|Year : 2016 | Volume
| Issue : 1 | Page : 28-34
Isolation, identification, and in vivoevaluation of flavonoid fractions of chloroform/methanol extracts of Rheum emodi roots for their hepatoprotective activity in Wistar rats
Muhammad Shoaib Akhtar1, Aamna Habib1, Amanat Ali2, Sajid Bashir1
1 Department of Pharmacology, University of Sargodha, Sargodha, Pakistan
2 Department of Food Science and Nutrition, College of Agricultural and Marine Sciences, Sultan Qaboos University, Al-Khoud, Muscat, Oman
|Date of Submission||04-Jun-2015|
|Date of Acceptance||06-Aug-2015|
|Date of Web Publication||12-Jan-2016|
Department of Food Science and Nutrition, College of Agricultural and Marine Sciences, Sultan Qaboos University, PO Box 34, PC 123, Al-Khoud, Muscat
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Objective: Even though the rhizome of Rheum emodi (Chinese rhubarb) has been used since centuries as a traditional medicinal plant in treating a number of disease conditions, the bioactive components responsible for its hepatoprotective activity have not been identified. Therefore, we isolated, identified, and evaluated in vivo the compounds in chloroform/methanol extracts of Rheum emodi roots for their hepatoprotective activities in rats. Materials and Methods: Nine different fractions were collected by column chromatography and were further isolated and identified through thin layer chromatography (TLC) analysis for the presence of flavonoids. The isolated flavonoids containing fractions were then evaluated for their hepatoprotective activity in paracetamol-induced toxicity in male Wistar rats. Silymarin [50 mg/kg body weight (BW)] was used as a control hepatoprotective drug. To assess liver functions, serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), albumin, and bilirubin (total and direct) were determined. Results: Only five collected fractions (F1to F5) showed the presence of different flavonoids and the fraction F2showed the presence of five different types of flavonoids. The isolated flavonoid containing fractions of Rheum emodi were significantly effective in decreasing the elevated the levels of ALT, AST, ALP, and bilirubin (total and direct) due to paracetamol-induced hepatotoxicity in Wistar rats. The fractions at dose level of 0.125 mL/kg BW showed significant hepatoprotective effects in rats. The fraction F2at a dose level of 0.5 mL/kg BW showed the maximum therapeutic efficacy followed by the same fraction at 0.25 mL/kg BW and 0.125 mL/kg BW, fractions F1, silymarin, F3, F4and F5. Conclusion: The results suggest that isolated fractions of Rheum emodi roots contained flavonoids, which showed significant hepatoprotective activity in Wistar rats. Further investigations are however, required for the identification of individual flavonoids as well as other bioactive components in Rheum emodi roots, and to establish their structure and mechanism of action for their hepatoprotective activity.
Keywords: Flavonoids, hepatoprotective activity, Rheum emodi root extracts
|How to cite this article:|
Akhtar MS, Habib A, Ali A, Bashir S. Isolation, identification, and in vivoevaluation of flavonoid fractions of chloroform/methanol extracts of Rheum emodi roots for their hepatoprotective activity in Wistar rats. Int J Nutr Pharmacol Neurol Dis 2016;6:28-34
|How to cite this URL:|
Akhtar MS, Habib A, Ali A, Bashir S. Isolation, identification, and in vivoevaluation of flavonoid fractions of chloroform/methanol extracts of Rheum emodi roots for their hepatoprotective activity in Wistar rats. Int J Nutr Pharmacol Neurol Dis [serial online] 2016 [cited 2020 Jun 6];6:28-34. Available from: http://www.ijnpnd.com/text.asp?2016/6/1/28/173784
| Introduction|| |
Recently, therapeutic approaches have shifted toward the evaluation of natural products in liver ailments after evidence-based evaluation, standardization, and establishment of safety profiles through in vivo animal model studies and randomized controlled clinical trials.,, Liver is the main organ to exclusively detoxify and excrete a majority of the xenobiotics and their metabolites from the body. However, it is subjected to potential harm from a massive array of pharmaceutical chemicals and environmental toxins including the plant natural products, which may carry the risk of herb-induced liver injury., Impaired liver functions are one of the major reasons for morbidity and mortality in humans. Developing effective therapies to treat liver ailments using herbal preparations however, still require systematic studies to establish their safety and efficacy profiles.,
