A REVIEW OF MEDICINAL PLANTS WITH HEPATOPROTECTIVE ACTIVITY

ABOUT AUTHORS:
Shristi Badhani*, Shivani Sharma, Amrita Kainth, Bharat Parashar
Department of Pharmacy,
Manav Bharti University, Solan, H.P.
*shristibadhani0104@gmail.com

ABSTRACT:
Hepatic diseases are a major worldwide health problem, with frequently found in developing countries. They are mainly caused by uses of high doses of chemicals and some drugs. There is no effective drug available that stimulates liver function, offer protection to the liver from damage or help to regenerate hepatic cells. Therefore there is urgent need, for effective drugs to replace/add those in current use. Medicinal herbs are significant source of pharmaceutical drugs. Latest trends have shown increasing demand of phytoconstituents from some medicinal herbs and those medicinal herbs have proven hepatotprotective potential.A number of herbal preparations are available in the market. The present review is aimed at compiling data on promising phytochemicals from medicinal plants that have been tested in hepatotoxicity models using modern scientific system. In this century clinicalresearch has confirmed the efficacy of  some herbs in the treatment of liver related disease. Hence, this review article contributes to the knowledge of reported indigenous plants, which are prevalent for prevention and treatment ofliver disorders.

REFERENCE ID: PHARMATUTOR-ART-1926

INTRODUCTION:
The liver has more functions than any other human organ and also is a largest part of the body. The blood supply passes through the liver several times a day. The Liver has a important role in human metabolism. Liver produces and secretes bile, it also produces prothrombin and fibrinogen, both blood clotting factors, and heparin. It converts sugar into glycogen. Liver diseases have become one of the major causes of morbidity and mortality in man and animals. Hepatotoxicity due to drugs appears to be the most common factor ^[1]. The most common disease that can affect the liver is 'viral hepatitis'. Hepatitis mainly caused by drugs, viruses, bacteria, parasites like amoebas or giardiasis. The use of natural remedies to treat the liver diseases has a long history. There are some medicinal plants and their derivatives which still used all over the world in one form or the other, have been tested and found to contain active principles with curative properties against a variety of diseases ^[2]. Hepatoprotective plants contain a variety of chemical constituents like phenols, coumarins, lignans, essential oil, monoterpenes, carotinoids, glycosides, flavanoids, organic acids, lipids, alkaloids and xanthenes ^[3]. Recent experience has shown that plant drugs are non-toxic, safe and even free from side effects ^[4].

There are many plants and traditional formulations available to treat the liver diseases ^{[5, 6]}. About 600 commercial herbal formulations with hepatoprotective activity are being sold all over the world. Around 170 phytoconstituents isolated from 110 plants belonging to 55 families have been reported to possess hepatoprotective activity. In India, more than 93 medicinal plants are used in different combinations in the preparations of 40 patented herbal formulations ^[7]. However, only a small proportion of hepatoprotective plants as well as formulations used in traditional medicine are pharmacologically evaluated for their safety and efficacy ^[8].

DRUG HEPATOTOXICITY:
Chemicals produce a wide variety of clinical and pathological hepatic injury. Biochemical markers (e.g. alanine transferase, alkaline phosphatase and bilirubin) are often used to indicate liver damage. Liver injury is defined as a rise in either
(a) ALT level more than three times of upper limit of normal (ULN),
(b) ALP level more than twice ULN, or
(c) total bilirubin level more than twice ULN when associated with increased ALT or ALP ^{[32, 33]}.

Mechanism of liver damage:
Drugs continue to be taken off the market due to late discovery of hepatotoxicity. Due to its unique metabolism and close relationship with the gastrointestinal tract, the liver is susceptible to injury from drugs and other substances. 75% of blood coming to the liver arrives directly from gastrointestinal organs and then spleen via portal veins which bring drugs and xenobiotics in near-undiluted form. Several mechanisms are responsible for either inducing hepatic injury or worsening the damage process. Many chemicals damage mitochondria, an intracellular organelle that produce energy. Its dysfunction releases excessive amount of oxidants which, in turn, injure hepatic cells. Activation of some enzymes in the cytochrome P-450 system such as CYP2E1 also lead to oxidative stress ^[34]. Injury to hepatocyte and bile duct cells lead to accumulation of bile acid inside the liver. This promotes further liver damage. Non-parenchymal cells such as Kupffer cells, fat storing stellate cells, and leukocytes (i.e. neutrophil and monocyte) also have a role in the mechanism ^[35].

