A review on plant-based rutin extraction methods and its pharmacological activities.

Journal of Ethnopharmacology ∎ (∎∎∎∎) ∎∎∎–∎∎∎

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Review

A review on plant-based rutin extraction methods and its pharmacological activities Q1

Lee Suan Chua n Metabolites Profiling Laboratory, Institute of Bioproduct Development, Universiti Teknologi Malaysia, 81310 UTM Skudai, Johor Bahru, Johor, Malaysia

art ic l e i nf o Article history: Received 16 June 2013 Received in revised form 16 October 2013 Accepted 17 October 2013

Keywords: Rutin Extraction Solid phase extraction Antioxidant Anti-inflammation

a b s t r a c t Q3 Ethnopharmacological relevance: Rutin is a common dietary flavonoid that is widely consumed from plant-derived beverages and foods as traditional and folkloric medicine worldwide. Rutin is believed to exhibit significant pharmacological activities, including anti-oxidation, anti-inflammation, anti-diabetic, anti-adipogenic, neuroprotective and hormone therapy. Till date, over 130 registered therapeutic medicinal preparations are containing rutin in their formulations. This article aims to critically review the extraction methods for plant-based rutin and its pharmacological activities. This review provides comprehensive data on the performance of rutin extraction methods and the extent of its pharmacological activities using various in vitro and in vivo experimental models. Materials and methods: Literatures including journals, patents, books and leaflets reporting on rutin from natural resources are systematically reviewed, particularly in the aspect of its extraction methods and biological activities. Factors affecting the efficiency of rutin extraction such as extraction temperature, duration and solvent to sample ratio are presented based on the findings of previous studies. The observed biological activities followed by clear explanation are also provided accordingly. Results: The biological activities of rutin varied largely dependent on the geographical and plant origins. The complexity of natural rutin has impeded the development of rutin derived drugs. The detail mechanism of rutin in human body after consumption is still unclear. Therefore, studies are intensively carried out both in vitro and in vivo for the better understanding of the underlying mechanism. The studies are not limited to the pharmacological properties, but also on the extraction methods of rutin. Many studies have focused on the optimization of extraction method to increase the extraction yield of rutin. Currently, the performances of modern extraction approaches have also been compared to the conventional heat reflux method as a benchmark. Conclusion: There are various extraction methods for plant-based rutin ranging from conventional method up to the use of modern techniques such as ultrasound, mechanochemical, microwave, infrared and pressurized assisted methods. However, proper comparison between the methods is very difficult because of the variance in plant origin and extraction conditions. It is important to optimize the extraction method in order to produce high yield and acceptable purity of rutin with a reasonable cost. Even though rutin has been proven to be effective in numerous pharmacological activities, the dosage and toxicity of rutin for such activities are still unknown. Future research should relate the dosage and toxicity of rutin for the ethnobotanical claims based on the underlying mechanisms. & 2013 Elsevier Ireland Ltd. All rights reserved.

Contents 1. 2.

Introduction to plant-based rutin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Extraction methods for rutin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

Abbreviations: 3,4-DHPAA, 3,4-dihydroxyphenylacetic acid; 3,4-DHT, 3,4-dihydroxytoluene; 3-HPAA, 3-hydroxyphenylacetic acid; HVA, homovanillic acid (4-hydroxy-3ε methoxyphenylacetic acid); AGE, advanced glycation end product; BHT, butylated hydroxytoluene; CML, N -carboxymethylysine; COX-1, cyclo-oxygenase 1; COX-2, cyclooxygenase 2; DMPD, N,N-dimethyl-p-phenylendiamine; DNA, deoxyribonucleic acid; DPPH, 2,2-diphenyl-1-picrylhydrazyl; FRAP, ferric-reducing antioxidant power; ICR, Imprinting Control Region; PRAP, phosphomolibdenum-reducing antioxidant power; RNS, reactive nitrogen species; ROS, reactive oxygen species; SPE, solid phase extraction; TNF-α, tumor necrosis factor-α; topo I and II, topoisomerases I and II; UV, ultraviolet; WHO, World Health Organization n Q2 Tel.: þ 60 19 7214378; fax: þ 60 7 5569706. E-mail addresses: [email protected], [email protected] 0378-8741/$ - see front matter & 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jep.2013.10.036

Please cite this article as: Chua, L.S., A review on plant-based rutin extraction methods and its pharmacological activities. Journal of Ethnopharmacology (2013), http://dx.doi.org/10.1016/j.jep.2013.10.036i

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L.S. Chua / Journal of Ethnopharmacology ∎ (∎∎∎∎) ∎∎∎–∎∎∎

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2.1. Heat reflux extraction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 2.2. Ultrasound assisted extraction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 2.3. Mechanochemical assisted extraction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 2.4. Microwave assisted extraction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 2.5. Infrared assisted extraction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 2.6. Pressurized liquid extraction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 2.7. Solid phase extraction for rutin purification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 3. Pharmacological activities of rutin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 3.1. Antioxidant activity of rutin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 3.2. Anti-inflammation of rutin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 3.3. Medical property of rutin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 3.4. Hormone therapy of rutin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 4. Metabolism of rutin in body . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

1. Introduction to plant-based rutin In recent decades, many herbs and natural compounds have increasingly been receiving public interest as complementary and alternative medicines (Ahmed et al., 2005). World Health Organization (WHO) has urged the evaluation on the effectiveness of plant-based drugs due to the lack of scientific information (Ayyanar et al., 2008). The natural rutin (3′,4′,5,7-tetrahydroxyflavone-3-rutinoside) is one of the attractive phytochemicals because of its pharmacological activities. Therefore, it is considered as an important flavonoid in pharmaceutical industry (Buszewski et al., 1993). Over 130 therapeutic medicinal preparations that have been registered as drugs worldwide are containing rutin in their formulations (Reynolds, 1996; Sun and Sheng, 1998; Erlund et al., 2000). Since the demand for natural rutin is in the increasing trend, it is crucial to review the extraction methods and the pharmacological activities of rutin critically. Flavonoids are reported as the major dietary constituents of plant-based food (Carnat et al., 1998; Goncalves et al., 2012). They are polyphenolic compounds that occur ubiquitously in food of plant origin because they are usually present in substantial amount in plant kingdom. Till date, over 4000 chemically vary flavonoids have been reported and they can be categorized into the class of flavonols, flavones, flavanones, catechins, anthocyanidins and chalcones (Hollman and Batan, 1997). It is estimated approximately 3–80 mg of flavonoids is consumed daily and quercetin represents 50–75% of the total intake (Hertog et al., 1995; Rimm et al., 1996). Quercetin is the aglycone moiety of rutin after hydrolysis by the microflora in the intestines. Rutin belongs to a kind of flavone glycoside which is also known as vitamin P. The hydrolysis of rutin produces quercetin and rutinose catalyzed by glucosidase (Shen et al., 2002). Quercetin usually coexists with rutin (Chen et al., 2000) and they are mostly found in edible plants such as onions, apples, berries, tea and wine (Manach et al., 1997). Both rutin and quercetin are excellent sources of pharmaceutical products for phytotherapy (Yang and Zhang, 2008). Buckwheat (Fagopyrum esculentum Moench) from the family Polygonaceae is reported as a major source of natural rutin (Kim et al., 2005; Gupta et al., 2011). Significantly, the aerial part of the plant (flowers and leaves) was found to be in the highest concentration, approximately 2–10% of dry weight (Kalinova and Dadakova, 2004; Suzuki et al., 2005). The similar study also reported that young leaves contained more than 15% of rutin. The plants contain the highest concentration of rutin in the period of beginning flowering (Choi et al., 1996). Nevertheless, rutin could be detected from the whole plant of buckwheat including leaves, flowers, stalks and seeds. The amount of rutin at different parts of