Plant phenolics have been symbolized as important modules of secondary metabolites and the flavonoids represent one of the most ubiquitous families., Traditional medicinal plants containing higher levels of flavonoids have been reported to possess the hepatoprotective properties.,,, A number of diverse varieties of flavonoids have been shown to possess antioxidant, anti-inflammatory, antibacterial, antifungal, antiviral, antidiabetic, anticancer, cardioprotective, and hepatoprotective activities.,,,,,, Catechin, a type of disease-fighting flavonoid and a potent antioxidant, is extensively used to treat hepatitis. Pattanayak et al. (2011) reported that crude flavonoid extracts of Cajanus scarabaeoides (L) possessed hepatoprotective activity. Various flavonoids isolated from Lespedeza cuneata (hirsutrin, quercetin, and avicularin) also showed hepatoprotective activity in HepG2 cells against tert-butyl hydroperoxide (t-BHP)-induced liver injury. Flavonoids have also been shown to have the triple recycling (enterohepatic, enteric, and local recycling) impact on the site-specific bioavailability and duration ofpolyphenol's pharmacokinetics in vivo.
Rheum emodi (Chinese rhubarb), locally known as “revand-chini,” is a medicinal plant that has a long history of medicinal use. The roots as a whole and certain components isolated from Rheum emodi roots have been reported to possess antidiabetic, antioxidant, antifungal, antimicrobial, hepatoprotective, and cytotoxic as well as nephroprotective activities.,,,, Ibrahim et al. (2008) observed that rhizomes of Rheum emodi showed a protective effect on primary rat hepatocyte cultures in vitro and CCl4-induced hepatotoxicity in vivo in the rat model. Zargar et al. (2014) observed that the aqueous extracts of Paeonia emodi rhizome at the dose of 200mg/kg body weight (BW) for 30 days were found to be safe and significantly reduced the serum triglycerides (TGs), total cholesterol (TC), low density lipoprotein cholesterol (LDL-c), and atherogenic index (AI) while high density lipoprotein cholesterol (HDL-c), superoxide dismutase (SOD), and glutathione peroxidase (GPx) levels rose to a considerable extent in hyperlipidemic Wistar rats. Kumar et al. (2014) showed that hot ethyl acetate extracts of Rheum emodi rhizome exhibited cancer-specific chemopreventive and antimetastatic properties. Ye et al. (2014) indicated that the no-observed-adverse-effect level (NOAEL) for the aqueous extract of Rheum emodi (AERE) was 4,000 mg/kg/day in both genders of Sprague Dawley (SD) rats that received doses of 0 mg/kg/day, 1,000 mg/kg/day, 2,000 mg/kg/day, and 4,000 mg/kg/day of AERE for 90 days. Although the dietary recommendations with regard to the types and amounts of flavonoids have not yet been established, based on the seasonal availability of food sources a provisional recommended daily allowance (RDA) of total flavonoids intake between 250 mg/day and 400 mg/day has been recommended. In a previous study, we evaluated the hepatoprotective effects of dried powder and crude aqueous and methanolic extracts of Rheum emodi roots against paracetamol-induced liver damage in albino rats. However, the bioactive components responsible for the hepatoprotective activity of Rheum emodi roots were not isolated and identified. Therefore, in the present study we isolated, identified, and evaluated the various flavonoids containing fractions of chloroform/methanolic extracts of Rheum emodi roots for their hepatoprotective activity in Wistar rats.
| Materials and Methods|| |
The dried roots (rhizome) of Rheum emodi, locally known as “revand-chini,” were purchased from the local herbal market of Faisalabad, Punjab, Pakistan. The identification and authentication were done by the experts (taxonomists) from the Department of Botany, University of Agriculture, Faisalabad, Punjab Pakistan. The dried Rheum emodi roots were powdered in a China herbal grinder and stored in air-tight containers at 4°C until the analysis, as described earlier by Akhtar et al.