Drug-related hepatotoxicity cannot be viewed as a single disease. Many different mechanisms lead to hepatotoxicity, including disruption of the cell membrane and cell death resulting from covalent binding of the drug to cell proteins, which creates new adducts that serve as immune targets, thus inciting an immunologic reaction ^{[36, 37]}; inhibition of cellular pathways of drug metabolism ^{[38, 39]}; abnormal bile flow resulting from disruption of subcellular actin filaments or interruption of transport pumps, leading to cholestasis and jaundice, sometimes with minimal cell injury ^[40]; apoptosis occurring through tumor-necrosis-factor and fas pathways ^[41]; and inhibition of mitochondrial function, with accumulation of reactive oxygen species and lipid peroxidation, fat accumulation and cell death ^[42].

HEPATOPROTECTIVE PLANTS:

• Andrographis lineataNees: Hepatoprotective effect of Andrographis lineata (Acanthaceae) extracts in CCl₄ induced liver injury in rats. Male Wistar rats with chronic liver damage, induced by subcutaneous injection of 50% v/v CCl₄ in liquid paraffin at a dose of 3 mL/kg on alternate days for a period of 4 weeks, were treated with methanol and aqueous extracts of A. lineata orally at a dose of 845 mg/kg/day. The biochemical parameters such as serum glutamate oxaloacetate transaminase, serum glutamate pyruvate transaminase, serum bilirubin and alkaline phosphatise were estimated to assess the liver function. Histopathological examinations of liver tissue corroborated well with the biochemical changes. The activities of extracts were comparable to a standard drug ^[9].
• Azadirachta indica: Neem (Azadirachta indica A. Juss) is perhaps the most commonly used traditional medicinal plant of India. In India, Neem is known as "Divine Tree", "Heal All", “the village pharmacy”, because of its healing versatility, and it has been used by various traditional means of medicine due to its multiple medicinal properties ^[45]. The aqueous extract of Neem leaf was found to offer protection against paracetamol induced liver necrosis in rats. The elevated levels of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) and gamma glutamyl transpeptidase (GGT) indicative of liver damage were found to be significantly reduced on administration of the Neem leaf aqueous extract. In the present study we have evaluated the hepatoprotective role of Azadirachta indica ^[46].

• Careya arborea: The methanol extract of Careya arborea bark, (myrtaceae) was tested for antioxidant and hepatoprotective activity in Ehrlich ascites carcinoma (EAC) tumor-bearing mice. Tumor control animals inoculated with EAC showed a significant alteration in the levels of antioxidant and hepatoprotectiven parameters8. The extract treatment at 50, 100 and 200 mg/kg body weight doses given orally caused a significant reversal of these biochemical changes towards the normal in serum. Liver and kidney when compared to tumor control animals indicating the potent antioxidant and hepatoprotective nature of the standardized extract ^[11].

• Cassia fistula: Hepatoprotective activity of the n-heptane extract of Cassia fistula (Fabaceae) leaves was investigated by inducing hepatotoxicity with paracetamol in rats. The extract at a dose of 400 mg/kg body wt. exhibited orally, significant protective effect by lowering the serum levels of transaminases (SGOT and SGPT), bilirubin and alkaline phosphatase (ALP). The effects produced were comparable to that of a standard hepatoprotective agent ^[12].

• Cleome viscosaLinn: The hepatoprotective activity of the Cleome viscose Linn (Capparidaceae) extract was assessed in CCl₄ induced hepatotoxic rats. The test material was found effective as hepatoprotective, through in vivo and histopathological studies. The extract was found to be effective in shortening the thiopental induced sleep in mice poisoned with CCl₄. The hepatoprotective effect of ethanolic extract was comparable to that of silymarin, a standard hepatoprotective agent ^[13].

• Eclipta alba: The hepatoprotective effect of the ethanol/water (1:1) extract of Eclipta alba (Asteraceae) was studied at subcellular levels in rats against (CCl₄) induced hepatotoxicity. The loss of hepatic lysomal acid phosphatase and alkaline phosphatase by (CCl₄) was significantly restored by Eclipta alba. The study shows that hepatoprotective activity of Eclipta alba is by regulating the levels of hepatic microsomal drug metabolising enzymes ^[14].

• Fumaria indica: Fumaria indica(Fumariceae) were studied for their hepatoprotective activity against carbontetrachloride, paracetamol and rifampicin-induced heptatotoxicites in albino rats. The petroleum ether extract against carbonetrachloride, total aqueous extract against paracetamol and methanolic extract against rifampicin induced hepatotoxicities showed similar reductions in the elevated levels of some of the serum biochemical parameters in a manner similar that of silymarin indicating its potential as a hepatoprotective agent ^[15].