the plant is greatly depended on the variance in plant species and of its geographical origin. Indeed, the interest in rutin from buckwheat can date back to 1940s, when buckwheat was cultivated as a source of rutin for medicinal use in the United States (Ohsawa and Tsutsumi, 1995). To date, it is reported that more than 70 plant species contain rutin. The other major commercial sources of rutin include Ruta graveolens L. (Rutaceae), Sophora japonica L. (Fabaceae), Maranta leuconeura E. Morren (Marantaceae), Orchidantha maxillarioides (Ridl.) Schum (Lowiaceae), Strelitzia reginae Banks ex Aiton (Strelitziaceae), Eucalyptus spp. (Myrtaceae), Canna indica L. (Cannaceae), Canna edulis Ker Gawl. (Cannaceae) and Labisia pumila (Blume) Mez (Primulaceae) (Williams and Harborne, 1977; Afshar and Delazar, 1994; Evans, 1996; Middleton et al., 2000; Abdullah et al., 2008; Chua et al., 2011; Li et al., 2012). There was also up to 1.5% of rutin could be extracted from tobacco leaves (Fathiazad et al., 2006). It was found that more than half of the amount of rutin was distributed in the upper epidermis of tartary buckwheat leaf (Suzuki et al., 2005). The concentration of rutin also increased rapidly after UV-B radiation. This finding has reinforced the idea that rutin plays a role in UV screening which in good agreement with many studies reporting flavonoids are good in protecting plants from UV-B radiation (Harborne and Williams, 2000). On the other hand, peroxidases such as rutin glucosidase which mostly located in the lower epidermis will be activated under stress condition. The activation of peroxidases is to protect plants against oxidation by increasing the rate of respiration. Quercetin which is produced from the hydrolysis of rutin is used as a substrate for guaiacol peroxidases, whereas rutinose is acquired as carbohydrate source for respiration (Amako et al., 1994). The oxidation of quercetin produces 3,4-dihydroxybenzoic acid which is an antifungal agent for plants (Takahama and Hirota, 2000). This phenomenon explains rutin and quercetin are always coexisting.

2. Extraction methods for rutin Numerous extraction methods have been investigating in order to extract rutin optimally from various plant samples. The effort is driven by the renewed interest in plant-based rutin. The techniques range from the traditional solvent extraction to modern methods such as supercritical fluid extraction (Dimitrieska-Stojkovic and Zdravkovski, 2003), pressurized liquid extraction (Zhang et al., 2008; Macikova et al., 2012), microwave-assisted extraction (Zhang et al., 2009), solid phase micro-extraction (Michalkiewicz et al., 2008) and ultrasound-assisted extraction (Yang and Zhang, 2008). These methods consist of two phases; liquid (solvent) and solid


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(plant matrix) phases during extraction. Regardless the kind of extraction method, solid–liquid extraction is a two stages of process; (1) swelling and hydrating of plant matrix, and (2) mass transfer of solute from plant materials to bulk solvent by diffusion and osmotic pressure (Vinatoru, 2001). It is strongly believed that each method has its advantages and limitations. The method of choice is highly depended on the yield and purity of rutin.

significantly increased the extraction yield which covered for more than 90% of the total yield. Therefore, many researchers performed successive extraction to increase the efficiency of extraction for high complexity of plant samples (Altiok et al., 2008). Successive extraction could reduce the problem of diffusion for solute migrating into bulk solvent.

2.1. Heat reflux extraction

2.2. Ultrasound assisted extraction

Heat reflux extraction is the conventional extraction method involving heating, boiling and refluxing for a period of time (Yang and Zhang, 2008). This method is widely used for plant samples extraction because the instrumentation required is simpler and easy for operation. However, the yield of rutin might be lower due to ionization, hydrolysis and oxidation after long duration of extraction (Ohnishi et al., 1994; Paganga et al., 1999). The method also requires a large volume of hazardous solvent, which is not considered as an environmental friendly approach. Several studies reported that a larger solvent volume could dissolve phytochemicals more effectively than extraction process with lower solvent to sample ratio (Pinelo et al., 2005; Altiok et al., 2008). In a large solvent to sample ratio, the solvent can diffuse into the plant matrix easily and the phytochemicals can also diffuse out of the matrix into surrounding solvent with lesser mass transfer limitation. This is because extraction is a dissolution- and diffusionbased process. The choice of solvent is the prominent factor determining the success of a particular extraction process, particularly for liquid– solid extraction. According to the principle of “like dissolves like”, solvent with the polarity value near to the polarity of target compound is likely to be dissolved better and vice versa. This principle explains polar rutin extraction is usually performed by using polar alcoholic solvent such as ethanol and methanol (Fathiazad et al., 2006). Ethanol is more preferable solvent because it is non-toxic and cost effective solvent. Back to the year of 1924, rutin had been extracted from the flower of elder (Sambucus Canadensis L., Adoxaceae) using 95% alcohol by researchers from the United States (Sando and Lloyd, 1924). In 1948, Koones and Clifton had patented the extraction method for rutin from plant materials using alcoholic solvent. Even though organic solvent is the choice of solvent for rutin extraction, a small portion of water would enhance the efficiency of extraction (Altiok et al., 2008). Water could increase the diffusion of extractable polyphenols through plant tissues. The swelling effect of water on plant tissues would increase the surface area of contact between solute and solvent (Li et al., 2004b). Kreft et al. (1999) and Kim et al. (2005) reported that 50–60% of ethanol produced the highest yield of rutin from buckwheat. Somehow, the variation in extraction yield was not only due to the solubility of rutin in the solvent system, but also the effect of the solvent system on the interaction between rutin and buckwheat starch. Extraction temperature and time are the other factors need to be taken into consideration during heat reflux extraction. The high temperature of extraction normally increases mass transfer process. Too high extraction temperature might degrade rutin, especially under aqueous extraction system. The aqueous system can go up to 100 1C, but mostly flavanoids are heat sensitive compounds. Theoretically, longer extraction time produces higher extraction yield. However, the concentration of rutin will proportionally be decreasing with the length of extraction duration, particularly when the extraction is performed at high temperature. A single step of extraction is also not as effective as multiple steps of extraction. The first few cycles of extraction are usually higher in extraction yield compared to the latter extraction cycle. Xie et al. (2011) showed that the first two cycles of extraction had

Ultrasound assisted extraction is likely to be more effective than heat reflux method for rutin extraction. The extraction yield of ultrasound assisted method was approximately increased for 50% at 40 1C for an hour, compared to the similar extraction process performed by heat reflux method at 80 1C for 2 h (Zhao et al., 1991). Interestingly, ultrasonic extraction of rutin was found to be less suitable in aqueous medium. The apparent stability of rutin against oxidation in methanol was relatively high compared to water (Paniwnyk et al., 2001). The observation could be attributed to the phenomenon of acoustic cavitation in the solution (Paniwnyk et al., 2001; Yang and Zhang, 2008). This acoustic cavitation produced by the passage of ultrasonic wave was significant in aqueous medium. The cavities or micro-bubbles are produced when the ultrasound intensity is sufficient during the expansion cycle. Free radicals that are generated within the cavitation bubbles can produce undesirable chemical effects to rutin extraction. Sonication in water is believed promoting the formation of highly reactive hydroxyl radicals. The combination of hydroxyl radicals produces hydrogen peroxide which could degrade rutin during extraction. This phenomenon can be illustrated by Fig. 1. Paniwnyk et al. (2001) and Yang and Zhang (2008) reported that the reduction in extraction yield of rutin from Sophora japonica L. (Fabaceae) was mainly due to the degradation rutin by the interaction with highly reactive hydroxyl radicals during sonication in aqueous. In contradiction to aqueous sonication, ultrasound assisted extraction in methanol appears to be more effective in increasing the extraction yield and reducing the extraction time (Paniwnyk et al., 2001). Sonication in methanol does not produce a large proportion of radicals under cavitation (Paniwnyk et al., 2001). The cavitational effect appears to be lower because lower extraction temperature is applied in methanol (boiling point, 64.7 1C). Furthermore, rutin is more soluble in methanol. The increase of ultrasonic extraction efficiency in methanol could be explained by the creation of ultrasonic wave (Paniwnyk et al., 2001). The creation of ultrasonic wave promotes greater contact area between plant matrix and bulk solvent. The ultrasonic wave is produced from the collapse of cavitation bubbles that filling with solvent vapor. Before explosion, these bubbles absorb energy from the sound waves, leading to compression between the bubbles and the gas. The compression increases the temperature and pressure in the solution. This phenomenon promotes mass transfer, in

Fig. 1. Acoustic cavitation produced by ultrasonic wave during extraction.


