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Protective Activity of Fumaria vaillantii Extract and Monomethyl Fumarate on Acetaminophen Induced Hepatotoxicity in Mice



Ezzat Zamani-Moghaddam, Kian Azami, Bagher Minaei-Zangi, Seyedeh Zahra Mousavi and Omid Sabzevari
 
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ABSTRACT

Mono Methyl Fumarate (MMF) is active component of Fumaria sp. methanolic extract. In Iranian traditional medicine, Fumitory is used widely as a remedy for several diseases including liver dysfunction. In the present study, effect of monomethyl fumarate and Fumaria extract was investigated against acetaminophen-induced acute liver damage and compared to a known hepatoprotective plant, Silybum marianum and its active ingredient, silymarin. Biochemical parameters including AST, ALT, LDH, ALKP and total and direct bilirubin were measured in serum samples. Glutathione (GSH and GSSG) and Malon Di Aldehyde (MDA) contents were determined in mouse liver homogenates. Liver sections were also collected for histopathological examination. Acetaminophen produced acute toxicity at the dose of 640 mg kg-1 in mice while pretreatment and post treatment of animals (i.p., twice daily for 48 h) with monomethyl fumarate, silymarin (25, 50 and 100 mg kg-1) or the plant extracts (300 and 500 mg kg-1) significantly lowered the rise of ALT, AST, LDH, ALKP and bilirubin (Total and direct) in serum. In addition, both compounds and the plant extracts significantly increased glutathione content and reduced MDA level of the liver. Taken collectively, the results indicate that monomethyl fumarate and Fumaria extract exhibited hepatoprotective action against acetaminophen liver injury which is comparable to that of Silybum marianum and silymarin.

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  How to cite this article:

Ezzat Zamani-Moghaddam, Kian Azami, Bagher Minaei-Zangi, Seyedeh Zahra Mousavi and Omid Sabzevari, 2012. Protective Activity of Fumaria vaillantii Extract and Monomethyl Fumarate on Acetaminophen Induced Hepatotoxicity in Mice. International Journal of Pharmacology, 8: 177-184.

DOI: 10.3923/ijp.2012.177.184

URL: https://scialert.net/abstract/?doi=ijp.2012.177.184
 
Received: November 05, 2011; Accepted: February 16, 2012; Published: March 26, 2012



INTRODUCTION

Liver as the key organ in the human body plays an important role for detoxification of entered xenobiotics through phase I and II process. Liver cells therefore, are exposed to high concentration of toxic agents (their metabolites) and can metabolize toxicants for elimination (Guengrich, 2000). Acetaminophen, an analgesic and antipyretic medicine, is mostly metabolized in the liver through glucuronidation and sulfation pathway (Moling et al., 2006). It is transformed, however, to a reactive intermediate, N-acetyl parabenzo quinoreinine which is known to cause centrilobular liver damage and mediate oxidative stress (Zhang et al., 2004; Olaleye and Rocha, 2008). Acetaminophen induced hepatotoxicity is now a commonly used model for liver damage study to screen hepatoprotective activity of natural medicines (Handa et al., 1986; Natanzi et al., 2009). Application of natural products for liver disease is growing because of their safety and efficacy as an alternative remedy.

