Maharaja P1, Sengottuvel T1, Aarthi A2, Gopalasatheeskumar K3
1Department of Pharmacology, KMCH College of Pharmacy (The Tamil Nadu Dr. M. G. R. Medical University), Kovai Estate, Kalapatti Road, Coimbatore-641048, Tamil Nadu, India.
2College of Pharmacy, MMC. Chennai.
3Research Scholar, Department of Pharmacy, Annamalai University, Annamalai Nagar, Chidambaram- 608002, Tamil Nadu, India.
Paracetamol is widely used analgesic and antipyretic which can lead to liver damage. Excessive and inappropriate use of paracetamol can lead to liver injury. Hepatotoxicity occurs due to drugs, steroids, vaccines, antiviral and other drugs. The hepatotoxic reactions by drugs are due to elevated ROS generation, oxidative stress and suppressed immune responses. The increase in the number of patients with liver dysfunction due to the overwhelming use of alcohol and drugs has paved the path for researchers and scientists to search for potential sources of new therapeutic agents for the prevention of drug -induced hepatotoxicity. Herbal drugs play a role in the management of various liver disorders most of them speed up the natural healing process of the liver. Many antioxidant agents have been studied in experimental and clinical studies to reduce or prevent acetaminophen-induced hepatotoxicity. An alternate view is that oxidative stress has a major role in hepatotoxicity. Antioxidants are agents that are capable of scavenging the free radicals by inhibiting oxidation, indirectly through iron chelation and quenching of triplet oxygen. The protective potential of medicinal plants could also be attributed to their phytoconstituent's ability to enhance the endogenous antioxidants. Hence there has been a great deal of interest recently in investigating the medicinal plants containing phenolic compounds that hold antioxidants.
The Liver is a vital organ as it helps to regulate an astounding range of imperative physiological functions that help in the maintenance, performance and regulating homeostasis of the body. Being involved in the metabolism processes, the liver is usually exposed to various types of endogenous and exogenous substances including those with toxic potentials.
Normally the liver will detoxify and excrete these substances from the body. Continuous or overexposure of the liver to toxic chemicals can inflict damages to the liver because of the release of free radicals. Drugs have been one of the important causes of liver injury. In the United States, it is reported that approximately 2000 cases of liver failure occur annually and drugs account for over 50% of them (37% are due to acetaminophen, 13% are idiosyncratic reactions due to other medications). Paracetamol is commonly considered as a “safe drug” when taken within the suggested therapeutic dose, and it can be hepatotoxic when an overdose is administered . Paracetamol toxicity is the result of oxidation of paracetamol by CYP2E1 to the reactive metabolite N-acetyl-P-benzoquinoneimine (NAPQI) . Excessive intake of PCM causes the metabolic pathways particularly the sulphation and glucuronidation pathways to become saturated resulting in the accumulation of NAPQI. This molecule binds to cellular macromolecules within the hepatocyte, eventually leading to cellular death and hepatic necrosis. This is a minor metabolic pathway and the vast majority of NAQPI is detoxified by hepatic glutathione (GSH) during a therapeutic dose. However following an overdose, hepatic glutathione stores can be depleted, when GSH supply decreases to 30% than the normal, the unbound NAPQI will bind non-specifically to macromolecules, including intracellular proteins, particularly those with sulfhydryl groups allowing the hepatic injury to develop and leads to cell death .
Oxidative stress is the most prevalent cause of drug-induced hepatotoxicity . Oxidative stress can be caused in the human body due to the overproduction of reactive oxygen species (ROS) over the capability of cells to present an effective antioxidant response. Oxidative stress results in cellular dysfunction and is involved in various chronic disease initiation and progression.