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addition to plant cell disruption for the release of phytochemicals into the bulk medium (Toma et al., 2001). Besides cell wall disruption, the reduction in particle size and the formation of finestras in the stalks of Euonymus alatus (Thunb.) Siebold (Celastraceae) were also observed by Yang and Zhang (2008) from the result of scanning electron microscopy. The induction of ultrasound caused a subsequent change in the surface tension of cellulose, making the plant to crumble and rupture more readily. Besides rutin, sonication has widely been employed to extract other compounds such as hydrocarbon (Jacques et al., 2007), fatty acid esters (Stavarache et al., 2007), antioxidants (Albu et al., 2004), steroids (Schinor et al., 2004) and anthraquinones (Hemwimol et al., 2006) from plant materials. The wide application of ultrasound assisted technique for phytochemicals extraction indirectly reveals the feasibility and reliability of this technique for rutin separation. Again, previous results showed that successive extraction (a three step extraction with fresh solvent for each extraction) could produce higher extraction yield of rutin and quercetin from Euonymus alatus (Thunb.) Siebold (Celastraceae) by sonication (Yang and Zhang, 2008). The comparison was made between successive extraction and single cycle of extraction with similar accumulative extraction time (90 min). 2.3. Mechanochemical assisted extraction Recently, a newly developed extraction technology called mechanochemical assisted extraction has been used to efficiently and rapidly extract rutin from Hibicus mutabilis L. (Malvaceae) (Xie et al., 2011). The advancement of this technology is the combination of chemical and mechanical force under solvent free system at far lower extraction temperature. The mechanical force is applied to explore plant cells for rutin diffusion, whereas the chemicals are added to promote neutralization reaction between rutin and the basic agents, namely sodium carbonate (Na2CO3) and disodium tetraborate (Na2B4O7 10H2O). Since rutin is a weak acid and its pKa is about 4.3, it is unstable in alkaline solution (Jovanovic et al., 1994). This technology is of high efficiency for compounds have low solubility in water such as rutin (12.5 g/100 mL). The addition of solid basic agents will transform rutin into salt form, while grinding with powdered sample matrix. Disodium tetraborate is used to protect o-phenolic hydroxyl of rutin from oxidation. Based on the chemical structure of rutin, it has several acidic hydroxyl groups on its aromatic rings (Fig. 2). The presence of these hydroxyl groups suggested that rutin could be transformed into a highly polar compound under high energy mechanical action (Xie et al., 2011). The minimal concentration of solid basic agents that required for extraction is highly dependent on the amount of target compound in the plant materials and its conversion capacity under high energy mechanical action. Therefore, the critical factor for high efficiency of mechanochemical extraction is grinding time.

Quercetin (Aglycone)

Rutinose

Fig. 2. Chemical structure of rutin (quercetin-3-O-rutinoside).

Too long grinding time was reported to reduce extraction yield resulted from rutin oxidation. Conglomeration might also be formed after long time of grinding under intense mechanical action. The formation of conglomeration would reduce the contact surface area for mass transfer, as well as change the physiocochemical of rutin (Xie et al., 2011). Indeed, the introduction of a water soluble borate solution to dissolve rutin from plant materials had been reported by Koones and Clifton (1948) long time ago. However, the extraction method reported by them was purely chemical method because acids were used to precipitate impurity from rutin containing extract solution. During that time, no mechanical force was introduced to enhance the efficiency of rutin extraction. The solubilization of rutin increased when an adequate amount of borate solution had been added to bring the pH of the solution to 7.2–7.5. Another 20–30% of salting out agents such as sodium chloride, ammonium sulfate or magnesium chloride could be added to precipitate impurities. The remaining impurities could be further precipitated by adjusting the pH of solution to 5.2–5.5 using hydrochloric acid, acetic acid or phosphoric acid and subsequently removed from the solution by filtration. By making the solution slightly acidic, quercetin which is considered as the impurity for rutin extraction, could be precipitated out. Further acidification of the filtrate with dilute sulfuric acid to a pH of 1.0–4.0 would obtain pure rutin after removal of impurities from the aqueous solution. 2.4. Microwave assisted extraction Microwave energy is well known for its heating effect to increase the rate of various analytical and biological processes (Kaufmann and Christen, 2002; Deng et al., 2006). The significant advantages of microwave assisted extraction are the reduction of extraction time and the amount of solvent used (Li et al., 2004a). According to Pare et al. (1994), microwave would induce a sudden increase of temperature inside the cellular structure, which might result in an eventual rupturing of cell walls and the rapid release of plant constituents into surrounding medium. Even though the mechanism of extraction using microwave irradiation is still unclear, much attention has been given to the application of microwave heating for compound extraction from herbal plants (Kaufmann and Christen, 2002; Deng et al., 2006). This method had been applied by Zhang et al. (2009) to extract rutin from the samples of Euonymus alatus (Thunb.) Siebold (Celastraceae). They reported microwave assisted extraction of rutin was better than Soxhlet (360 min) and ultrasonic assisted extraction (30 min) in term of shorter extraction time (6 min). Furthermore, the high capability of ionic liquid in microwave extraction had also been utilized for rutin extraction using microwave assisted technology. Zeng et al. (2010) demonstrated that ionic liquid-based microwave-assisted extraction was found to be higher in extraction efficiency which was 4.88 mg/g in Schisandra chinensis (Turcz.) Baill. (Schisandraceae) with a relative standard deviation, 1.33% and 171.82 mg/g in Flos Sophorae (Sophora japonica L., Fabaceae) with a relative standard deviation, 1.47% compared to those results in both ionic liquid-based heating extraction and ultrasonicassisted extraction. A series of 1-butyl-3-methylimidazolium ionic liquids with different anions were investigated and the study reported that 1-butyl-3-methylimidazolium bromide ([bmim]Br) aqueous solution was the best ionic liquid. As other extraction methods, the liquid to solid ratio is the prominent factor for rutin extraction using ionic liquids. The higher liquid to solid ratio, the higher yield of rutin would be obtained because of sufficient contact area between sample matrixes and ionic liquids. Even though higher temperature reduced the viscosity of ionic liquid for mass transfer, 60 and 70 1C were the optimal temperature for rutin extraction from Sophora japonica L. (Fabaceae) and Schisandra chinensis (Turcz.) Baill


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Experimental model In vitro

Anti-oxidation

Wistar albino rats

Spectrophotometric antioxidant assay

20–150 min

Yang et al. (2008) Guardia et al. (2001) Han (2009)

20 nM

Lee et al. (2012)

6 mg/kg

Shen et al. (2002)

Lee et al. (2012)

150 mM

16 days

10, 30, 90 mg/kg

10 weeks

Cervantes-Laurean et al. (2006) Hao et al. (2012)

20% casein diet supplemented with 0.2% G-rutin 100 mg/kg

4 weeks

Nagasawa et al. (2002)

45 days

Stanley Mainzen Prince and Kamalakkannan (2006)

