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HEPATOPROTECTIVE ACTIVITY A REVIEW

 

Clinical courses

About Author:
SOWJANYA GUDUGUNTLA,
M.Pharmacy, Pharmaceutical Chemistry department
ANNAMACHRYA COLLEGE OF PHARMACY,
RAJAMPET, KADAPA Dist, A.P, INDIA.

Sowjanya09.pharma@gmail.com

1. INTRODUCTION:
The Greek word for liver is hepar, so medicinal terms related to liver often start with hepato or hepatic. Liver plays a pivotal role in metabolism, secretion and storage and is sometimes referred as the “ great chemical factory” of the  body, because the body depends on the liver to regulate, synthesize, store and secrete many important proteins, nutrients, chemicals and to purify and clear toxins or unnecessary  substances  from the body1 . The bile secreted by the liver, among other things, plays an important role in digestion. The risk of the liver intoxication has recently increased by the higher exposure to environmental toxins, pesticides and frequent use of chemotherapeutics.

REFERENCE ID: PHARMATUTOR-ART-1701

Liver damage is always associated with cellular necrosis, increase in tissue lipid peroxidation  and depletion in the tissue glutathione (GSH) levels. In addition, serum levels of many biochemical markers like serum glutamate oxaloacetate transaminase (SGOT/AST) and serum glutamate pyruvate transaminase (SGPT/ALT) triglycerides, cholesterol, bilirubin and alkaline phosphatase are elevated 2,3.


The following are some of the liver diseases that are commonly observed.
a) Necrosis
b) Cirrhosis
c) Hepatitis- may be of viral, toxic or deficiency type.
d) Hepatic failure - Acute or chronic
e) Liver disorders due to impaired metabolic function. Generally the disorders associated with fat (liposis) and bilirubin (jaundice) metabolisms are very commonly seen.
1. Disorders associated with fat metabolism: Fatty Liver
2. Disorders associated with bilirubin metabolism: jaundice or which may be of different types based upon mechanisms of action and etiology.
i. Hemolytic/Pre-hepatic jaundice.
ii. Obstructive (post-hepatic / cholestatic jaundice)
iii. Hepatogenous/ hepatic jaundice/cholestasis.
In these three conditions there occurs unconjugated hyperbilirubinaemia.
iv.  Hereditary jaundice or pure cholestasis: Gilbert’s syndrome, Dubin Johnson syndrome       and   Crigler-Najjar syndrome etc, Rotor’s syndrome  are some of the hereditary jaundice types.   

f) Chemical/Drug induced hepatotoxicity: Generally may be hepatitis, jaundice   and carcinogenesis.


1.1. HEPATOTOXICITY:
Hepatotoxin is atoxic chemical substance which damages the liver. Toxic liver injury produced by drugs and chemicals may virtually mimic any form of naturally occurring liver disease. Hepatoprotective effect was studied against chemicals and drugs induced hepatotoxicity in rats like alcohol, carbon tetrachloride, galactosamine, paracetamol, isoniazid and rifampicin, antibiotics, peroxidised oil, aflatoxin etc.

Severity of hepatotoxicity is greatly increased if the drug is continued after symptoms develop. Among the various inorganic compounds producing hepatotoxicity are arsenic, phosphorus, copper and iron. The organic agents include certain naturally occuring plant toxins such as pyrrolizidine alkaloids, myotoxins and bacterial toxins.

Liver injury caused by hepatotoxins, such as carbon tetra chloride (CCl4), ethanol and acetaminophen, is characterised by varying degrees of hepatocyte degeneration and cell death via either apoptosis or necrosis. The generation of reactive intermediate metabolites from the metabolism of hepatotoxins  and the occurrence of reactive oxygen species (ROS) during the inflammatory reaction,  account for a variety of pathophysiologic pathways  leading to cell death, such as covalent binding, disordered cytosolic calcium homeostasis, GSH depletion, onset of mitochondrial permeability transition (MPT) and associated lipid peroxidation. The metabolism of hepatotoxins by cytochrome P-450 enzyme subtypes is a key step of the intoxication; therefore, enzyme inhibitors are shown to minimize the hepatotoxin-associated liver damage. Moreover, substantial evidence exists that MPT is involved in ROS-associated hepatocellular injury and new findings offer a novel therapeutic approach to attenuate cell damage by blocking the onset of MPT. Thus, oxidant stress and lipid peroxidation are crucial elements leading to hepatotoxin-associated liver injury. In addition to specific treatment for a given hepatotoxin, the general strategy for prevention and treatment of the damage includes reducing the production of reactive metabolites of the hepatotoxins, using anti-oxidative agents and selectively targeting therapeutics to Kupffer cells or hepatocytes for on-going processes, which play a role in mediating a second phase of the injury4 .