In addition to mitochondrial oxidative stress, many other cellular processes including phase I/ II metabolism, endoplasmic reticulum stress, autophagy, sterile inflammation, microcirculatory dysfunction and liver regeneration have been identified to be involved in the pathogenesis of paracetamol-induced hepatotoxicity . The basis behind the protection provided by the medicinal plants is hypothesized to be through their ability to remove free radicals from the cellular environment and therefore protection against ROS mediated damage to membrane lipids and macromolecules . Liver cells acquire several balance mechanisms to deal with an excess amount of ROS and their end products through natural antioxidants such as Superoxide Dimutase (SOD), catalase (CAT), glutathione (GSH). Antioxidants are agents that are capable of scavenging the free radicals by inhibiting oxidation, indirectly through iron chelation and quenching of triplet oxygen. In that case, there has been a great deal of interest recently in phenolic substances present in edible plants, fruits and vegetables that hold antioxidants . Phenolics, the most extensive secondary metabolites in the plant kingdom, have received much interest as a prospective natural antioxidant in terms of their abilities to act as both efficient radical scavengers and metal chelators . Other than flavonoids or phenolic based compounds, saponins themselves have also been reported to possess radical scavenging and antioxidant activity . The protective potential of medicinal plants could also be attributed to their phytoconstituent's ability to enhance endogenous antioxidants such as GSH and SOD biosynthesis/bioactivity as well as to interact with various CYP450 isoforms and to inhibit the entry of toxins to the cells. As oxidative stress has been proven to play a major role in drug-induced hepatotoxicity, compounds with antioxidant activity might plausibly be good agents to reduce drug-induced hepatotoxicity. The synthetic drugs having side effects, nowadays phyto-medicines are essential for the cure diseases . This review focused on antioxidant and hepatoprotective activity of medicinal plants.
The hepatoprotective activity of methanolic extract of Dicranopteris linearis (MEDL) leaves was studied . MEDL exerts hepatoprotective activity against paracetamol-induced intoxication through its ability to activate the endogenous antioxidant system such as SOD, CAT, and GSH. The hepatoprotective potential of MEDL could also be attributed to its potent antioxidant and anti-inflammatory activities and the presence of various non-volatile bioactive compounds that might act synergistically to enhance the hepatoprotective effect.
Dipteracanthus patulus (DP) is an important medicinal plant and popularly known as black weed. Dipteracanthus patulus belongs to Acanthaceace family and very important indigenous medicinal plant. The treatment with the ethyl acetate and chloroform extracts of DP to the paracetamol induced liver toxic rats shows the significant reduction of SGOT, SGPT, ALP, total cholesterol, triglycerides, urea and uric acid levels. However the CAT, GSH, GPx and SOD levels were significant increase in ethyl acetate and chloroform extracts of Dipteracanthus patulus treated paracetamol induced liver toxic rats .
Dyschoriste littoralis nees:
The antioxidant potential of D.littoralis Nees was examined on paracetamol-induced hepatotoxicity in rats . The aerial parts of D.littoralis Nees were used and the powder was extracted with various solvents (PE, EA, and methanol). The administration of EA concentrates on D.littoralis attenuated the concentration of Glutathione peroxidase in liver and GST in liver and kidney, and silymarin restored enzyme activities to normal values. The study showed that EA concentrates on D.littoralis against paracetamol-induced hepatic tissue damage by reducing the activities of TBARS and increase the activities of antioxidant enzymes.
The effect of A. tripedale plant was investigated against acetaminophen (APAP)-induced acute liver damage . After preliminary studies, the A. tripedale methanol fraction (ATMF) was subjected for in vivo study. ATMF can prevent hepatic APAP toxicity by enhancing hepatic tissue oxidant/antioxidant balance. ATMF administration reduced the levels of these enzymes as compared to the control group, which may be due to the stabilization of cell membranes and repairing hepatic tissue damage caused by APAP. After administration of ATMF, LPO and NO hepatic levels decreased, which may be related to the improvement of the thiol molecules and the antioxidant capacity of the liver tissues.
Sphaeranthus indicus Linn:
SIEE comprises triterpenoids, carbohydrate, alkaloids, flavonoids, glycosides, and sterols , SIEAE consists of tannins and flavonoids; SICHE consists of phytosterols and triterpenoids despite that SIAQE consists of glycoside, carbohydrate and alkaloids. Amino acids and proteins were lacking in all extracts whereas fats and fixed oil were present only in the SIPEE of SI. Further SI extracts, namely SICHE, SIAQE, and SIPEE show a smaller amount of antioxidant action against standard Vitamin C.
Manihot esculenta Crantz:
The hepatoprotective activity of Manihot esculenta crantz was studied on paracetamol-induced toxicity in rats. Administration of CSAE as a protective and therapeutic agent in two different doses attenuates liver enzymes, increased liver antioxidant, decreased liver oxidant, and significantly decreased serum Hyc level from the paracetamol group in a dose-dependent manner. Administration of CSAE significantly decreased liver enzymes alanine transaminase (ALT) and aspartate aminotransferase (AST) compared to the paracetamol group. In this study, paracetamol increased total cholesterol concomitant with the pro-inflammatory marker homocysteine (Hyc) level, compared to the control group .