• Morinda citrifoliaLinn:The hepatoprotective effects of Noni juice (NJ) (Rubiaceae) against CCl₄ induced chronic liver damage in female Sprague Dawley (SD) rats. Histopathological examination revealed that liver sections from the NJ + CCl₄ appeared similar to controls, whereas typical hepatic steatosis was observedmin the placebo + CCl₄ group. Serum alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine transaminase (ALT), total cholesterol (TC), triglycerides (TG), low-density lipoprotein (LDL), and very low-density lipoprotein (VLDL) levels were increased in the placebo group compared with the NJ group. In contrast, high-density lipoprotein (HDL) was increased in the NJ group and decreased in the placebo group. Thus, NJ juice appears to protect the liver from chronic exogenous CCl₄ exposures ^[16].

• Phyllanthus amarus: Ethanolic extract of Phyllanthus amarus (euphorbiaceae), at (0.3g kg (-1) BW 0.2 ml (-1) day (-1) was given to all groups except control groups (gp. I and gp. V), after 30 min of aflatoxin administration. The entire study was carried out for 3 months and animals were sacrificed after an interval of 30 days till the completion of study. Phyllanthus amarus extract was found to show hepatoprotective effect by lowering down the content of thiobarbituric acid reactive substances (TBARS) and enhancing the reduced glutathione level and the activities of antioxidant enzymes, glutathione peroxidase (GPx), glutathionetransferase (GST), superoxide dismutase (SOD) and catalase (CAT) ^[17].

• Phyllanthus emblica: Ethanol extract of Phyllanthus emblica Linn. (Euphorbiaceous) (PE) induced rat hepatic injury. PE (0.5 and 1 mg/ml) increased cell viability of rat primary cultured hepatocytes being treated with ethanol (96 μl/m) by increasing % MTT and decreasing the release of transaminase. Pretreatment of rats with PE at oral dose of 25, 50 and 75 mg/kg or SL (silymarin, a reference hepatoprotective agent) at 5 mg/kg, 4 h before ethanol lowered the ethanol induced levels of AST, ALT and IL-1beta. The 75 mg/kg PE dose gave the best result similar to SL. Treatment of rats with PE (75g/kg/day) or SL (5 mg/kg/day) for 7 days after 21 days with ethanol (4 g/kg/day, p.o.) enhanced liver cell recovery by bringing the levels of AST, ALT, IL- 1beta back to normal ^[18].

• Phyllanthus polyphyllus: Methanolic extract of Phyllanthus polyphyllus (euphorbiaceae) was evaluated for hepatoprotective and antioxidant activities in rats. The plant extract (200 and 300 mg/kg, p.o.) showed a remarkable hepatoprotective and antioxidant activity against acetaminophen induced hepatotoxicity as judged from the serum marker enzymes and antioxidant levels in liver tissues. The activity of the extract at dose of 300 mg/kg was comparable to the standard drug, silymarin (50g/kg, p.o.). Histopathological changes of liver sample were compared with respective control ^[19].

• Phyllanthus reticulates: Two partially purified organic fractions designated by PR1 and PR2 of the fat free ethanol (95%) extract of aerial parts of Phyllanthus reticulatus (Euphorbiaceae), were tested for the hepatoprotective activity in rats against CCl₄ induced liver damage. The rats receiving the fractions showed promising hepatoprotective activity as evident from significant changes of pentobarbital-induced sleeping time, changes in serum levels of sGPT, sGOT, sALP and bilirubin and also from histopathological changes as compared to CCl₄ intoxicated rats ^[20].

• Picrorhiza kurroa: Administration of picroliv, a standardized fraction of alcoholic extent of Picrorhiza kurroa (Scrophulariaceae) (3-12 mg/kg/day for two weeks) simultaneously with P. Bergheim infection showed significant protection against hepatic damage in Mastomys natalensis. The increased levels of serum glutamate oxaloacetate transaminase (GOT), glutamate pyruvate transaminase (GPT), alkaline phosphatase, lipoprotein-X (LP-X) and bilirubin in the infected animals were marked reduced by different doses of picroliv. In the liver, picroliv decreased the levels of lipid peroxides and hydroperoxides and facilitated the recovery of superoxide dismutase and glycogen ^{[21, 22]}.