Silymarin, a flavolignan component of Silybum marianum seeds, has been studied extensively for its protective action against acetaminophen induced liver toxicity (Anundi, 2006; Ellithy and Nada, 2006). In vitro studies have showed that it has an inhibitory effect on phase I and II drug metabolizing enzymes (Ramellini and Meldolesi, 1976). By stabilizing the structure of biological membranes, silymarin prevents liver damage which is possibly due to its ability to scavenge free radicals. This limits lipid-peroxidation process that contributes in membrane damage by hepatotoxins (Valenzuela et al., 1985). Motivation of lipid peroxidation may arise from the free radicals formation through a weakness of antioxidants leading to oxidative stress (Mortazavi et al., 2007; Meera et al., 2008; Diallo et al., 2009; Prasanna and Purnima, 2011). Fumaria vaillantii Loisei. (Fumariaceae) is a species of flowering plant which grows widely in Iran (Zargari, 1989), is used in the Iranian folk medicine for diseases of skin and stimulation of hepatic function and gall bladder. It has also been used as anti-bronchite, antineoplastic, antipyretic, antiscabies, antiscorbite, appetizer, diaphoretic, diuretic and expectorant (Amin, 1991). Monomethyl fumarate (MMF), isolated from the methanolic extract of the whole plant of Fumaria indica (another species of genus Fumaria), has demonstrated antihepatotoxic activity (Rao and Mishra, 1998) against thioacetamide in vitro and against carbon tetrachloride, paracetamol and rifampin toxicities in vivo (Rao and Mishra, 1996). Limited information is available on protective effect of monomethyl fumarate and Fumaria sp. extract against acetaminophen-induced liver toxicity. A good protection of Fumaria parviflora and Momordica balsamina extracts from carbon tetrachloride induced hepatotoxicity in rats has been reported (Alqasoumi et al., 2009).

Damage to the structural integrity of the liver is concluded from histopathological examine and elevated activities of aspartate aminotransferase (AST), Alanine aminotransferase (ALT), Lactate Dehydrogenase (LDH) and Alkaline Phosphatase (ALKP), as well as Malondialdehyde (MDA) concentrations as the end product of lipid peroxidation (Ghazi-Khansari et al., 2005; Iyawe et al., 2006; Koriem et al., 2009; Kanbur et al., 2009; Chavda et al., 2010; Natanzi et al., 2010).

Evaluations of these parameters in the serum and tissue samples of experimental animals are used to asses liver toxicity and protective effects of novel compounds as indicators of hepatoprotective activity (Kumar et al., 2009; Dahiru and Obidoa, 2007). The aim of this study was to investigate effect of monomethyl fumarate and Fumaria extract against acetaminophen-induced acute liver damage and to compare with a known hepatoprotective plant, Silybum marianum and its active ingredient, silymarin.

MATERIALS AND METHODS

Plant collection: The whole plant of Fumaria vaillantii Loisei. was collected from Bojnourd region, North East of Iran and Silybum marianum was collected from Kelardasht region, North of Iran.

Chemicals: Acetaminophen, ethanol, methanol and Tween 80 were purchased from Merck Company (Germany). Monomethyl fumarate and silymarin were purchased from Sigma-Aldrich Company (USA).

Preparation of extracts: Aerial parts of the F. vaillantii washed and cleaned with water, then dried and were macerated with 80% ethanol solution by 4-6 times extraction within five days. The resulting extract was filtered and then evaporated by rotary instrument under reduced pressure.

Animals: Male mice (25-30 g) purchased from Pasteur institute (Tehran, Iran), were used through this study. The animals were treated on the standard condition with free access to drinking water and feed under constant room temperature (25°C) and humidity (50±10%) with an automatic 12 h light and 12 h dark cycle. The experimental procedures were carried out under policy of MOH Convention for the Protection of Vertebrate Animals Used for Experimental and other Scientific Purposes and the protocol was approved by the Ethics Committee of the Tehran University of Medicine Sciences (TUMS), Tehran, Iran.

Experimental procedure: The hepatoprotective effect of the total plant extracts and the active components were studied at two (300 and 500 mg kg-1, i.p.) and three doses (25, 50 and 100 mg kg-1, i.p.), respectively according to pre- and post-treatment schedule:

Pre-treatment: Mice were divided into 6 groups of 6 animals each:

