytyramine-betaxanthin > betanin/isobeta- cells and alter mitochondrial membrane integrity, leading nin > celosianins > iresinins > amaranthine/isoamar- to cytochrome-C leakage, activation of caspases, and anthine. Cai et al. (2005) also studied the relationship nuclear disruption. They observed ultrastructural between the chemical structure and the antioxidant changes typical of apoptotic cells. Betanin was shown activity of the betalains, and concluded that the free to be a potent inhibitor in the growth of tumor cell lines radical scavenging activity of the betalains usually when tested against breast, colon, stomach, central ner- increased with the numbers of hydroxyl/imino groups, vous system, and lung tumor cells. It showed a dose- with dependence on the position of hydroxyl groups dependent growth inhibition at concentrations ranging and glycosylation of aglycones in the betalain mole- from 12.5 to 200 μg/mL. Interestingly, the efficacy in cules. The C-5 position of the hydroxyl group on inhibition of tumor cell growth by betanin was remarkably aglycones in the betalain molecules significantly reduced when it was administered in combination with improved activity, whereas more glycosylation of agly- (Reddy et al., 2005). Lee et al. (2014) showed cones clearly reduced the activity. The strong free that betanin purified from beetroot has anticancer activ- radical scavenging capacity of betalains and its modu- ity, especially against HepG2 cells at relatively high con- lation by different structural factors is well docu- centration of betanin. In an in vitro study, cancer cell mented, according to Gandía-Herrero et al. (2010) cytotoxicity was evaluated using a 3-(4,5-dimethylthiazol- and Gliszczynska-Swigło et al. (2006). However, the 2-yl)-2,5-diphenyl tetrazolium bromide assay on HepG2 importance of the antioxidant capacity of betalains cells after exposure to betanin at concentrations ranging relates to its potential to reduce a problematic oxidative from 0 to 400 μg/mL for 48 h. Betanin resulted in a 49% stress in the human body. In this respect, it is known inhibition of HepG2 cell proliferation at 200 μg/mL, that betalains may prevent oxidative processes in showing some anticancer effects against HepG2 cells. humans and provide protection against certain oxida- tive stress-related disorders (Kanner et al., 2001). In an experiment in which human volunteers consumed cac- 17.4.5 Other Effects of Betalain-Rich Extracts tus pear fruit pulp, the presence of betalains was detected in LDL, and it was suggested that betanin Lu et al. (2009) reported that a betalain-rich beet extract and indicaxanthin may protect LDL against oxidative appeared to provide protection against gamma radiation. modifications (Tesoriere et al., 2004). Erythrocytes are Prahoveanu et al. (1986) reported a prophylactic effect of a highly susceptible to oxidation by the oxygen-derived Beta vulgaris extract against an experimental influenza free radicals that may be formed when high oxygen infection in mice. The serum level, atherogenic tension and large amounts of iron are present (Halliwell index, and body weight in rats were significantly reduced and Gutteridge, 1999). Erythrocytes enriched with in rats that were fed with betalain-enriched beet crisps betalain by ex vivo spiking with purified betanin or (Wroblewska et al., 2011). Significant antimalarial activity indicaxanthin showed greater resistance to cumene- due to apparently high levels of betanin and amaranthin hydroperoxide-induced oxidative hemolysis than from Amaranthus spinosus was reported in mice by Hilou homologous non-enriched erythrocytes in a dose- et al. (2006), whereas an inhibition of growth rate of dependent manner: the greater the incorporation of Escherichia coli O157:H7 by extracts of xoconostle pears betalains, the higher the resistance to oxidative hemo- (Opuntia matudae) was reported by Hayek and Ibrahim lysis (Tesoriere et al., 2005). (2012). A broad antimicrobial activity of betalain-rich extracts from red pitaya (Hylocereus polyrhizus) was shown by Tenore et al. (2012). A concentration of 17.4.4 Anticancer Properties 7.8 μg/mL of extract inhibited Gram-positive bacteria (B. cereus, S. aureus, Escherichia faecalis, and Listeria A significant anticancer activity by a red beetroot extract monocytogenes), whereas 15.6–62.5 μg/mL inhibited (red food color E162) was reported by Kapadia et al. Gram-negative bacteria (E. coli, Proteus mirabilis, P. (1996) when the induction of lung