Sixty healthy adult male Wistar albino rats, weighing 200–250 g were used for this study. They were randomly divided into 10 groups with six rats in each group. They were housed in individual metal cages in the animal house of the Department of Pharmacy, University of Sargodha, Sargodha, Punjab, Pakistan. The rats were maintained at 25 ± 2°C, with 12-h light and dark cycles. They were fed ad libitum on a normal standard rat cow and had 24 h free access to water. The study protocols were approved by the institutional ethical committee of University of Sargodha, Sargodha, Punjab, Pakistan.
Preparation of extracts
Seven and half kilograms (7.5 kg) of powdered roots of Rheum emodi were successively extracted with petroleum ether, chloroform, and methanol using 30 L of each solvent for cold maceration. The process of maceration and extraction continued for 7 days at room temperature (25 ± 2°C) with occasional shaking with each solvent, as described by Pattanayak et al. The solid waste residue was rejected. The solvents from each extraction were evaporated in a rotary evaporator till completely evaporation and the dried extracted residue was weighed. The final yield of the extracted material was found to be 435 g that was used to prepare the chloroform/methanol fractions, which were then tested for the presence of flavonoids. The flow diagram indicating the steps for the extraction, isolation, and identification of various flavonoids extracts from Rheum emodi roots are shown in [Figure 1].
|Figure 1: The flow diagram indicating the steps for the extraction, isolation, and identification of various flavonoids extracts from Rheum emodi roots|
Click here to view
Isolation, purification, and identification of flavonoids
The chloroform/methanol fractions were separated, isolated, and purified using column chromatographs over silica gel 60, 70–240 mesh. The column was run with various proportions of chloroform/methanol (CHCl3/MeOH) solvent systems. In the first place, pure chloroform was used and then the quantity of methanol in the solvent system was changed gradually to change the polarity as shown in [Table 1]. Two hundred and fifty milliliter (250 mL) of nine different isolated fractions was collected at various ratios of CHCl3/MeOH solvent system as mobile phase [Table 1]. The isolated fractions collected periodically were pooled collectively after separating them with thin layer chromatography (TLC) and examining them under ultraviolet (UV)-light as described by Yaqing et al. The isolated fractions were tested for the presence of flavonoids using Shibata's test  and other tests as described by Edeoga et al. The isolated fractions were further subjected to evaporation using rotary evaporator at 40°C and the final dried fractions were then evaluated for their hepatoprotective activity in Wistar rats.
|Table 1: Comparative thin layer chromatography (TLC) analysis of isolated chloroform/methanol fractions of Rheum emodi roots|
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Hepatotoxicity induction in rats
Paracetamol (acetaminophen) was used as an inducer of hepatotoxicity. A single oral dose of paracetamol (640 mg/kg BW) in 1% methyl cellulose solution was used for the induction of hepatic damage in rats.