Co-administration of P. chaba extract to paracetamol-induced rats resulted in a partial recovery in the serum biochemical parameters (SGOT, SGPT, ALP and Bilirubin). However, ethanolic extract of Piper chaba at a lower dose (200mg/kg b.w.) was more effective than the higher dose (400mg/kg b.w.) in reducing serum dysfunction biomarker enzymes. The histopathological studies of liver tissues also showed better hepatoprotective activity of Piper chaba roots at the lower dose (200 mg/kg b.w.). The hepatoprotective activity of ethanolic extract of P. chaba roots is likely due to its scavenging of free radicals and antioxidant properties. It is also possible due to the presence of a large amount of piperine in the roots .
An aqueous ethanolic extract of Calotropis Procera flowers was tested for its hepatoprotective effect against paracetamol-induced hepatitis in rats . Paracetamol (2000mg/kg) has been reported to enhance SGPT, SGOT, ALP, bilirubin and cholesterol levels and reduce serum levels of HDL and the tissue level of GSH, while treatment with an aqueous ethanolic extract of C. procera flowers (200mg/kg and 400 mg/kg) restored the altered levels of biochemical markers to almost normal levels in a dose-dependent manner.
The ethanolic extract of Clerodendron inerme leaves was screened for its hepatoprotective activity in paracetamol-induced liver damage in Swiss albino rats at a dose of 200mg/kg bw. The ethanolic extract exhibited a protective effect by lowering serum enzyme levels and total bilirubin .
The effects of the water extract of the dried flowers of Hibiscus sabdariffa and Hibiscus anthocyanins (HAs) were investigated in paracetamol-induced hepatotoxicity in rats. The extract for 4 weeks (but not for 2 or 3 weeks significantly improved some of the liver function tests, but did not alter the histology of the paracetamol-treated rats. At a dose of 200mg/Kg, the hepatic histology and the biochemical indices of liver damage were restored to normal .
Protective effects of Nigella sativa seed extract (NSSE) against acetaminophen- (APAP) induced hepatotoxicity in TIB-73 cells and rats were investigated (35).Toxicity in TIB- 73 cells were induced with 10mmol/L APAP, and the protective effects of NSSE were evaluated at 25, 50, 75, and 100mg/mL. Cotreatment with NSSE at 25, 50, 75, and 100mg/mL significantly improved cell viability and suppressed reactive oxygen species generation. NSSE also significantly decreased serum ALT, AST, and ALP, which correlated with decreased levels of hepatic lipid peroxidation (malondialdehyde), increased superoxide dismutase levels, and reduced glutathione concentrations. Improved hepatic histology was also found in the treatment groups other than the APAP group . Protective effects of N. sativa seed extract against APAP-induced hepatotoxicity and metabolic disturbances in rats might be related to improved antioxidant activity and attenuation of oxidative stress, lipid peroxidation, and ROS generation.
The hepatoprotective effect of Garcinia kola seed extract was investigated in rats treated with high doses of paracetamol . The extracts when administered at 100 mg/kg three times a day for five consecutive days reduced paracetamol (800, 1000, 1200mg/kg) induced lethality from 50, 90 and 100% to 0, 20 and 40%, respectively. There was a significant reduction in the liver enzymes SGOT and SGPT and histology scores. The hepatoprotective activity of the extract possibly due to inhibition of cytochrome P-450 which usually converts paracetamol to the toxic intermediate metabolite N-aeetyl-p benzoquinoneimine.
The flowering inflorescence of Cocos nucifera, the main constituent of several traditional drug formulations was investigated to study the effect of the acetone extract of C. nucifera inflorescence (CnAE) on acetaminophen-induced hepatotoxicity. The study showed that CnAE pre-treated groups remarkably prevented the increase in serum alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase level and decrease in the level of liver superoxide dismutase, reduced glutathione, glutathione-S-transferase and glutathione peroxidize. The extract also suppressed the elevated level of malondialdehyde. The biochemical determinations supported the histopathological examination and blood parameter findings. The findings of the study indicated that the phenolic-rich CnAE could be an interesting alternative candidate against acetaminophen-induced hepatotoxicity .
