Professional Documents
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Journal of Ethnopharmacology
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Review
art ic l e i nf o
a b s t r a c t
Article history:
Received 16 June 2013
Received in revised form
16 October 2013
Accepted 17 October 2013
Available online 30 October 2013
Ethnopharmacological relevance: Rutin is a common dietary avonoid that is widely consumed from
plant-derived beverages and foods as traditional and folkloric medicine worldwide. Rutin is believed to
exhibit signicant pharmacological activities, including anti-oxidation, anti-inammation, 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 leaets reporting on rutin from
natural resources are systematically reviewed, particularly in the aspect of its extraction methods and
biological activities. Factors affecting the efciency of rutin extraction such as extraction temperature,
duration and solvent to sample ratio are presented based on the ndings 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 reux 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 difcult
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.
Keywords:
Rutin
Extraction
Solid phase extraction
Antioxidant
Anti-inammation
Contents
1.
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-3
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-, tumor necrosis factor-; topo I and II, topoisomerases I and II; UV, ultraviolet; WHO, World Health Organization
n
Tel.: 60 19 7214378; fax: 60 7 5569706.
E-mail addresses: lschua@ibd.utm.my, chualeesuan@utm.my
0378-8741/$ - see front matter & 2013 Elsevier Ireland Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.jep.2013.10.036
806
2.1.
Heat reux extraction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2.
Ultrasound assisted extraction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.3.
Mechanochemical assisted extraction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.4.
Microwave assisted extraction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.5.
Infrared assisted extraction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.6.
Pressurized liquid extraction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.7.
Solid phase extraction for rutin purication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3. Pharmacological activities of rutin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1.
Antioxidant activity of rutin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2.
Anti-inammation of rutin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.3.
Medical property of rutin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.4.
Hormone therapy of rutin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4. Metabolism of rutin in body . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
807
807
808
808
810
810
810
811
811
812
813
814
814
815
815
815
807
808
Quercetin
(Aglycone)
Rutinose
Table 1
Pharmacological activities of rutin in different experimental models reported by previous investigators.
Biological activity
Experimental model
In vitro
Anti-oxidation
20150 min
20 nM
6 mg/kg
16 days
10 weeks
Cervantes-Laurean et al.
(2006)
Hao et al. (2012)
4 weeks
45 days
100 mg/kg
45 days
Kamalakkannan and
Stanley Mainzen Prince
(2006)
4 weeks
50200 mg/mL
0.75%w/w
15 min
2 weeks
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
150 mM
Agar diffusion
21 days
Anti-microorganism
80 mg/kg
80 mM
25 mg/kg
Cardioprotection
Anti-cancer
30 days
Neuroprotective
72 h
Anti-adipogenic
8 weeks
Kidney protection
Reference
Anti-diabetes
Duration
In vivo
Anti-inammation
Rutin dosage
809
24 h
2h
7 days
7.5 and 15 mg/kg
50, 100 and 200 mg/kg
60 mg/kg
Guinea-pigs treated by aerosolized ovalbumin
Wistar rats (180200 g) induced by 50% ethanol
Female Wistar rats (200 g) were ovariotized
In vitro
Experimental model
In vivo
Duration
Rutin dosage
Reference
810
Anti-asthma
Gastroprotection
Phytoestrogen
Biological activity
Table 1 (continued )
C o C e V o
m
E%
C o C e
100%
Co
C V
R% d d 100%
Co V o
D%
CdV d
100%
C o C e V d
1
2
3
4
811
C o C e
Ce
K d1
K d2
kadsorbent1
kadsorbent2
qe
qmax qe K d
Ce
812
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 HaberWeiss
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 specic 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 uidity 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-inammation of rutin
Inammation is a physiological response of organism to injuries such as trauma, infection or immune response. It occurs and
813
in N -carboxymethylysine (CML) formation, especially during inammation. 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 uorescent and non-uorescent AGEs through oxidation
(Cervantes-Laurean et al., 2006). Pentosidine is an example of uorescent AGE, whereas CML is non-uorescent 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
glucose-induced collagen uorescent 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 uorescent 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-3hydroxyphenylacetic acid (m-3-HPAA) were less effective in CML
formation (Cervantes-Laurean et al., 2006).
Prolong diabetic problem always accompanied by kidney
damage due to the deterioration of kidney function for excessive
glucose ltration. 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 SpragueDawley rats. A group of researchers from Thailand reported that
814
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 signicant 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 scientically 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 efcacy 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.
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