Male abino Wistar rats (150–180 g)

100 mg/kg

45 days

Stanley Mainzen Prince and Kamalakkannan (2006)

C57BL/6 mice fed with high-fat diet

Dosage dependent manner 25, 50 mg/kg

4 weeks

Choi et al. (2006) Choi et al. (2006)

50–200 mg/mL 0.75%w/w

15 min 2 weeks

Gulpinar et al. (2012) Koda et al. (2008)

60 mg/kg

21 days

Tongjaroenbuangam et al. (2011)

5 and 10 mg/kg 1 and 10 mg/100 g diet

2 weeks 2 weeks

Annapurna et al. (2009) Webster et al. (1996)

Male albino Wistar rats (150–180 g) induced by streptozotocin

Adipocyte in 3T3-L1 cells Spectrophotometric enzymatic assays Male Sprague-Dawley rats (4 weeks old) induced by trimethyltin Male ICR mice (25–30 g) treated by dexamethasone Albino Wistar rats (200–250 g) Weanling male Wistar rats (100 g) treated with hepatocarcinogens aflatoxin B1 and N-nitrosodimethylamine Agar diffusion

5 mg/mL 3 times daily for an 17 days interval of 2 days 10 mg/mouse 6h

21 days

Male Sprague-Dawley rats (180–220 g) induced by streptozotocin Male Wistar strain rats

Anti-microorganism

80 mg/kg

80 mM 25 mg/kg

Fluorometric glucose glycation of collagen I-linked fluorescent and non-fluorescent adduct formation

Cardioprotection Anti-cancer

Asgary et al. (1999) Korkmaz and Kolankaya (2010) Mahmoud (2012)

30 days

Male Wistar rats (150–170g) induced by collagen for arthritis

Neuroprotective

72 h

Female Wistar rats (150–180 g) induced by adjuvantcarrageenan Balb/c mice induced by mixture of Candida albicans & Complete Freund's Adjuvant Female ICR mice (6 weeks old) hyperpermeability induced by acetic acid and leukocyte migration induced by carboxymethylcellulose.

Mouse macrophage cell line (RAW 264.7)

Anti-adipogenic

0.5, 5 and 10 mg/mL 1 g/kg

8 weeks

Balb/c mice induced by lipopolysaccharide for nitric oxide and prostagladin E2 production

Kidney protection

Reference

Hyperammonemia male Wistar rats (150–200 g) induced 50 kg/kg by ammonium chloride 0.05 mg/mL

Human umbilical vein endothelial cells treated with lipopolysaccharide

Anti-diabetes

Duration

In vivo

Colorimetric method of hemoglobin glycosylation

Anti-inflammation

Rutin dosage

100–200 mg/mL methanolic extract of Hypericum perforatum L. (Hypericaceae)

Shen et al. (2002) Umar et al. (2012)

Q6



Table 1 Pharmacological activities of rutin in different experimental models reported by previous investigators.

DallAgnol et al. (2003)

5

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Jung et al. (2007) La Casa et al. (2000) Guo et al. (2012) 24 h 2h 7 days Guinea-pigs treated by aerosolized ovalbumin Wistar rats (180–200 g) induced by 50% ethanol Female Wistar rats (200 g) were ovariotized

In vitro

In vivo

7.5 and 15 mg/kg 50, 100 and 200 mg/kg 60 mg/kg

Reference Duration Rutin dosage Experimental model

(Schisandraceae), respectively (Zeng et al., 2010). The temperature beyond optimal value would decompose rutin. Ionic liquids are a new class of solvent composed of heterocyclic organic cations, and inorganic or organic anions, which are liquid near room temperature (Du et al., 2009). They are nonmolecular in nature providing intrinsic solvent properties such as wider liquidus range, good solvation capacity, excellent microwave absorption, excellent ionic conductivity, designable structures and low vapor pressure, as well as high chemical and thermal stability (Van Rantwijk and Sheldon, 2007; Macikova et al., 2012). Because of low vapor pressure, ionic liquids are very difficult to evaporate and they can even be recycled. Therefore, ionic liquids are getting much attention from researchers as green solvent. Both the selectivity and extraction efficiency were also found to be improved, particularly for extracting marker compounds from complicated plant samples such as traditional Chinese medicine. Several studies revealed that ionic liquids exhibited multiple interactions including hydrogen bonding, polarity, π–π, π–n and ionic charge with rutin (Beyene et al., 2004; Shahrokhian et al., 2009). The interaction had increased the solubility of rutin in ionic liquid solution (Dursun and Nisli, 2004). 2.5. Infrared assisted extraction Recently, infrared assisted extraction has been proven to be an alternative method for the extraction of active components from medicinal plants (Chen et al., 2010; Duan et al., 2010). This method uses infrared energy to heat solvent in contact with a sample in order to partition analytes from the sample matrix into solvent. High efficiency of heating is achieved by matching the wavelength of infrared heater to the absorption characteristics of samples (Duan et al., 2010). It might not as efficient as microwave assisted extraction method in term of extraction yield, but infrared assisted extraction is easier and cheaper as well as free of irradiation. 2.6. Pressurized liquid extraction The unique property of ionic liquids has also widened its usage to enhance extraction efficiency using pressurized liquid extraction approach. Pressurized liquid extraction is sometimes called as accelerated solvent extraction. The advantage of this technique is the use of high pressure to accelerate the rate of extraction from sample matrix that packed together with inert material in a column. The efficiency of the method can be improved by increasing the number of extraction cycle, gradient profile of mobile phase and solvent type. Wu et al. (2012) reported a novel ionic liquid-based pressurized liquid extraction procedure coupled with high performance liquid chromatography tandem chemiluminescence detection to measure trace amounts of rutin and quercetin in Chinese medicine plants including Sophora japonica L. (Fabaceae), Crateagus pinnatifida Bunge (Rosaceae), Hypericum japonicum Thunb. (Hypericaceae) and Morus alba L. (Moraceae). This is the first contribution to utilize a combination of ionic liquid-based pressurized liquid extraction with chemiluminescence detection. The experimental results indicated this approach was likely to be a promising prospect in extraction and determination of rutin and quercetin in medicinal plants.

Anti-asthma Gastroprotection Phytoestrogen

Biological activity

2.7. Solid phase extraction for rutin purification Table 1 (continued )

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66


6

After extraction, further purification is usually required to obtain more concentrated rutin. The concentration of rutin can be increased by removing many other plant components such as sugars, proteins and metals (Yoon et al., 1997; Aehle et al., 2004). As reported by Kim et al. (2005), after 1 h alcoholic extraction at 80 1C, a styrene-based resin column was used to elute rutin from


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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66