1.2. CLASSIFICATION OF HEPATOTOXINS:

A.Intrinsic
It consists of agents that are predictable hepatotoxins. They are recognized by high incidence of hepatic injury exposed individuals and in experimental animals. There is a consistant latent period between exposure to a particular agent and the development of hepatic injury and the injury appeared to be dose related5,6.There are two types of intrinsic hepatotoxins:

1.Direct hepatotoxins:
It may be so called because they (metabolic products) produce direct injury to hepatocytes and its organelles, especially the endoplasmic reticulum. CCl4, the prototype, produces peroxidation of the membrane lipids and other chemicals that lead to degeneration of the membranes.

2. Indirect hepatotoxins:
They are anti-metabolites and related compounds that produce hepatic injury by interference with the specific metabolic pathway or processes. The structural injury produced by indirect hepatotoxins, appear to be secondary to a metabolic region. While in that produced by direct hepatotoxins,  the metabolic dearrangement is secondary to the structural injury. The hepatic damage produced by indirect hepatotoxins may be mainly cytotoxic injury (by interfering with metabolic pathway or processes essential for parenchyma integrity) expressed as steatiosis or necrosis, or may be mainly cholestasis, interfering only or mainly with biliary secretion.

 B. Host idiosyncrasy:
It consists of agents that are not predictably hepatotoxic, but produces hepatic injury in only a small portion of exposed individual. Who are uniquely susceptible. In several instances auto antibodies directed against normal cellular constituents are detected. The injury does not appear to be dose related and is not reproducible in experimental animals and appears after a variable latent period6,7 .

1.3. EVALUATION of HEPATOPROTECTIVE ACTIVITY:
A review of literature reveals that several chemical substances and drugs having specific actions on liver are used as hepatotoxins in experimental animals to simulate ideal diseased conditions. The hepatoprotective activity can be most easily evaluated /screened with the aid of several model systems of liver damage in experimental animals.

In all test model systems, conditions for liver damage are implemented and an attempt is made to counteract this toxicosis with the substance/preparation under test. The magnitude of the protective effect can be measured by estimating the enzyme activities and the rate of survival and can be verified histologically. The available methods are in vivo, ex vivo and in vitro methods8 . All these methods are used to study the protective or curative effects of any compound under test. In order to test for hepatoprotective activity the test substance and the hepatotoxin are administered simultaneously whereas in case of antihepatotoxic or curative activity the test substance is generally administered after induction of hepatotoxicity

a.      In vitromethods:
Hepatocytes are generally isolated by using in-situ, two step recirculating collagenase perfusion technique. These are then seeded in small containers and exposed to test samples and toxins. After a specified time period, the degree of toxicity or protection is assessed by viability tests and enzyme levels such as GOT and GPT. By employing primary culture hepatocytes  using  CCl4, galactosamine, thioacetamide, ethanol, paracetamol (PCML) etc. as hepatotoxins several hepatoprotective screening models have been devised. These have a number of advantages over in vivo methods such as their ability to dispose numerous samples at a time, low cost with a small size, little variation  and reproducibility of results. The major disadvantage is that sometimes it may not reflect the events which occur in animals.

b.      Ex- vivo models:
In this model, after completion of preselected in vivo test protocol hepatocytes are isolated and the percentage of viable cells and biochemical parameters are determined as liver function tests. These methods are somewhat better correlated to clinical models than in vitro or in vivo methods.