Group 1: Vehicle control (NS: sodium chloride 0.9%), Blank
Group 2: Six doses of acetaminophen (640 mg kg-1, i.p.) were administrated
Groups 3/4: 6 doses of F. vaillantii extract (300/500 mg kg-1) at 12 h intervals
Groups 5/6: 6 doses of Siylbum marianum extract (300/500 mg kg-1) at 12 h intervals
Groups 7/8/9: 6 doses of monomethyl fumarate (25/50/100 mg kg-1) at 12 h intervals
Groups 10/11/12: 6 doses of silymarin (25/50/100 mg kg-1) at 12 h intervals. Acetaminophen (640 mg kg-1, i.p.) was administered 1 h after the last dose in groups 3-12

Post-treatment: Mice were divided into 6 groups of 6 animals each:

Groups 13/14: Six doses of F. vaillantii extract (300/500 mg kg-1) at 12 h intervals
Groups 15/16: 6 doses of Siylbum marianum extract (300/500 mg kg-1) at 12 h intervals
Groups 17/18/19: 6 doses of monomethyl fumarate (25/50/100 mg kg-1) at 12 h intervals
Groups 20/21/22: 6 doses of silymarin (25/50/100 mg kg-1) at 12 h intervals. Acetaminophen (640 mg kg-1, i.p.) was administered 1 h before the first dose ingroups 13-22. Then, 24 h after the last dose, the animals were anaesthetized by ketamine/xylazine and blood samples were obtained from heart. The blood serum was separated by centrifugation at 2000 g for 20 min and kept at -70°C until use. The assays of bilirubin (Total and direct), aspartate aminotransferase (AST), alanineamino transferase (ALT), Lactate Dehydrogenase (LDH), Alkaline Phosphatase (ALKP) activities were performed using Ellitech diagnostic kits (Sees, France)

Estimation of MDA: The quantitative measurement of lipid peroxidation in liver homogenate was determined according to the method described by Esterbauer and Cheeseman (1990). The amount of MDA formed was quantified by reaction with Thiobarbituric Acid (TBA) as the red colored complex measured at the wavelength 532 nm.

Determination of GSH, GSSG: Liver GSH content was measured by a colorimetric technique, based on the production of a yellow color when 5, 5-dithiobis-2-nitrobenzoic acid (DTNB) is added to compounds with sulfhydryl groups. Homogenates of liver tissue were acidified with 50% (W/V) trichloroacetic acid and centrifuged at 8000 g for 20 min. The supernatant was divided into two equal tubes: To the first tube, 2 mL of 0.4 M tris buffer, pH 8.9 and 0.5 mL of 0.1 M DTNB were added, vortexed and the absorbance read at 412 nm after 5 min, in order to analyze GSH. For GSSG determination, 1 mL of 5% NaBH4 slowly was added to the second tube and incubated for 1 h at 45°C. Consequently, 0.5 mL of 0.3 M Na2HPO4 was added and the pH adjusted to 7.2 by 2 N HCl. Then, 0.5 mL of 0.1 M DTNB was added, vortexed and the absorbance was read at 412 nm after 5 min. The amounts of GSH measured in the second tube minus the amount of GSH in the first tube gives the extra amount of GSH in the first tube. Dividing the result by 2 gives the equivalent of GSSG.

Histopathological studies: Following autopsy, livers were immediately removed and fixed in 10% formalin for at least 24 h. The paraffin sections were then prepared and cut into 5 μm-thick sections using a rotary microtome. The sections were stained with haematoxylin-eosin dye and mounted with Canada balsam. The histopathological slides were examined and photographs were taken using Carl Zeiss Jena amplual type photomicroscope.

Statistical analysis: Data are presented as Mean ±SE and all comparisons were analyzed by one-way analysis of variance (ANOVA) and probability levels of less than 0.05 were considered significant.

RESULTS

Administration of acetaminophen (640 mg kg-1, i.p.) significantly increased measured serum biochemical parameters including ALT, AST, LDH, ALKP and bilirubin (Total and direct). In liver tissue homogenate, GSH content was reduced while GSSG and MDA concentrations were markedly increased.

Effects of total plant extract treatment on biochemical serum parameters: Plant extracts (300 and 500 mg kg-1) significantly lowered the rise of ALT, AST, LDH, ALKP and bilirubin (Total and direct) in serum.