the buckwheat extract, and followed by rutin crystallization at 4 1C for 12 h. This low cost process had obtained 92% of total rutin with 95% purity. The use of styrene-based resin column for rutin elution is also called solid phase extraction (SPE). SPE is a commonly employed method because adsorption is a low cost separation technique. It can be a static or dynamic adsorption and desorption process (Wang et al., 2008). In a static SPE, a certain amount of adsorbent is added into the solution for target compound adsorption in a batch system. After adsorption, the solution is filtered and the target compound is then desorbed from the adsorbent into solvent medium with the opposite polarity to the adsorbent. The kinetic of adsorption and desorption processes could be increased by vigorous shaking to reduce mass transfer limitation. Dynamic SPE is carried out in a packed column where solute is separated using the principle of column chromatography at a certain flow rate. Some researchers even reported that SPE was more efficient for purification of natural constituent in term of recovery percent through the process of adsorption and desorption (Wang et al., 2008). Many synthetic adsorbents (Scordino et al., 2003; Aehle et al., 2004; Silva et al., 2007) and biopolymers such as collagen and celluloses had been applied to recover polyphenolic compounds from plant extract. The efficiency of the method is mainly determined by the chemical property of adsorbents (packing materials) and the composition of mobile phase as eluent (Buszewski et al., 1993). The typical packing materials differ based on the structure and coverage density of silica support with alkylsilyl ligands. Previous results reported that rutin showed the highest adsorption capacity in non-polar packing materials, namely C18 phase (Buszewski et al., 1993). This long organosilyl ligand phase has higher carbon percentage and lower polarity in chemically bonded packing materials compared to C8 and C4. This chromatographic separation technique is usually performed in a vacuum manifold processor at a constant flow rate. The SPE column needs to be preconditioned before use. The preconditioning solvents are water and methanol for non-polar packing materials, whereas 1,4-dioxane for polar packing materials (NH2, CN and DIOL) (Buszewski et al., 1993). The adsorbent bed is preconditioned to remove any monomers and porogenic agents trapped inside the pores during the synthesis process. The adsorption (qe, E) and desorption (D) capacity, as well as recovery percent of a particular adsorbent (R) can be determined from the equations below. The adsorption equilibrium data can be fitted to the Henry, Langmuir and Freundlich isotherm equations to describe the interaction of solute with the adsorbent (Jung et al., 2001). The Henry, Langmuir and Freundlich isotherms are the most often used isotherms for the adsorption of solute from a solution in a separation process. The Langmuir model assumes mono-molecular layer adsorption with a homogeneous distribution of adsorption energies and without mutual interaction between adsorbed molecules. The Freundlich model can be used to describe the adsorption behavior of mono-molecular layer as well as that of the multi-molecular layer (Fu et al., 2005) qe ¼

ðC o C e ÞV o m

Eð%Þ ¼

ðC o C e Þ 100% Co

C V Rð%Þ ¼ d d 100% Co V o Dð%Þ ¼

CdV d 100% ðC o C e ÞV d

ð1Þ ð2Þ ð3Þ ð4Þ

where qe is the adsorption capacity at equilibrium (mg/g resin); E is the adsorption ratio (%), R is the recovery (%), D is the

7

desorption ratio (%), Co is the initial concentration of solute in solution (mg/mL), Ce is the equilibrium concentration of solute in solution (mg/mL), Cd is the concentration of the solute in desorption solution (mg/mL), Vo is the volume of initial sample solution (mL), Vd is the volume of the desorption solution (mL) and m is the weight of dry resin (g). The performance of SPE in separation can be evaluated based on the distribution coefficient (Kd), selective coefficient (k) and relative selectivity coefficient (k′). The adsorption process is the distribution of the solutes between the adsorbents and the liquid phase (Scordino et al., 2003). Kd reflects the migration and separation capacity of the solute in two phases, k indicates the difference of two compounds adsorbed by stationary phase or the ratio of Kd values for two competitive compounds, whereas k′ is defined as the ratio of K values of two competitive compounds by different stationary phases (Zeng et al., 2012). Scatchard curve can be plotted (qe/Ce versus qe) in order to further evaluate the binding properties of packing materials (Eq. (8)). Kd ¼

ðC o C e Þ Ce

ð5Þ

K d1 K d2

ð6Þ

kadsorbent1 kadsorbent2

ð7Þ

qe ¼ ðqmax qe ÞK d Ce

ð8Þ

k¼

k′ ¼

3. Pharmacological activities of rutin A lot of studies have reported the amazing physiological and pharmacological properties of rutin in mammalian systems either in vivo or in vitro. Table 1 summarizes the important information for the recently reported pharmacological activities of rutin using various experimental models as cited in this article. Most of the biological activities such as anti-inflammation (Guardia et al., 2001; Shen et al., 2002; Han, 2009; Umar et al., 2012), anti-microbial (Dall'Agnol et al., 2003), anti-tumor (Ramanathan et al., 1993; Ren et al., 2003) and anti-asthma (Jung et al., 2007) were mainly attributed to the potent antioxidant property of rutin, particularly as a free radical scavenger (Abraham et al., 2008; Yang et al., 2008). Interestingly, the stability of rutin against oxidation was found to be higher than its aglycone, quercetin (Suzuki et al., 2005). Because of the antioxidative capacity of rutin, it is also widely used in pharmaceutical, nutraceutical and cosmeceutical industries as a stabilizer, preservative and natural colorant (Gonnet, 1999). It is often used in combination with vitamin C since rutin is a bioflavonoid which is essential for the absorption of vitamin C and acts as an anti-oxidizer (Buszewski et al., 1993). Human body cannot produce bioflavonoids and rutin can be supplied through diet. Hence, rutin is used not only for prolonging the shelf life of products, but also enriching the nutritional value of products. 3.1. Antioxidant activity of rutin The strong antioxidative capacity of rutin has been proven by numerous studies, particularly for excellent scavenging activity (Duthie and Dobson, 1999; Nagasawa et al., 2002; Abraham et al., 2008). The scavenging activity was widely measured by 2,2-diphenyl1-picrylhydrazyl (DPPH), N,N-dimethyl-p-phenylendiamine (DMPD), superoxide and hydrogen peroxide produced from linoleic acid in β-carotene bleaching assay. Besides, there are also metal-related methods such as metal-chelating capacity and ferric-reducing


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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66


8

antioxidant power (FRAP) and phosphomolibdenum-reducing antioxidant power (PRAP) assays for radical inhibition (Gulpinar et al., 2012). These are calorimetric assays measuring the antioxidant capacity of rutin resulted from the change of color density in the presence of antioxidant spectrophotometrically. Free radicals are produced during mitochondrial respiration and also released by peroxisomes to catalyze several redox reactions of various compounds in living tissues and cells. It is known that the production of free radicals in human body is enhanced under certain circumstances stimulated by external stimuli and improper diet. Free radicals are highly reactive oxygen species (ROS) such as superoxide (O2d ), hydroxyl (OHd ), hydrogen peroxide (H2O2), peroxyl (ROOd ), peroxinitrite (d ONOOd ), and nitric oxide (NOd ) radicals which are produced through oxidation within the mammalian body. They are atom, molecule or compound that present unpaired electron. They are produced as defense mechanism against infection caused by the external stimuli, but excessive generation of free radical may damage cells and tissues. The toxicity of superoxide radical (O2d ) and H2O2 in living organisms is due to their conversion into dOH and reactive radical metal complexes via either the iron-catalyzed Haber–Weiss reaction or the superoxide driven Fenton reaction (Aruoma et al., 2010). This complex is nephrotoxic and induces renal proximal tubular damage which eventually leads to a high incidence of renal cell carcinoma (Toyokuni, 1996). These free radicals can cause oxidative stress and cellular damage, especially to sensitive mitochondrial membrane phospholipids, proteins and DNA (Adibhatla and Hatcher, 2010; Montero et al., 2010). The hydroxyl radicals can access cell membrane at the specific sites to react with DNA, and leading to cell death and tissue damage. They initiate lipid peroxidation which is deleterious to cell membrane by impairing membrane function through membrane fluidity depletion and modifying membranebound enzyme activity (Baynes, 1995). The formation of lipid peroxides by the action of free radicals on unsaturated fatty acids has been implicated in the pathogenesis of various diseases (Mosquera et al., 2007). Since antioxidant is well known for its role in preventing various pathologies (Middleton and Kandaswami, 1994), the protective action of rutin against free radicals could be used for therapeutic purposes (Mahmoud, 2012). Khan et al. (2009) reported that rutin might attach to iron ions in human body in order to prevent the metal ions from binding to hydrogen peroxides which would otherwise create more highly reactive free radicals. The administration of buckwheat hull extract which is known for high content of natural rutin was reported to suppress the production of reactive nitrogen species (RNS) such as NO2 and NO3 . Yang et al. (2008) investigated the antioxidant mechanism of rutin, including the total antioxidant activity, reducing power, free radical and superoxide anion radical scavenging, hydroxyl radical scavenging activity, and lipid peroxidation assay. At the concentration of 0.05 mg/mL, the scavenging activity of rutin (90.4% inhibition) was comparable to vitamin C (92.8% inhibition) and approximately doubles the antioxidant activity of butylated hydroxytoluene (58.8% inhibition, BHT). However, the reducing power of rutin was similar to BHT, but lower than vitamin C. The results suggested rutin has a remarkable potency to donate electron to reactive free radicals by converting them into more stable species and quenching the free radical chain reaction (Yang et al., 2008). The potent antioxidant activity of rutin is mainly due to the presence of phenolic rings and free hydroxyl groups in the chemical structure. These free hydroxyl groups could donate hydrogen to prevent further oxidation. 3.2. Anti-inflammation of rutin Inflammation is a physiological response of organism to injuries such as trauma, infection or immune response. It occurs and