Treatments of groups
The test drugs were administered with normal saline (10 mL/kg BW) to various treatment groups with the help of gavage. The doses for the isolated fractions of extract and silymarin were calculated on body weight basis for each individual animal. Group I (untreated control) received 1% methyl cellulose (13 mL/kg BW) orally at 0 h and four doses of normal saline (10 mL/kg BW) at 6-h intervals. Group II received a single dose of paracetamol 640 mg/kg BW at 0 h and then four doses of normal saline (10 mL/kg BW) at 6-h intervals. Group III was given paracetamol 640 mg/kg at 0 h and four doses of isolated fraction of Rheum emodi (F1) 0.125 mL/kg BW at 6-h intervals. Group IV was given paracetamol 640 mg/kg BW at 0 h and four doses of isolated fraction of Rheum emodi (F2) 0.125 mL/kg BW at 6-h intervals. Group V was given paracetamol 640 mg/kg BW at 0 h and four doses of isolated fraction of Rheum emodi (F3) 0.125 mL/kg BW at 6 h intervals. Group VI was given paracetamol 640 mg/kg BW at 0 h and four doses of isolated fraction of Rheum emodi (F4) 0.125 mL/kg BW at 6-h intervals. Group VII was given paracetamol 640 mg/kg BW at 0 h and four doses of isolated fraction of Rheum emodi (F5) 0.125 mL/kg BW at 6-h intervals. Group VIII (treated control) was given paracetamol 640 mg/kg BW at 0 h and four doses of silymarin (50 mg/kg BW) at 6-h intervals. As the isolated fraction of Rheum emodi (F2) showed higher hepatoprotective activity, two additional higher doses of this fraction were further tested for their graded impact on hepatoprotection in groups IX and X. Group IX was given paracetamol 640 mg/kg BW at 0 h and four doses of isolated fraction of Rheum emodi (F2) 0.25 mL/kg BW at 6-h intervals. Group X was given paracetamol 640 mg/kg BW at 0 h and four doses of isolated fraction of Rheum emodi (F2) 0.5 mL/kg BW at 6-h intervals.
At the end of the experiment, the animals were anesthetized using ether and 5 mL of blood was collected from each animal in centrifuge tubes by cutting the carotid artery. The blood samples were placed at 4°C for 12 h and then centrifuged at 3000 rpm for 15 min for the separation of serum (El-Sawi and Sleem, 2010). The serum was used for the determination of alanine transaminase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), albumin, and bilirubin (both direct and total) with the help of BTS-330, a semi-automated chemistry analyzer (Bio-systems S.A., Barcelona, Spain).
Statistical analysis of the data was done using one-way analysis of variance (ANOVA) technique and the results are presented as means ± standard deviation (SD). The means were compared for significance level by using the least significance difference (LSD) test and Duncan's multiple range test (DMRT) as described by Steel and Torrie. The level of significance was set at P < 0.05.
| Results|| |
Comparative thin layer chromatography analysis of different flavonoid fractions isolated from the methanolic extract ofRheum emodi roots
The data obtained through the comparative TLC analysis on the isolated and identified components of nine different fractions of chloroform/methanolic extracts of Rheum emodi roots are presented in [Table 1]. The periodic changes in the ratio of the solvent system helped to collect the appropriate resultant fractions through column chromatography, which was further analyzed with the help of TLC analysis using UV light to verify the presence of flavonoids. The chemical tests performed on isolated fractions confirmed the presence of flavonoids. Out of nine different fractions (F1 to F9) only five fractions (F1 to F5) showed the presence of flavonoids. The solvent systems CHCl3/MeOH (90:10 and 70:30) revealed the presence of three bioactive components, and it was confirmed that the detected bioactive components were flavonoids. The solvent system CHCl3/MeOH (90:10) revealed the presence of five bioactive constituents of flavonoids. The solvent system (CHCl3/MeOH 50:50) revealed the presence of only one bioactive constituent in the extracted fractions. These constituents were confirmed to be the flavonoids through chemical tests. The solvent systems from (CHCl3/MeOH 40:60 to 10:90) also revealed the presence of three, four, two, and two constituents, respectively. However, chemical tests did not show the presence of flavonoids in these fractions.