and skin tumors vulgaris, P. aeruginosa, Salmonella typhi Ty2, Yersinia was inhibited in chemical carcinogen-treated mice by enterocolitica, Klebsiella pneumonia, Enterobacter cloa- beetroot extract administered in drinking water. In other cae, and E. aerogenes), 125–250 μg/mL inhibited yeasts research, the effect of a purified betanin pigment (MW (Candida albicans and Rhizoctonia solani), and 500 μg/ 551) isolated from Opuntia ficus-indica on cellular lines mL inhibited moulds (Fusarium oxysporum, Cladospo- of human chronic myeloid leukemia (K562 cells) was rium herbarum, Botrytis cinerea, and Aspergillus flavus). studied by Sreekanth et al. (2007). They found that the An anti-lipidemic effect of an Amaranthus tricolor extract isolated betanin showed an antiproliferative effect with an containing betalains (200 g/kg) was shown in diabetic rats C17 06/07/2017 3:55:54 Page 388

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by Clemente and Desai (2011). When they administered betalain pigments has not been addressed in any of the 400 mg/kg body weight, the rats significantly reduced foregoing studies. Chemopreventive and chemo- their levels of blood , triglycerides, and low- therapeutic properties of betalains such as antiprolifer- density lipoproteins, and increased their level of high- ative, antioxidative, anti-inflammatory, antimicrobial, density lipoproteins. Sani et al. (2009) reported that red and antilipidemic must be characterized more widely pitaya extracts containing betalains caused a reduction of andmoredeeplyandshouldfollowdifferentresearch 43.45% in total cholesterol level of hypercholesterolemic approaches, e.g. studies of simple betalains and of com- rats when they consumed 300 mg/kg body weight of the binations of two or more betalains, in order to establish extract. synergistic activities. Furthermore, studies are needed of combination therapy with currently used potent anti- cancer drugs to achieve synergistic effects and to miti- 17.5 Applications in Food Industry gate treatment-related drug toxicity. The inability of cell cultures to behave like tumors, and their interactions Since synthetic dyes are being viewed more and more with the host, mean that the efficacy of betalains as an critically by the consumer, and because of their wide pH anticancer agent in human clinical trials may not be the stability, betalains have been used as coloring substances same as in studies in vitro. However, future studies using in low-acid food processing. For example, food products human cancer cell lines combined with in vivo testing in such as ice creams, confectionery, soups, sauces, dairy a model that closely approximates the targeted human products, beverages, and drinks have included betalain- cancer has a greater chance of success in evaluating the based pigments (Azeredo, 2009; Stintzing and Carle, anticancer activity of betalains. There is a need for the 2004, 2007; Vaillant et al., 2005; Cai et al., 2001). elaboration of further clinical research that corroborates the effectiveness of the betalains against diseases previ- ously addressed and for other health problems. It is 17.6 Future Trends highly likely that present and future studies will increase people’s awareness of the positive health benefits of Systematic studies designed to isolate, identify, and consumption of products that are sources of betalains. delineate mechanisms of action of molecules of beta- Consequently, the demand for better natural-colored lains against different human diseases are beginning to foods by an important sector of the society will be multiply. The characterization of the LOX and COX increased. In this sense, more studies should be carried inactivating capacity of betalains, and the identification out in order to frame a complete vision of the bio- of the most effective molecules, open up new perspec- synthesis and regulation of betalain production by plant- tives in the study of these plant pigments and reinforce s or plant tissue cultures; this requires the development their bioactive potential. It has recently been docu- of better biotechnological approaches. The most mented that natural food colors such as betanin can impressive advances in these aspects have been achieved inhibit the cell proliferation of a variety of human tumor using molecular biology techniques, and this will con- cells; however, the exact mechanism of action of the tinuetobesointhenearfuture.

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