c.       In vivomethods:
This method is used not only to study the nature of the given compound but also to study the mechanism of the toxicant. Hepatotoxicity  is produced  in experimental animals by the administration of  known dose of  hepatotoxins like CCl4, galactosamine, thioacetamide, ethanol and paracetamol etc., which produce marked measurable  effects, the magnitude of which can be measured by carrying out various liver function tests viz. morphological, metabolic or functional, biochemical and histopathological  determinations.  Although it is a very convenient laboratory method, reproducibility of results is rather poor. The compounds having hepatoprotective claims are also  evaluated in general for their choleretic or anticholestatic activity in order to know whether the liver disorder is due to an abnormality of bilirubin metabolism or not. Choleretics are those agents which increase the out puts of bile by stimulating the liver where as anticholestatics are those which correct the retention and accumulation of bile due to intrinsic and extrinsic factors in the liver. These activities are evaluated by studying bile flow content in conscious and anaesthetized animals for 5 hours.

1.4 .Experimental modelS for hepatoprotectivE SCREENING:
Several chemical reagents and drugs which induce liposis, necrosis, cirrhosis, carcinogenesis and hepatobiliary dysfunctions in experimental animals are classified as hepatotoxins. The following are some of the experimental models explained by employing some of the important hepatotoxins.

1.      CCl4 model:
A number of CCl4 models are devised depending upon its dosage through different routes of administration.
a)      Acute hepatic damage: Acute liver damage, characterized by ischemia, hydropic degeneration and central necrosis is caused by oral or subcutaneous administration of CCl4 (1.25ml/kg). The maximum elevation of biochemical parameters are found to be 24 hours after the CCl4 administration normally administered as 50% v/v solution in liquid paraffin or olive oil9 .
b)      Chronic reversible hepatic damage: Administration of CCl4 (1ml/kg S.C.) twice weekly for 8 weeks produces chronic, reversible liver damage 10.
c)      Chronic, irreversible hepatic damage: Administration of CCl4 (1ml/kg S.C.) twice weekly for 12 weeks simulates chronic, irreversible liver damage11.

2.Thioacetamide model:Thioacetamide (100mg/kg s.c.) induces acute hepatic damage after 48 hrs of administration by causing sinusoidal congestion and hydropic swelling with increased mitosis12.

3.D-galactosamine model: D-galactosamine (800mg/kg i.p.) induces acute hepatotoxocity after 48 hrs of  administration with diffused necrosis and steatosis13.

4 .Paracetamol model:
Paracetamol induces acute hepatotoxicity depending upon its dosage through different routes of administration, such as
a. Paracetamol (800mg/kg i.p.) induces centrilobular necrosis without  steatosis 14.
b.Paracetamol at a single dose of 3g/kg p.o. stimulates acute hepatic damage. It takes 48 hrs to induce the toxicity15.

5.Chloroform model:
It produces hepatotoxicity with extensive central necrosis, fatty metamorphosis, hepatic cell degeneration and necrosis either by inhalation or by subcutaneous administration (0.4-1.5ml/kg)16 .

6.Ethanol model:
Ethanol induces liposis to a different degree depending upon its dose, route and period of administration as follows:
a.  A single dose of ethanol (1ml/kg) induces fatty degeneration17.
b. Administration of 40%v/v ethanol (2 ml/100g/day p.o.) for 21 days produces fatty liver18.
c.  Administration  of country made liquor (3ml/100 g/day p.o.) for 21 days produces liposis19.

Paracetamol induced hepatotoxicity
Paracetamol or acetaminophen (N-acetyl-P-aminophenol, APAP) induced hepatic injuries are commonly used models  for screening of hepatoprotective  drugs 20,21 and it causes acute centrilobular necrosis in rats, mice, guinea pig, hamsters, rabbits, cats, dogs and22 pigs and centrizonal heamorrhagic necrosis in humans mostly characterized by pyknosis and eosinophilic cytoplasm22,23 .