causes various diseases ranging from allergies to kidney failure, stroke, cancer, colon carcinoma, asthma, rheumatoid arthritis and many age related problems. Hence, the occurrence of chronic diseases is mainly due to the metabolic disorder as a result of inflammation. The inflammatory process is characterized by the production of pro-inflammatory mediators such as eicosanoids, ROS and cytokines. Cytokines are small protein molecules and include interleukins (IL), lymphokines, chemokines and related signaling molecules such as tumor necrosis factor (TNF)-α and interferons. They are released by cells and affect cell–cell interaction and communication. Both ROS and RNS might perpetuate inflammation by facilitating the generation of chemotactic factors at the local site (Umar et al., 2012). In particular, nitric oxide is an important messenger molecule for inflammatory condition (Sharma et al., 2011). It induces expression of matrix metalloproteinases and formation of new blood vessels which are stimulated by prostaglandins. Cyclo-oxygenases consisted of cyclo-oxygenase 1 (COX-1) and cyclo-oxygenase 2 (COX-2) are the catalysts for prostaglandin synthesis by converting arachidonic acids to prostaglandins. COX-2 is the inducible isomer of cyclo-oxygenase which is responsible for the production of large amount of pro-inflammatory prostaglandins at the inflammatory sites. Prostaglandin is also known as mediator for the inflammatory response. High concentration of prostaglandin E2 was reported at the inflammation sites during the conversion of arachidonic acid catalyzed by COX-2 (Shen et al., 2002). The conversion also produced prostaglandin H2, prostacyclin and thomboxane A2 as intermediates (Picot et al., 1994). Landolfi et al. (1984) reported that quercetin, aglycone of rutin could block both cyclo-oxygenase and lipo-oxygenase pathways at high concentration. Somehow, the lipo-oxygenase pathway was the primary target of inflammation inhibition at low concentration of quercetin. There is a great interest to look for effective natural bioactive compound in inhibiting COX-2. This enzyme is the target of pharmacologic action of the non-steroidal anti-inflammatory drugs (Guardia et al., 2001). Until now, most of the non-steroidal anti-inflammatory drugs such as aspirin and indomethacin are specifically targeted for COX-1 inhibition. It is hypothesized that selective inhibition of COX-2 isoenzyme might reduce the side effects of synthetic drugs. Therefore, the identification of selective COX-2 inhibitor from natural resources has become an important area of pharmaceutical research recently. In most of the cases, the existing drugs are unable to prevent the progression of inflammation, and thus leading to the irreversible joint erosion and deformity (Guardia et al., 2001). Rutin might be a potential candidate for COX-2 inhibition with unique mechanism of action (Teresita et al., 2001). The treatment at 80 mM of rutin produced obvious inhibitory effect on lipopolysaccharide-induced nitric oxide production in in vitro primary peritoneal macrophages. The similar observation was also reported for in vivo lipopolysaccharide-injected mice at the dose of 6 mg rutin per kg body weight (Shen et al., 2002). In the following year, in vivo administration of rutin to the septic arthritis induced mice was reported to exhibit 92% of inhibition on the nitric oxide production at the dose of 20 mg rutin per mL without killing the macrophages (Han, 2009). Most anti-arthritis drugs reduce inflammation with the removal of macrophages aggravating arthritis (Han, 2009). If assumed a kilogram equals to a liter, then approximately three times increment of rutin dosage administrated to mice could exhibit nearly 100% of inhibition in the production of nitric oxide. Levy (1997) and Wong et al. (1998) reported that the inhibition of COX-2 could attenuate the symptom of inflammation and reduce the rate of cancer occurrence. Therefore, the anti-inflammatory activity of rutin was found to be beneficial for the treatment of rheumatoid arthritis and osteoarthritis (Umar et al., 2012).


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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66

The anti-arthritis property of rutin was evaluated based on the articular elastase activity, which is known as a marker for joint inflammation. Its activity is directly proportional to the accumulation and activation of polymorphonuclear leukocytes that released from stimulated granulocyctes from the site of injury. Apart from enzymatic assay, the detection of nitric oxide, which is an important signaling molecule, relates to the inflammatory response from activated T-cells and macrophages (Han, 2009). The T-cell proliferation induces inflammatory cytokine secretion. The induction of nitric oxide production in excess by inflammatory cytokines could induce apoptosis in chondrocytes (Blanco et al., 1995). The biochemical alteration due to arthritis was supported by histopathological observation of infected joints (Umar et al., 2012). Kauss et al. (2008) also reported that rutin could inhibit the transcription of more than 20 genes encoding for critical pro-inflammatory factors including TNF-α, IL-1, IL-8 and migration inhibitory factor. Rutin (50–100 mM) could protect vascular barrier integrity by inhibiting hyperpermeability, expression of cell adhesion molecules, adhesion and migration of leukocytes to suppress vascular inflammatory diseases (Lee et al., 2012). They highlighted that the vascular barrier protection of rutin was not due to the cytotoxicity in endothelial cells and in mice. This was because the concentration of rutin used in their study was below the lethal dose at 50% (950 mg/kg). Guardia et al. (2001) reported the higher anti-inflammatory activity of rutin than its aglycone, quecertin was because of the presence of rutinose in the position 3 of rutin. The additional component of rutinose had contributed to the improved activity in antiinflammation in term of its pharmacokinetic factor (Guardia et al., 2001). The conclusion was made based on the inhibition percentage of adema pedal after intraperitoneal administration of rutin at the dose of 80 mg/kg to female Wistar rats from day 1 to day 30. Interestingly, rutin was also found to be effective in inhibiting Candida albicans and resulted in no hemolysis (Han, 2009). The findings indicated that rutin could be used for both anti-arthritic and anti-candidal treatment caused by the yeast cells. The result was in line with the finding of Handa et al. (1992) who reported flavonoids displayed significant activity in both proliferative and exudative phases of inflammation. Mostly, flavonoids affect non-specific immunological responses (acute inflammatory reaction) by suppressing macrophage phagocytosis, releasing oxidant by neutrophils and activation of mast cells. Only a small portion of flavanoids exhibit complex biphasic action towards the specific immunological system. It is noteworthy that flavonoids appear to be function at low concentration, but inhibitory at high concentration (Formica and Regelson, 1995). 3.3. Medical property of rutin Although there are many studies relating to biological activities of rutin, the mechanism of these activities are still unclear (Shen et al., 2002). This explains the application of rutin in treating human diseases is still uncommon in western medication (Hao et al., 2012). This might be due to the high effective concentration and poor absorption of rutin after oral intake (Shen et al., 2002). Nevertheless, rutin has been proven to be effective in reducing the risk of chronic diseases (Knekt et al., 2002). This prevalence accelerates the elucidation of their underlying mechanism, especially for medical application of rutin. The anti-diabetic property of rutin had been proven by the Stanely Mainzen Prince group on the treatment of diabetic mellitus by improving glucose homeostasis of diabetic rats (Stanley Mainzen Prince and Kamalakkannan, 2006). The homeostasis of glucose was achieved by increasing insulin level, and increasing glycogen content in liver and muscle, but decreasing the glycogen content in kidney. The fasting plasma glucose was reduced by increasing the activity of hexakinase, but decreasing the activities of glucose6-phosphatase and fructose-6-bisphosphatase in the tissues.