Table 1: Effect of Fumaria vaillantii total extract (FTE), Silybum marianum total extract (STE), monomethyl fumarate (MMF) and silymarin on biochemical serum parameters in pre-treatment study
Image for - Protective Activity of Fumaria vaillantii Extract and Monomethyl 
  Fumarate on Acetaminophen Induced Hepatotoxicity in Mice
AST: Aspartate aminotransferase, ALT: Alanine aminotransferase, LDH: Lactate dehydrogenase, ALKP: Alkaline phosphatase, B.T: Bilirubin total, B.D: Bilirubin direct, STE: Total extract of Silybum marianum, FTE: Total extract of Fumaria vaillantii, MMF: Monomethyl fumarate, Values represent the Mean±SE (n = 5), 1p<0.001 as compared with blank, 2p<0.01 and 3p<0.05 as compared with acetaminophen

Table 2: Effect of Fumaria vaillantii total extract (FTE), Silybum marianum total extract (STE), monomethyl fumarate (MMF) and silymarin on biochemical serum parameters in post-treatment study
Image for - Protective Activity of Fumaria vaillantii Extract and Monomethyl 
  Fumarate on Acetaminophen Induced Hepatotoxicity in Mice
AST: Aspartate aminotransferase, ALT: Alanine aminotransferase, LDH: Lactate dehydrogenase, ALKP: Alkaline phosphatase, B.T: Bilirubin total, B.D: Bilirubin direct, STE: Total extract of Silybum marianum, FTE: Total extract of Fumaria vaillantii, MMF: Monomethyl fumarate. Values represent the mean±SE (n = 5), 1p<0.001 as compared with blank, 2p<0.01 and 3(\p<0.05 as compared with acetaminophen

Furthermore, treatment with 300 mg kg-1 showed the best response from two plants extracts. In this context, the extracts were more effective in the pre-treatment study (Table 1, 2).

Effects of plant active components (MMF and silymarin) on biochemical serum parameters: The data showed that MMF and silymarin (25, 50 and 100 mg kg-1) significantly lowered the rise of LDH, ALT, AST, ALKP and bilirubin (Total and direct) in serum. Among the employed doses, the best response was achieved from 25 mg kg-1. In addition, the pre-treatment study considerably was effective (Table 1, 2).

Effect of plant extracts on GSH, GSSG and MDA in liver tissue homogenate: Treatment with plant extracts showed a significant increase in the GSH content and decrease in the GSSG (Table 3). The remarkable increase of MDA by acetaminophen was significantly inhibited by administration of F. vaillantii and S. marianum extracts. The observed effect in the pre-treatment study was more apparent (Table 3).

Effect of plant active components (MMF and silymarin) on GSH, GSSG and MDA: Administration of MMF and silymarin effectively increased GSH content and decreased GSSG. MDA concentration was also lowered by MMF and Silymarin which was more significant in the pre-treatment study (Table 3).

Histological studies: The results of histological study have presented in Fig. 2. Exposures of rat hepatocytes to acetaminophen (640 mg kg-1) lead to histopathological changes including increased mononuclear infiltration, hemorrhage and degeneration of hepatocytes (necrosis) at 24 h (Fig. 2b) in comparison with blank (Fig. 2a). Liver tissue of rats treated with plant extracts (Fig. 2c-f), MMF (Fig. 2g-h) and silymarin (Fig. 2i, j) showed good recovery with absence of necrosis and fatty depositions of hepatocytes.

DISCUSSION

To screen hepatoprotective activity of medicines, acetaminophen induced liver toxicity is a commonly used model (Handa et al., 1986). In the pharmaceutical market, herbal medicines have considerable portion in which a good number of marketed drugs are directly or indirectly derived from plants. The present study shows that F. vaillantii and MMF can reduce acute liver damage caused by acetaminophen, as indicated by significant reduction of the elevated serum biochemical parameters such as ALT, AST, LDH, ALKP, D.B and T.B; increase of GSH content, reduction of GSSG and MDA in liver tissue homogenate, as well as classic histological changes, in a similar manner to that of S. marianum and silymarin.