Paracetamol is one of the most widely used drug 24 for   analgesic and antipyretic activity worldwide. It is one of the most common pharmaceutical associated with both intentional and accidental poisoning. It is a major cause of liver failure and causes death when taken in excess 25  and is assumed to be safe in recommended doses. It produces hepatic necrosis at higher doses22 . Paracetamol is rapidly absorbed from the stomach and small intestine and metabolized by conjugation in the liver to non-toxic agents. Therapeutic doses of drug are metabolized mostly to sulphate and glucuronide conjugates. The rest is metabolized to a reactive intermediate which is detoxified by conjugation with glutathione. In acute overdose or when the maximum daily dose is exceeded over a prolonged period, the normal conjugative pathway of metabolism becomes saturated. Excess paracetamol is then oxidatively metabolized in the liver via the mixed function oxidase P450 system to a toxic metabolite N-acetyl-P-benzo-quinoneimine (NAPQI).  NAPQI has extremely, short half-life and is rapidly conjugated with glutathione, a sulphydryl donor. Under conditions of excessive NAPQI formation or reduced glutathione store, NAPQI covalently binds to vital proteins and the lipid bilayer of hepatocyte membranes. The result is hepatocellular death and centrilobular liver necrosis25 . Small doses are eliminated by conjugation followed by excretion but when the conjugation enzymes are saturated, the drug is diverted to an alternative metabolic pathway, resulting in the formation of a hydroxylamine derivative by cytochrome P450 enzyme. The hydroxylamine derivative, a reactive electrophilic agent, reacts non-enzymatically with glutathione reacts with macromolecules and disrupts their structure and function. Extensive liver damage by paracetamol itself decreases its rate of metabolism and other substrates for hepatic microsomal enzymes. Induction of cytochrome P450 or depletion of hepatic glutathione is a prerequisite for paracetamol-induced toxicity26 . In over dose, the sulphate and glucuronide conjugation pathways are saturated and more drugs are converted to the reactive metabolite. The glutathione available for its detoxification is rapidly depleted and the metabolites accumulated bind covalently to liver cell proteins, causing irreversible damage. Liver damage can be prevented by providing glutathione like substances, such as acetylcysteine, so that the reactive metabolite can be removed by conjugation and the liver cells are protected27.

An alternative view is that oxidative stress has a role in hepatotoxicity. There are many characteristic features of oxidative stress in APAP hepatotoxicity, including lipid peroxidation, mitochondrial damage, ATP depletion, and formation of nitrotyrosine adducts in proteins, presumably owing to formation of superoxide-derived peroxynitrite28 .However, these processes may be consequences of the damage  mediated by protein adduction rather than the direct effect of hepatotoxicity29 .

 

Analysis of bio-chemical parameters to assess liver function
In keeping with the multiplicity of the liver function, a variety of tests are available to assess them. The choice of the test is influenced by its simplicity, reliability and sensitivity as well as the particular function, one is interested in assessing30 .

1.      Serum enzyme parameters:
Transaminases  31
A.Transamination is a process in which an amino group is transferred from an amino acid to an alpha- keto acid. It is an important step in the metabolism of amino acids. The enzyme responsible for  transamination  are called transaminases or amino-transferases. Two diagnostically useful transaminases are glutamate oxaloacetate transaminase SGOT/AST and glutamate pyruvate transaminase SGPT/ALT. These two enzymes are sensitive markers of hepato-cellular injury.

A.    Estimation of SGOT/AST:
SGOT is an enzyme found mainly in heart muscle, liver cells, skeletal muscle and kidneys. Injury to these tissues results in the release of the enzyme in blood. Elevated levels are found in myocardial infarction, cardiac operations, hepatitis, cirrhosis, acute pancreatitis, acute renal diseases and primary muscle diseases. Decreased levels may be found in pregnancy, Beri Beri and Diabetic ketoacidosis. Its normal serum level is 5-40 units/l.

Principle:
SGOT (AST) catalyzes the transfer of amino group between L-Aspartate and a Ketoglutarate to form Oxaloacetate and Glutamate. The Oxaloacetate formed reacts with NADH in the presence of Malate Dehydrogenase to form NAD. The rate of oxidation of NADH to NAD is measured as a decrease in absorbance which is proportional to the SGOT (AST) activity in the sample.