Effects of flavonoid fractions of Rheum emodi
roots and silymarin on serum biochemical parameters against paracetamol-induced hepatotoxicity
The data on the posttreatment effects of isolated flavonoid fractions of Rheum emodi roots and silymarin on the serum biochemical parameters against the paracetamol-induced hepatotoxicity in Wistar rats is shown in [Table 2]. The serum levels of ALT, AST, ALP, bilirubin (total and direct), and albumin in the treated groups and the untreated control group differed significantly (P < 0.05). The mean values in the control group for various parameters were 37.83 ± 3.43 IU/L, 41.4 ± 2.42 IU/L,131.3 ± 2.5 IU/L, 0.32 ± 0.02 (g/dL), 0.21 ± 0.03 (g/dL), and 3.92 ± 0.21 (g/dL) [Table 2]. Significantly elevated levels of serum ALT, AST, ALP, and bilirubin (total and direct) levels were observed in the paracetamol-induced toxicity group (II) as shown in [Table 2], whereas the serum albumin levels decreased significantly 2.02 ± 0.06 (g/dL) as compared to the control group. The various isolated flavonoid fractions of Rheum emodi showed significantly variable results and were found to be effective in decreasing the elevated the levels of ALT, AST, ALP, and bilirubin (total and direct) due to paracetamol-induced hepatotoxicity in Wistar rats. The albumin levels, which decreased due to paracetamol-induced hepatotoxicity in rats, were found to be similar as compared to the control group when the isolated fraction F2 was given at either 0.25 mL/kg BW or 0.5 mL/kg BW. The most marked efficacy in reversing the paracetamol-induced hepatotoxicity in rats was shown by the isolated fraction F2 at 0.5 mL/kg BW followed by the same fraction F2 at 0.25 mL/kg BW and at 0.125 mL/kg BW. The hepatoprotective effects of isolated fractions F1 and F2 at 0.125 mL/kg BW were even found to significantly (P < 0.05) better for ALT and AST as compared to Silymarin, the commonly used hepatoprotective drug [Table 2].
|Table 2: Posttreatment effects of isolated flavonoid fractions of Rheum emodi roots and silymarin on the serum biochemical parameters against the paracetamol-induced hepatotoxicity in Wistar rats (n=6)|
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| Discussion|| |
The main objective of this study was to isolate, identify and evaluate the bioactive components in the isolated fractions of Rheum emodi root extracts for their hepatoprotective activity against the paracetamol-induced liver damage in Wister rats. Our results indicated the presence of flavonoids in the isolated fractions of Rheum emodi roots and confirm the earlier findings of Potchoo et al., who showed the presence of flavonoids in Rheum emodi roots. Flavonoids have been shown to possess antioxidant, anti-inflammatory, antibacterial, antifungal, antiviral, anticancer, cardio-protective and hepatoprotective activities.,,,, As some of the medicinal plants as a whole or their parts have already been identified to possess hepatoprotective actions because of the presence of relatively high amounts of flavonoids,, 21, ,,, we therefore anticipated that it may be the flavonoids in Rheum emodi roots, which may be responsible for its hepatoprotective capability. The extracted materials from Rheum emodi roots were therefore used to separate various flavonoid compounds and the presence of flavonoids was confirmed in the five isolated fractions by thin layer chromatography under UV light. The high performance liquid chromatography (HPLC) and high performance thin layer chromatography (HPTLC) as well as the silica gel column chromatography (SGCC) and high-speed countercurrent chromatography (HSCCC) extraction procedures have already been shown to be useful, efficient and robust for isolating the flavonoids and other bioactive components from the various extracts of polyherbal formulations containing Rheum emodi.,
The isolated flavonoid fractions were then evaluated for their hepatoprotective activity against the paracetamol-induced liver damage in Wister rats. Overdoses of paracetamol may cause severe hepatotoxicity and even may lead to fatal liver failure due to centrilobular hepatic necrosis and hepatic oxidative stress., It has been well-established that paracetamol at toxic dose level affects the liver enzymes (including cytochrome P-450) accountable for metabolism via sulphation and glucuronidation, which become saturated and consequently the elevated levels of paracetamol moieties are oxidized to n-acetyl-p-benzoquinoneimine, a highly reactive toxic metabolite., We therefore studied the serum levels of ALT, AST, ALP, bilirubin (total and direct), and albumin to assess the changes in liver functions as a result of hepatocyte damage. The levels of ALT, AST, ALP, bilirubin total, and direct increased significantly (P < 0.05), whereas the levels of albumin decreased after the administration of acute toxic dose of paracetamol as compared to control group. Our results indicated that various isolated flavonoid fractions of Rheum emodi were significantly effective in decreasing the elevated the levels of ALT, AST, ALP, and bilirubin (total and direct) due to paracetamol-induced hepatotoxicity in Wistar rats. The albumin levels, which decreased due to paracetamol-induced hepatotoxicity in rats, were restored back when the isolated fraction F2 was given at either 0.25 mL/kg BW or 0.5 mL/kg BW. The most marked efficacy in reversing the paracetamol induced hepatotoxicity in rats was shown by the isolated fraction F2 at 0.5 mL/kg BW followed by the same fraction F2 at 0.25 mL/kg BW and at 0.125 mL/kg BW, respectively. The hepatoprotective effects of isolated fractions F1 and F2 at 0.125 mL/kg BW were even found to be significantly (P < 0.05) better for ALT and AST as compared to silymarin, the commonly used hepatoprotective drug [Table 2]. Our results clearly indicated that the most active fraction among the five isolated flavonoid fractions was the fraction F2, which showed the highest hepatoprotective activity against the paracetamol-induced hepatotoxicity in Wistar rats, even better than silymarin, the commonly used standard hepatoprotective drug [Table 2]. The fraction F2 showed the presence of five different flavonoid compounds, which suggest that the active principles responsible for the hepatoprotective activity of Rheum emodi root extracts are its flavonoids. Flavonoids have triple recycling (enterohepatic, enteric, and local recycling) impact on the site-specific bioavailability and duration of polyphenols pharmacokinetics in vivo. Our results confirm these findings. Our results are also in agreement with those reported by Ibrahim et al. who observed that the extracts of Rheum emodi showed protective effects on both in vitro studies on primary hepatocytes cultures as well as against CCl4-mediated liver injury in in vivo rat model. The aqueous extracts of Rheum emodi have been shown to be relatively safe., The presence of a number of other phenolic compounds such as eugenol, gallic acid, quercetin, rutin, epicatechin, desoxyrhapontigenin, rhapontigenin, and mesopsin in the rhizome of Rheum emodi have also been shown to possess the free radical scavenging antioxidant activity., However, further studies are needed to explore the safety and efficacy of these components for their hepatoprotective activities.
| Conclusion|| |
The data presented in this study clearly indicated the presence of flavonoids in the various extracted fractions of Rheum emodi roots, which exerted significant hepatoprotective effects against paracetamol-induced liver toxicity in Wistar rats. The fraction F2 showed the presence of five different flavonoid compounds, which suggest that the active component responsible for the hepatoprotective activity of Rheum emodi root extracts are its flavonoids. Further studies are however, needed to explicate the presence of various types of flavonoids in the isolated fractions of Rheum emodi extracts as well as to establish their structure through spectroscopic investigations and the mechanism (s) of action for their hepatoprotective activity.
We are thankful to the University of Sargodha for providing the facilities and financial assistance.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2]
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| ||Shahzad A. Pandith,Riyaz Ahmad Dar,Surrinder K. Lattoo,Manzoor A. Shah,Zafar A. Reshi |
| ||Phytochemistry Reviews. 2018; |
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||The use of Chinese herbal medicine as an adjuvant therapy to reduce incidence of chronic hepatitis in colon cancer patients: A Taiwanese population-based cohort study
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| ||Journal of Ethnopharmacology. 2017; 202: 225 |
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||Effects of a standardized extract of Rheum turkestanicum Janischew root on diabetic changes in the kidney, liver and heart of streptozotocin-induced diabetic rats
| ||Azar Hosseini,Hamid Mollazadeh,Mohammad Sadegh Amiri,Hamid Reza Sadeghnia,Ahmad Ghorbani |
| ||Biomedicine & Pharmacotherapy. 2017; 86: 605 |
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