• Polygala arvensis: Chloroform extract of leaves of Polygala arvensis (polygalaceae), in 0.3% carboxy methyl cellulose (CMC) was evaluated for hepatoprotective activity in Wistar albino rats by inducing hepatic injury with d-galactosamine (400 mg/kg). The chloroform extract of Polygala arvensis at an oral dose of 200 mg/kg and 400 mg/kg exhibited a significant (P<0.001, P<0.01 and P<0.05) protection effect by normalizing the levels of aspartate amino transferase. (ASAT, GOT), alanine amino transferase (ALAT, GPT), alkaline phosphatase (ALP), total bilirubin (TB), lactate dehydrogenase (LDH), total cholesterol (TC), triglycerides (TGL), albumin, total protein (TP) which were significantly (P<0.001) increased in rats by treatment with 400 mg/kg i.p. of dgalactosamine. Silymarin (25 mg/kg), a known hepatoprotective drug used for comparison exhibited significant activity (P<0.001) ^[23].

• Pterocarpus santalinus: The aqueous (45 mg/ml) and ethanol (30 mg/ml) extracts of Pterocarpus santalinus (Fabaceae) stem bark in 1% gum tragacanth was administered orally for 14 days and the hepatoprotective activity studied in CCl₄ induced hepatic damage model. There was a significant increase in serum levels of bilirubin, alanine transaminase, aspartate transaminase and alkaline phosphatase with a decrease in total protein level, in the CCl₄ treated animals, reflecting liver injury. In the extracts treated animals there was a decrease in serum levels of the markers and significant increase in total protein, indicating the recovery of hepatic cells. Ethanol extract treated animal’s revealed normal hepatic cords without any cellular necrosis and fatty infiltration ^[24].

• Ptrospermum acerifolium: The hepatoprotective activity of the ethanol extract of the leaf of Ptrospermum acerifolium (Sterculiaceae) was investigated in rats. Hepatotoxicity was induced in male Wistar rats by intraperitoneal injection of carbon tetrachloride (0.1 ml/kg/d p.o. for 14 d). Ethanol extract of Pterospermum acerifolium leaves were administered to the experimental rats (25 mg/kg/d p.o. for 14d). The Hepatoprotective effect of these extracts was evaluated by liver function biochemical parameters (total bilirubin, serum protein, alanine aminotransaminase, asparatate aminotransaminase and alkaline phosphates activites) and histopathological studies of liver. In ethanol extract-treated animals, the toxicity effect of carbon tetrachloride was controlled significantly by restoration of the levels of serum bilirubin and enzymes as compared to the normal and standard drug silymarin-treated groups ^[25].

• Solanum nigrum: In Ayurveda, the drug is known as kakamachi. Aromatic water extracted from the drug is widely prescribed by herbal vendors for liver disorders. Although clinical documentation is scare as far as hepatoprotective activity is concerned, but some traditional practitioners have reported favourable results with powdered extract of the plant ^[43].

• Swertia chirata: Simultaneous treatments with Swertia chirata (Gentianaceae). (in different doses, viz, 20, 50, and 100 mg/kg body wt daily) and (CCl₄) caused improvement at both biochemical and histopathological parameters compared to that of (CCl₄) treatment alone but it was most effective when Swertia chirata was administered in a moderate dose (50 mg/kg body wt) ^{[27, 28]}.

• Wedelia calendulaceaLinn: Hepatoprotective activity of the ethanol leaf extract of Wedelia calendulacea (Asteraceae) (EEWC) was studied by estimating serum enzyme activities of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), protein and bilirubin. The treatment with EEWC showed a dose-dependent reduction of CCl₄ induced elevated serum levels of enzyme activities with parallel increase in total protein and bilirubin, indicating the extract could preserve the normal functional status of the liver^[29].

• Ixora coccineaLinn: A small shrub with attractive flowers, widely distributed throughout India and grown in gardens. The flowers are extensively used in Ayurvedic medicine and have been reported to exihibit significant hepatoprotective effect against paracetamol induced hepatotoxicity in rats as judged by reduction of elevated levels of serum marker enzymes and liver lipid peroxide levels ^{[39, 40]}.

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CONCLUSION:
The liver plays an astonishing array of vital functions in the maintenance and performance of the body. Some of these major functions include carbohydrate, protein, and fat metabolism, detoxification, and secretion of bile. Unfortunately, the liver is often abused by environmental toxins, poor eating habits, alcohol, and prescription and over-the-counter drug use, which can damage and weaken the liver and eventually lead to hepatitis, cirrhosis, and alcoholic liver disease. These plants may offer new alternatives to the limited therapeutic options that exist at present in the treatment of liver diseases or their symptoms, and they should be considered for future studies. Many of these herbs have been evaluated in clinical studies and are currently being investigated phytochemically to better understand their actions. The presented review suggests that biologically active molecules derived from herbal extracts may serve as suitable primary compounds for effective and targeted hepatoprotective drugs.

ACKNOWLEDGEMENT:
The authors are grateful acknowledge to Manav Bharti University, Solan, for providing help and assistance.

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