9

Therefore, rutin was found to have anti-diabetic property (Ushida et al., 2008; Han, 2009). Cervantes-Laurean et al. (2006) explained the anti-diabetic property of rutin was due to its vicinyl hydroxyl group-containing metabolites for early glycation product formation inhibition. The serum and kidney proteins of diabetic rats showed ε 20% of reduction in the amount of N -fructoselysine after 4 weeks of feeding the Wistar strain rats with rutin rich diet (Nagasawa et al., 2002). Glycation is a reversible and non-enzymatic reaction of the aldehyde groups of reducing sugars with amino groups of proteins. The products from glycation due to excessive glucose can chemically modify DNA causing mutation and complex DNA rearrangement. A variety of sugars including glucoses, glucose autoxidation products (arabinose and glyoxal) and pentoses can also contribute to advanced glycation end products (AGEs) formation (CervantesLaurean et al., 1996). In addition to sugars, oxidation of lipids and ε amino acids can also result in N -carboxymethylysine (CML) formation, especially during inflammation. This non-enzymatic glycosylation of protein occurs between reducing sugars and primary amino groups in protein by direct reaction (Asgary et al., 1999). The reaction forms Schiff bases, followed by Amadori rearrangement to yield a stable ketoamine derivative of protein (Lee and Cerami, 1992). The ketoamine will then form a variety of fluorescent and non-fluorescent AGEs through oxidation (Cervantes-Laurean et al., 2006). Pentosidine is an example of fluorescent AGE, whereas CML is non-fluorescent AGE (Cervantes-Laurean et al., 2006). CML and pentosidine are AGEs that are increased in skin collagen I during both intrinsic aging and diabetes (Dyer et al., 1993). The extent of AGE formation is increased during diabetic hyperglycemia (Asgary et al., 1999). These AGEs always associate with numerous pathologies. Rutin metabolites were found to be able inhibiting glucoseinduced collagen fluorescent relevant to hyperglycemia (Vishwanath et al., 1986). Both rutin and its aglycone (quercetin) extracted from the stalks of Euonymus alatus (Thunb.) Siebold (Celastraceae) were found to exhibit identical therapeutic potency in treating diabetes (Yang and Zhang, 2008). Besides rutin and quercetin, its vicinyl dihydroxyl groups containing metabolites such as 3,4-dihydroxyphenylacetic acid (3,4-DHPAA), 3,4-dihydroxytoluene (3,4-DHT) had also been proven to inhibit the formation of pentosidine and fluorescent adducts, as well as glycation of collagen I in a dose-dependent manner. The non-vicinyl dihydroxyl group containing metabolites, namely homovanillic acid (HVA) and m-3-hydroxyphenylacetic acid (m-3-HPAA) were less effective in CML formation (CervantesLaurean et al., 2006). Prolong diabetic problem always accompanied by kidney damage due to the deterioration of kidney function for excessive glucose filtration. The same group of researchers also showed that rutin could protect the kidney of diabetic rats by decreasing the accumulation of hydroxyproline, laminin and type IV collagen, as well as decreasing the tissue inhibitors of metalloproteinases, but increasing the activity of matrix metalloproteinases in kidney (Kamalakkannan and Stanely Mainzen Prince, 2006). By increasing the activity of matrix metalloproteinases, the enzymes are capable to degrade all kinds of extracellular matrix proteins. It is known that a variety of proteins are also subjected to non-enzymatic glycation which is consequently contributed to various long-term complication of the disease. All these results indicated that rutin might postpone renal damage and might be a potential drug for the prevention of early diabetic neuropathy (Hu et al., 2009; Hao et al., 2012). It could prevent glycosylation of hemoglobin from getting serious which might then lead to other complication of diabetes such as nerve damage and blindness (Asgary et al., 1999). Rutin was able to reverse the trimethyltin induced spatial memory impairment and the damage to pyramidal neurons in the hippocampal region. The protective effect of rutin (0.75%w/w) had been proven by Koda et al. (2008) from their in vivo study on 4 weeks old of male


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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66

10


Sprague-Dawley rats. A group of researchers from Thailand reported that the administration of rutin at 60 mg/kg body weight to the dexamethasone-treated male ICR (Imprinting Control Region) mice had successfully reversed cognitive deficits including impaired dentate gyrus cell proliferation, and protected against morphological changes in the CA3 region (Tongjaroenbuangam et al., 2011). In vitro neuroprotective property of rutin was also reported by Gulpinar et al. (2012) using enzymatic methods such as acetylcholinesterase, butyrylcholinesterase and tyrosinase inhibition assays spectrophotometrically. These might explain the findings of other investigators who reported the positive effect of rutin for the improvement of sight and hearing capability (Campbell, 1997), hypertension (Ushida et al., 2008; Lee et al., 2012), hepatotoxicity (Janbaz et al., 2002) and memory impairment (Pu et al., 2007; Han, 2009). The high antioxidative activity of rutin could inhibit the glycosylation of protein, but its performance in the prevention of protein glycosylation was somehow lower than its aglycone, quercetin. The good performance of quercetin was due to the existence of o-dihydroxyl groups or non-glycosylation of hydroxyl group in the chemical structure. There were also investigators who proved that rutin could reduce blood fat and cholesterol by decreasing the levels of lipids, particularly the low density and very low density lipoprotein cholesterol in plasma, but increase the levels of plasma high density lipoprotein cholesterol (Kayashita et al., 1997; Zeng et al., 2010). The findings were in line with Jiang et al. (2007) who reported a dose response effect of rutin (0.025–8 mg buckwheat/ mL) in inhibiting low density lipoprotein peroxidation. Moreover, the development of fatty liver by body weight gain in mice treated with high fat plus rutin diet (25 and 50 mg/kg body weight daily) had been proven to be lower than those mice (C57BL/6) treated with high fat diet only, 64.4% of the total calories as fat for 4 weeks (Choi et al., 2006). Rutin even quoted as a promising flavanoid to reduce the risk of atherosclerosis because of its capacity in inhibiting low density lipoprotein oxidation (Milde et al., 2004). Rutin was reported to be effective in reducing abnormal leakage, capillary impairment and venous insufficiency in cardiovascular diseases (Hertog et al., 1995; Reynolds, 1996; Rimm et al., 1996; Annapurna et al., 2009). It showed the inhibition of human platelet aggregation which might cause stroke, myocardial infarction, pulmonary embolism or the blockage of blood vessels to other parts of the body (Pace-Asciak et al., 1995). The blood vessel hardening condition in atherosclerosis could subsequently lead to cardiovascular diseases. Korkmaz and Kolankaya (2010) reported that the effective treatment for fragility of blood vessel capillary was due to the high radical scavenging activity and antioxidant capacity of rutin. This quercetin glycoside; rutin has been recognized for its capability to decrease the permeability of capillaries. Another well known biological activity of rutin is its anti-cancer property. The anti-cancer property of rutin was observed from the inhibition of various cancer cell lines in vitro and the reduction of tumor development in experimental animals (Deschner et al., 1991; Webster et al., 1996; Van der Logt et al., 2003). The reduction might be attributed to the inhibition of DNA topoisomerases I and II (topo I and topo II), which are the markers of DNA and chromosome damage (Cantero et al., 2006). Indeed, cancer cells are produced in order to protect body from external stimuli. The aggressive growth of cancer cells because of weak immune system against the external stimuli has caused the killing effect. Other biological activity of rutin includes gastroprotective effect against gastric lesion and gastric mucosal ulceration (La Casa et al., 2000). 3.4. Hormone therapy of rutin Based on the previous studies, plants which have the compound with almost similar structure of rutin such as daidzein and

formononetin were found to be able regulating the endocrine system of body (Guo et al., 2012). They are phytoestrogens which act as estrogens. Estrogen is one of the main hormones and the development of mammary glands is mainly regulated by neuroendocrine system (Tucker, 1981). Therefore, rutin is also a phytoestrogen which could bind with estrogen receptor and then exert estrogen-like effects because of the structural similarity to endogenous estrogen (Suman and Saffron, 2008). Rutin has doubleglycoside structure that formed through the combination of hydroxyl at position C3 of quercetin and rutinose (Guo et al., 2012). This compound has a similar structure of planar double benzene rings to the endogenousestrogen17-β-estradiol (17-β-E2). It is considered that this structure could combine to the site of estrogen receptor occupied by 17-β-E2 and thus play an estrogen-like role (Tham et al., 1998).