Presence of isoquinoline alkaloids namely protropin, fumaridine fumaramine, adlumidine, d-bicuculline, vaillantine and rutin in F. vaillantii has been indicated (Suau et al., 2002; Ramellini and Meldolesi, 1976). It has been shown, however, that MMF is the active component of Fumaria sp. which can act as hepatoprotective agent in a dose-dependent manner (Rao and Mishra, 1998). S. marianum is used traditionally for treatment of some liver disease (Saller et al., 2001; Wellington and Jarvis, 2001), due to its ability for free radicals scavenging and chelating metal ions (Das and Vasudevan, 2006). The plant active flavonoid, silymarin, has hepatoprotective effect via antioxidant and scavengering properties (Kosina et al., 2002). Furthermore, silybin dihemisuccinate, soluble form of flavonoid silymarin, has protected rats against acetaminophen induced liver glutathione depletion and lipid peroxidation (Campos et al., 1989).

Present study showed that the best protective effect was achieved by treatment of animals with 300 mg kg-1 of F. vaillantii and S. marianum extracts and 25 mg kg-1 of the active components (MMF and silymarin) (Table 1, 2). These doses therefore, were chosen for the further experiments.

Table 3: Effect of Fumaria vaillantii total extract (FTE), Silybum marianum total extract (STE), monomethyl fumarate (MMF) and silymarin on liver tissue GSH, GSSG and MDA in pre and post-treatment study
Image for - Protective Activity of Fumaria vaillantii Extract and Monomethyl 
  Fumarate on Acetaminophen Induced Hepatotoxicity in Mice
GSH: Glutathione reduce, GSSG: Glutathione oxide, MDA: Malondialdehyde, MMF; Monomethyl fumarate, STE: Total extract of Silybum marianum, FTE: Total extract of Fumaria parviflora, Values represent the Mean±SE (n = 5), Liver GSH, GSSG and MDA levels were determined 24 h after acetaminophen (640 mg kg-1) intoxication, 1(p<0.001) as compared with blank, 2(p<0.01) and 3(p<0.05) as compared with acetaminophen

Image for - Protective Activity of Fumaria vaillantii Extract and Monomethyl 
  Fumarate on Acetaminophen Induced Hepatotoxicity in Mice
Fig. 1: Comparative study of pre-treatment with effective dose of Fumaria vaillantii total extract (FTE, 300 mg kg-1), Silybum marianum total extract (STE, 300 mg kg-1), monomethyl fumarate (MMF, 25 mg kg-1) and silymarin (25 mg kg-1) on serum AST, ALT, ALKP and LDH in mice. Bar represents Mean±SE, n = 5 mice ***p<0.001 compared to blank, *p<0.05 compared to acetaminophen

In addition, by comparison of the total extracts and the active components, we demonstrated that active components were more effective than total plant extracts (Fig. 1). Moreover, pre-treatment study presented a better protective effect than post-treatment (Table 1, 2 and 3).

Glutathione is a tripeptide which scavenges toxic metabolites and has found in many mammalian tissues and plays a very important role in antioxidant defense system. Determination of total GSH, concomitant to its reduced and oxidized fractions, is a key factor to show the amount of antioxidant reserve in the organism (Lu et al., 1999; Odukoya et al., 2007; Balouchzadeh et al., 2011). In the present study, the content of GSH in the acetaminophen group was significantly decreased 24 h after administration. Induction of cytochrome P450 and/or depletion of liver GSH is needed for acetaminophen induced liver toxicity (Handa and Sharma, 1990). NAPQI, the acetaminophen reactive metabolite, can conjugate with GSH and cause its depletion which leads to the cellular necrosis (Hinson et al., 2004). Pre- and post-treatments with plant extracts, MMF and silymarin restored GSH levels which further highlights their role against acetaminophen induced hepatotoxicity.