                                                    AST
L-Aspartate + α-ketoglutarate -------------->   Oxaloacetate +L-Glutamate

                                        MDH
Oxaloacetate+ NADH+H+
--------------> L- Malate + NAD+

SGOT levels are 10-200 fold elevated in patients with acute hepatic necrosis, viral hepatitis and drug induced poisoning. SGOT levels are also elevated by 10 fold in patients of post hepatic jaundice, intra hepatic cholestasis and less than 10 fold in alcoholic and hepatic steatosis. Very high levels are seen in extensive acute hepatic necrosis such as in severe viral hepatitis and acute cholestasis.

B.Estimation of ALT/SGPT:

ALT or SGPT is a cytosolic enzyme primarily present in the liver. Its normal serum level is 7-56 units/l.

Principle:

SGPT (ALT) catalyzes the transfer of amino group from L- alanine to alpha- ketoglutarate to yield pyruvate and L-glutamate. Lactate dehydrogenase then converts pyruvate and NADH into lactate and NAD. The conversion of  NADH to NAD decreases the absorption at 340 nm. The rate of decrease in absorbance is measured and is proportional to the SGPT activity.    

                                            ALT
L-alanine +α-ketoglutarate 
--------------> pyruvate +L-Glutamate

 

                                   LDH
Pyruvate +NADH+H
--------------> L-Lactate +NAD+

ALT activity is predominantly associated with liver tissues followed by comparatively lower levels in heart, muscles and kidneys.  Quantitation of ALT is a useful parameter in evaluating liver function.  Elevated levels of this enzyme are found in liver and kidney diseases such as infectious or toxic hepatitis, infectious mononucleosis and cirrhosis. Moderate increase is also found in obstructive jaundice, metastasis carcinoma, hepatic congestion and myocardial infarction.

Phosphatases 31
Phosphatases belong to the class of enzyme called hydrolases and they are characterized by their ability to hydrolyse a large variety of organic phosphate with the formation of an alcohol and phosphate ions.

Phosphatases of diagnostic significance are alkaline phosphatase and acid phosphatase. These are differentiated by their reaction in alkaline and acidic medium. The PH for measuring the alkaline phosphatase activity is 10 and for acid phosphatase is 5.

Alkaline phosphatase (ALP) 2,32,33
ALP is a membrane bound glycoprotein enzyme, produced by many tissues, especially bone, liver, intestine, placenta and is excreted into the bile. Elevation in activity of the enzyme can thus be found in diseases of bone, liver and in pregnancy. ALP levels in serum are abnormally high in biliary obstruction. Slight to moderate increase is seen in parenchymal liver diseases such as in hepatitis and cirrhosis and in metastatic liver disease.  Its normal serum level is 20-100 U/L.

Principle
The substrate, p- nitrophenyl phosphate (PNPP) is hydrolysed by ALP  to p- nitrophenol (PNP)(colourless) and phosphoric acid. PNPP is colorless in acid or alkaline medium while PNP is yellow in the alkaline medium and colourless in  acid medium and the concentration is determined by measuring the absorbance at 405 nm. 

     ALP

P-nitrophenyl phosphate + H2--------------> P-nitrophenol + H3PO4 Colourless                                                                        Yellow   

Increased alkaline phosphatase activity  may be related to hepatobiliary and bone disease. Very high alkaline phosphatase activity in serum is seen in patient with bone cancer and marked increased also occur in obstructive jaundice and biliary cirrhosis. Modetrate elevations have been noted in case of Hodgkin’s disease, congestive heart   failure, infective hepatitis and abdominal problems.

 2) Bile pigments:
Bilirubin or
hematoidin is the yellow breakdown product of normalheme catabolism. Heme is found in hemoglobin, a principal component of red blood cells. Bilirubin is excreted in bile and urine, and elevated levels may indicate certain diseases. It is responsible for the yellow color of brusis, urine and the yellow discoloration injundice.
Bilirubin in serum would only react with diazo reagent in the presence of alcohol, after the proteins had been removed by precipitation. Normally 0.25mg/dl of conjugated bilirubin is present in the blood of an adult. Bilirubin rises in disease of hepatocytes, obstruction to biliary excretion into duodenum, in haemolysis, and defects of hepatic uptake and conjugation of bilirubin pigment such as Gilbert’s disease34 .Estimation of bilirubin is one of the better liver function tests because the liver must take bilirubin away from the albumin to which it is bound in the circulation, conjugate it and excrete it into the bile-a truly complex series of reaction.        