4. Metabolism of rutin in body Although rutin has been reported to be widely consumed from edible plants, its precise metabolism is still unknown. Rutin, as other flavonoids usually occur as glycosides in dietary plants (Manach et al., 1997). It is generally considered that flavonoid glycosides are firstly hydrolyzed by the digestive microflora before being absorbed (Kuhnau, 1976). Therefore, rutin was found to be absorbed more slowly than quercetin because quercetin was ready available for digestive absorption both in the small intestine and in the large bowel (Manach et al., 1997). However, Hollman et al. (1995) reported rutin from onion was more readily absorbed than its aglycone moiety in ileostomy patients. Therefore, the characterization and structure–function relationship of rutin and its metabolites are of great importance for better understanding of the role of rutin in disease prevention and progression (CervantesLaurean et al., 2006). The understanding about the mechanism of rutin is essential for the evaluation of possible physiological effects of rutin (Manach et al., 1997). In recent years, the mechanism of flavonoid glycosides are gradually understood that they are generally hydrolyzed by intestinal and bacterial enzymes to corresponding aglycones and other smaller metabolites which is absorbable by the gut (Hollman and Batan, 1997). Studies reported that little or no dietary rutin is absorbed because gut microflora in the intestines metabolize rutin into a variety of small metabolites (Griffiths and Barrow, 1972; Winter et al., 1989). The reaction involves hydrolysis of rutin catalyzed by α-rhamnosidase and β-glucosidase (Bokkenheuser et al., 1987; Manach et al., 1995). The metabolites produced include quercetin (3,5,7,3′,5′-pentahydroxyflavonol), isoquercetin (quercetin 3-glycoside) and other phenol derivatives such as 3,4-DHPAA, 3,4-DHT, 3-HPAA, and HVA (Griffiths and Barrow, 1972; Baba et al., 1981; Winter et al., 1989; Schneider et al., 2000; Braune et al., 2001; Cervantes-Laurean et al., 2006; Arjumand et al., 2011). Manach et al. (1996) reported that about 80% of circulating plasma quercetin is present as methoxy derivative (isorhamnetin), and flavonol metabolites were circulating in plasma as conjugated derivatives. Conjugation or methylation arises from the presence of two –OH on the B-ring, or the presence of –OH in the position of 3 and 5 at the vicinity of the 4-oxo group probably plays a role in lowering the reactivity of quercetin (Manach et al., 1997). These metabolites, particularly quercetin, 3,4-DHPAA and 3,4-DHT contain vicinyl dihydroxyl groups in their chemical structure which are important for oxidation inhibition. The presence of vicinyl dihydroxyl groups was also shown to affect the phenols inhibiting iron and coppercatalyzed production of radical species (Cervantes-Laurean et al., 2006). It is likely that metal chelation and free radical scavenging properties contributed to the inhibition of glucose autoxidation by rutin metabolites containing vicinyl dihydroxyl groups.


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Quercetin plasma levels have been found to be 3.5 μmol/L, when doses of 50 mg of either rutin or quercetin were used in the diet of healthy human volunteers (Erlund et al., 2000). Moreover, up to 50% of an ingested dose of 75 mg rutin was recovered as microbial metabolites from urine of human volunteers (Sawai et al., 1987). This finding further supports the appearance of micromole per liter metabolite concentration after rutin consumption. Rutin is hydrolyzed into low molecular weight phenolic acids besides its aglycone, quercetin by the colonic microflora (Olthof et al., 2003). This is because the polyphenol rutin derivatives like quercetin-3-o-rhamnoglucoside were not found in urine after consumption. However, 3-HPAA, HVA, 3,4-DHPAA, and 3,4-DHT which are the metabolites resulted from colonic microflora degradation were detected (Baba et al., 1981).

5. Conclusion Rutin appears to be a potential phytochemical ingredient in food supplement and medicinal products nowadays. Numerous studies have reported the diverse pharmacological activities of rutin, as well as the risk reduction of diseases for health promotion. Owing to its significant functionality, the incorporation of rutin into food-based products is likely to be a promising practice for development of functional foods and nutraceuticals nowadays (Zhu et al., 2008). Somehow, the incorporation requires scientifically proven data for the ethnobotanical claims. On the one hand, biologists, botanists and pharmacists are actively involved in the studies in relation to biological activities of rutin both in vitro and in vivo. The biochemical properties and metabolic changes after rutin consumption are also being investigated intensively. On the other hand, technologists and engineers are focused on the optimization of rutin extraction and production. With the involvement of multidisciplinary profession, the mechanism of rutin will be clearly explained with the efficacy and safety data, whereas high yield of rutin can be obtained from the well optimized extraction method with cost effective operation approach in near future.

Acknowledgment The author would like to express her gratitude to Research Alliance of Biotechnology from Universiti Teknologi Malaysia for providing the research grant GUP (Tier 2) 05J84. References Abdullah, Y., Schneider, B., Petersen, M., 2008. Occurrence of rosmarinic acid, chlorogenic acid and rutin in Marantaceae species. Phytochem. Lett. 1, 199–203. Abraham, L.C.N., Masakuni, T., Isao, H., Hajime, T., 2008. Antioxidant flavonoid glycosides from the leaves of Ficus pumila L. Food Chem. 109, 415–420. Adibhatla, R.M., Hatcher, J.F., 2010. Lipid oxidation and peroxidation in CNS health and disease: from molecular mechanisms to therapeutic opportunities. Antioxid. Redox Signaling 12, 125–169. Aehle, E., Grandic, S.R.L., Ralainirina, R., Baltora-Rosset, S., Mesnard, F., Prouillet, C., Maziere, J.C., Fliniaux, M.A., 2004. Development and evaluation of an enriched natural antioxidant preparation obtained from aqueous spinach (Spinacia oleracea) extracts by an adsorption procedure. Food Chem. 86, 579–585. Afshar, J., Delazar, A., 1994. Rutin from Ruta graveolens L. J. Sch. Pharm. (Med. Sci. Univ. Tehran) 4, 1–12. Ahmed, S., Anuntiyo, J., Malemud, C.J., Haqqi, T.M., 2005. Biological basis for the use of botanicals in osteoarthritis and rheumatoid arthritis: a review. EvidenceBased Complementary Alternative Med. 2, 301–308. Albu, S., Joyce, E., Paniwnyk, L., Lorimer, J.P., Mason, T.J., 2004. Potential for the use of ultrasound in the extraction of antioxidants from Rosmarinus officinalis for the food and pharmaceutical industry. Ultrason. Sonochem. 11, 261–265. Altiok, E., Baycin, D., Bayraktar, O., Ulku, S., 2008. Isolation of polyphenols from the extracts of olive leaves (Olea europaea L.) by adsorption on silk fibroin. Sep. Purif. Technol. 62, 342–348.

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