The hepatoprotective potential of ethanolic extract of Aquilaria agallocha leaves (AAE) was evaluated against paracetamol (PCM) induced hepatotoxicity in SD rats . Hepatoprotective potential of AAE 400mg/kg/day was comparable to that of standard drug silymarin 100 mg/kg/day. This study confirms that AAE holds hepatoprotective potential proportionate to that of standard drug silymarin. The results proposed that the inhibition of elevated hepatic function markers may participate in the protective effect of the AAE against PCM induced hepatotoxicity. The hepatoprotection by AAE may be due to antioxidant property of the phytochemicals present in AAE which reduce the oxidative stress imposed by PCM and others like anti-inflammatory and analgesic properties preventing the inflammatory hepatic damage.
The Methanol extract of Bauhinia purpurea L. (family Fabaceae) (MEBP) possesses high antioxidant and anti-inflammatory activities and recently reported to exert hepatoprotection against paracetamol (PCM)-induced liver injury in rats . The plant possesses remarkable antioxidant and anti-inflammatory activities which have been generally known to play part in the mechanisms of hepatoprotection. Dried MEBP was partitioned to obtain petroleum ether (PEBP), ethyl acetate (EABP) and aqueous (AQBP) partitions. The most effective hepatoprotective activity against the PCM-induced liver intoxication in rats in the order of EABP>AQBP>PEBP. The hepatoprotective and antioxidant activities of EABP, which were independent of its low TPC value, could also be linked to the presence of several flavonoid-based bioactive compounds. These flavonoids might synergistically act with several saponins and tannins, detected during the phytoconstituent screening, to exert the hepatoprotective and antioxidant activities. The results support the medicinal value of B. purpurea in general and may suggest the therapeutic potential of EABP in particular, for the treatment of inflammatory disease, including liver injury.
Hepatroprotective effect of water cress extract was studied using Wistar rats. Liver injury induced in rats by acetaminophen. The animals were sacrificed and Alanine aminotransferase (ALT), aspartate aminotransferase (AST), the ferric reducing ability of plasma (FRAP), protein carbonyl (PCO), total thiol (T-SH), glutathione peroxidase (GPx), superoxide dismutase (SOD) and catalase (CAT) activities were measured in plasma. It was reported that APAP administration significantly reduced SOD, GPx and CAT activities . The results also showed that there was a significant increase in AST, ALT, FRAP and PCO content in the APAP group in comparison to control. Also, there was a significant reduction in T-SH levels and GPx activity in the APAP group compared to control. It should be noted that the chemical composition of WC extract was identified by GC-MS analysis. It showed the major compositions were found to be benzenepropanenitrile (48.30%), Phytol (10.10%), α-cadinene (9.50%) and linolenic acid (8.0). The results showed that WC extract reduced oxidative stress by increasing T-SH content as well as enhancing GPx activity. It should be noted that the hepatoprotective effects of WC extract are probably because of its antioxidant activity as a free radical scavenger.
Cuscuta chinensis Lam:
The seeds of Cuscuta chinensis Lam. (Convolvulaceae), were tested for its hepatoprotective activity against acetaminophen induced liver toxicity. The C. chinensis ethanolic extract at an oral dose reduces the levels of glutamate oxaloacetate transaminase (GOT), glutamate pyruvate transaminase (GPT), and alkaline phosphatase (ALP). The ethanolic extract inhibits the hepatotoxicity induced by APAP-intoxicated treatment as detected when assessing the liver histopathology. Regarding the antioxidant activity, C chinensis ethanolic extract exhibited a significant effect (P < 0.05) by increasing levels of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), and by reducing malondialdehyde (MDA) levels. The ethanolic extracts of Cuscuta chinensis with concentrations of 125 and 250 mg/kg, however, could lower the GOT, GPT, and ALP in these APAP-intoxicated animals. Besides, the examination of liver function correlated the histopathological changes from photomicroscopy observation. The centrilobular hepatic necrosis, fatty change, kupffer cell, ballooning degeneration, and infiltrating lymphocytes were displayed in APAP intoxication. Treatment with ethanolic extracts of Cuscuta chinensis prevented these histopathological changes. Thus, these results suggested that the inhibition of liver function markers elevation and liver damage may participate in the protective effect of the ethanolic extracts of Cuscuta chinensis against APAP-induced hepatotoxicity. The ethanolic extract of Cuscuta chinensis has a hepatoprotective effect against APAP-induced hepatotoxicity in rats. Interestingly, the main active hepatoprotective compound of Cuscuta chinensis appears to exist in the ethanolic extract and not in the aqueous fraction, which could include flavone and flavonoid. The enhanced levels of antioxidant enzymes and reduced amount of lipid peroxides are suggested to be the major mechanisms of Cuscuta chinensis ethanolic extract in preventing the development of liver damage induced by APAP .