MDA as one of the products of oxidative stress formed during lipid peroxidation process was increased following acetaminophen administration in comparison with control group. Pre- and post-treatments with plant extracts, MMF and silymarin, however, reduced MDA production. Silymarin treatment has previously shown to reduce MDA production (Velussi et al., 1997). It acts as cell membrane stabilizer and regulates permeability by which prevents toxic agents from entering to the hepatocytes via occupying the binding sites as well as inhibiting many transport proteins at the membrane (Faulstich et al., 1980). In addition, silymarin acts as promoters of ribosomal RNA synthesis, with biochemical effects on RNA, protein and DNA synthesis, stimulates liver regeneration (Sonnenbichler and Zetl, 1986). During the present study, MMF showed similar hepatoprotective effect to silymarin by evaluation of ALT, AST, LDH, ALKP, T.B and D.B levels in mouse serum, glutathione (GSH and GSSG) and MDA in mouse liver tissue homogenates.

Image for - Protective Activity of Fumaria vaillantii Extract and Monomethyl 
  Fumarate on Acetaminophen Induced Hepatotoxicity in Mice
Fig. 2(a-j): Microscopic view of liver sections obtained from (a) blank, (b) acetaminophen (640 mg kg-1), (c)Fumaria vaillantii (300 mg kg-1) pre-treatment study, (d) Fumaria vaillantii (300 mg kg-1) post- treatment study, (e) Silybum marianum (300 mg kg-1 pre-treatment administration, (f) Silybum marianum (300 mg kg-1) post-treatment study, (g) Monomethyl fumarate (25 mg kg-1) pre-treatment study, (h) Monomethyl fumarate (25 mg kg-1) post-treatment study, (i) Silymarin (25 mg kg-1) pre-treatment study and (j) Silymarin (25 mg kg-1) post-treatment study in mice. Haematoxylin and eosin stain and magnifications at x400. The blank mice were given distilled water

MMF protective activity may be due to its ability against formation of active metabolites, by reducing drug metabolism enzymes such as cytochrome P450, promotion of glucuronidation, activation of the reticuloendothelial system functions or inhibition of protein biosynthesis (Rao and Mishra, 1998). Furthermore, MMF antihepatotoxic activity may result from its stimulatory effects on hepatic regeneration and free radical scavenging properties (Rao and Mishra, 1998).

Exposure of hepatocytes to toxic agents such as acetaminophen leads to histopathological changes from the normal cell appearance. The hepatocytes of rat livers treated with a dose of 640 mg kg-1 acetaminophen, showed centrilobular hepatocyte necrosis, increased mononuclear infiltration, hemorrhage and extensive fatty change. Liver tissue of rats treated with plant extracts, MMF and silymarin in both pre- and post-treatment study plans showed good recovery with absence of necrosis, fatty depositions and recovery to normal histological appearance of hepatocytes (Fig. 2).

In summery our results demonstrate that acetaminophen produced acute toxicity can be treated with monomethyl fumarate and F. vaillantii extract in a similar and comparable manner to silymarin and S. marianum by significant lowering in the rise of ALT, AST, LDH, ALKP and bilirubin (Total and direct) in serum and significant increase in glutathione content and reduction of MDA level in the liver. These observations were more apparent in the pre-treatment study which proves that it provides better hepatoprotection than post-treatment (Table 1, 2). This finding is in agreements with a number studies using other protective agents (Oyagbemi and Odetola, 2010; Gilani et al., 1996).

Conflict of interest statement: The authors have no financial conflict of interest.

ACKNOWLEDGMENTS

The authors are thankful of Dr Faraz Mojab for his kind collaboration in preparation of plant extracts and Dr. HamidReza Rahimi for his assistance. This research was supported by a grant (86-02-33-5324) from vice chancellor for research, Tehran University of Medical Sciences (TUMS), Tehran, Iran.

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