Ichnocarpus frutescens (Linn.):
The chloroform and methanol extract (CEIF and MEIF) of the whole plant of I. frutescens (Linn.) by paracetamol-induced liver damage in Wistar albino rats were investigated for its hepatoprotective activity. The degree of protection was measured by using biochemical parameters such as serum glutamate oxalate transaminase (SGOT) and serum glutamate pyruvate transaminase (SGPT), alkaline phosphatase (ALP), bilirubin and total protein. Further, the effects of both extracts on lipid peroxidation (LPO), glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) were estimated. CEIF and MEIF significantly increased the levels of Glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) in a dose-dependent manner.e. The levels of TBARS were considerably increased in rats treated with paracetamol as compared to the normal rats. A significant decrease in the activities of glutathione and enzymic antioxidants (SOD and CAT) were noted after single administration of paracetamol. The CEIF and MEIF exert significant protection against paracetamol-induced toxicity by its ability to ameliorate the lipid peroxidation through the free radicals scavenging activity, which enhanced the levels of antioxidant defense system .
The antioxidant and hepatoprotective effect of polyphenolic-rich P.campechiana fruit extract was studied against acetaminophen intoxicated rats. Total phenolic and flavonoid contents of egg fruit were estimated followed by the determination of antioxidant activities . The Pouteria species was reported to posses many biologically active polyphenolic antioxidants including gallic acid, (+)-gallocatechin, (+)-catechin, (−)-epicatechin, dihydromyricetin, (+)-catechin- 3-O-gallate, and myricitrin. The presence of polyphenolic compounds was confirmed by high-performance thin-layer chromatography (HPTLC). The results suggested that P. campechiana could exert its hepatoprotective and radical scavenging activities by preventing the formation of free radicals, originated from acetaminophen metabolism as well as peroxidation products and increase the antioxidant defenses. These results show it has an antioxidant and significant hepatoprotective effect against acetaminophen-induced hepatotoxicity.
The ethanol root and stem extracts of Piper retrofractum were evaluated against paracetamol-induced acute hepatotoxicity in Sprague-Dawley rat. Hepatoprotective activity of P. retrofractum extracts against paracetamol (2g/kg, single dose) induced liver toxicity in rats was evaluated by measuring serum biomarker enzymes (SGPT and SGOT), serum biochemical parameters (total proteins, albumin, bilirubin) and serum lipid profiling (cholesterol, HDL-c, LDL-c). Effect of pretreatment with sample extracts (400mg/kg, 9 days) significantly reduced the elevated SGPT and SGOT levels when compared to paracetamol-induced toxicity group demonstrating a good hepatoprotection by our extracts. EtPRR confers more protective action than that of EtPRS in reducing the elevated serum enzyme level (p<0.001). Compared to the toxicity induced control group, a significant rise in serum protein and albumin level was observed in extracts and silymarin treated rats. The extracts brought back the reduced level of total protein and albumin which support hepatoprotective effect. Elevated serum bilirubin level induced by paracetamol was significantly reduced (p<0.001) by both extracts demonstrating effective protection against liver injury. Besides, both the extracts caused a significant increase in HDL-c but a decrease in LDL-c as compared to the induced control. Both stem and root extracts exerted a beneficial effect on total protein, albumin and serum lipid profile. Polyphenolic compounds with the antioxidant property might play a responsible role in hepatoprotective activity .
The protective effects of Hedera helix extract were investigated against acetaminophen -oxidative stress and hepatotoxicity using a mouse model. The mice were sacrificed and blood samples were collected to estimate the levels of glutathione peroxidase (GPx), malondialdehyde (MDA), superoxide dismutase (SOD) and total bilirubin. The hepatoprotective effects of H. helix extract are due to its free-radical scavenging antioxidant activity. The histopathological findings were consistent with the biochemical findings. H. helix extract exhibited antioxidant and hepatoprotective effects against acetaminophen-induced liver damage .
The current review discussed the medicinal plants possessed hepatoprotective effects against paracetamol-induced liver toxicity in various species of rat models. The review clearly shows that the medicinal plants possessing an antioxidant activity might have the hepatoprotective activity.
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Received on 13.04.2020 Modified on 26.04.2020
Accepted on 10.05.2020 ©AandV Publications All right reserved