Estimation of serum Total Bilirubin (TB) 35.
The serum bilirubin level is one of the best tests of liver function.  Bilirubin is the metabolic product of the breakdown of heme derived from senescent red blood cells.  Each day about 7.5g of hemoglobin is catabolized with the corresponding production of 250 mg bilirubin.
Normally, 0.25 mg/dl of conjugated bilirubin is present in the blood of an adult.  Bilirubin level rises in diseases of hepatocytes, obstruction to biliary excretion into duodenum, in hemolysis and defects of hepatic uptake and conjugation of bilirubin treatment such as Gilbert’s disease.

Principle:
Bilirubin reacts with diazotized sulphanilic acid to form an azo compound, the color of which is measured at 546 nm (536-560 nm) and is proportional to the concentration of bilirubin.  The stability of final color of reaction of mixture is 10 minutes for total bilirubin and 5 minutes for direct bilirubin.

1.5.    Hepatoactive medicaments:
The literature review reveals that a large number of drugs of plant origin are endowed with hepatoprotective claims either directly or indirectly. In recent years, the usage of herbal drugs for the treatment of liver diseases has increased all over the world36.The herbal drugs are believed to be harmless and free from serious adverse reactions, as they are obtained from nature  and are easily available. Also, the limited therapeutic options and disappointing therapeutic success of modern medicine including herbal preparations37 .

In recent years many researchers have examined the effects of plants used traditionally by many folklore remedies from plant origin have long been used for the treatment of liver diseases  38indigenous healers and herbalists to support liver function and treat diseases of the liver. In most cases, research has confirmed traditional experience and wisdom by discovering the mechanisms and mode of action of these plants as well as reaffirming the therapeutic effectiveness of certain plants or plant extracts in clinical studies. Several hundred plants have been examined for use in a wide variety of liver disorders. Just a handful has been fairly well researched 39

There are about 600 commercial herbal formulations, which are claimed to have hepatoprotective activity and many of them are being sold in market all over the world. In India, about 40 patented polyherbal formulations representing a variety of combinations of 93 herbs from 44 families are available40. It has been reported that 160 phytoconstituents from 101 plants possess hepatoprotective activity41 . Liver protective herbal drugs contain a variety of chemical constituents like phenols, coumarins, lignans, essential oil, monoterpenes, carotenoids, glycosides, flavonoids, organic acids, lipids, alkaloids and xanthone  derivatives40. Studies carried out in China and Japan resulted in the isolation of a hepatoprotective lignan, gomishin from the fruits of Chinese medicinal plant Schizandra chinensis. Gomishin is used for the treatment of chronic hepatitis. Studies carried out at Tropical Botanic Garden and Research Institute (TBGRI) have shown that Trichopus zeylanicus,Phyllanthus maderaspatensis and P. kozhikodianus are extremely active against paracetamol-induced liver damage in rats 42,43,44. A recent report indicates that fumaric acid obtained from Sida cordifolia has significant anti-hepatotoxic activity in rat45. Ursolic acid which occurs in many plants also showed promising hepatoprotection against paracetamol and CCl4  induced liver damage in rats46,47 .Some of the reported  constituents  with pharmacologically/therapeutically proved claims may be enlisted as silymarin, (+)- catechin, saikosaponins, curcumin, glycyrrhizin, picroside I and II gomisin etc48 , acetyl bergenin 49 and kolaviron50 . Most commonly used plants in herbal formulations in India and scientifically validated in experimental animals are Andrographis paniculat)51, Boerhaavia diffusa, Eclipta alba, Picrorrhiza kurroa52 , Cichorium intybus, Tinospora cordifolia53 .

Some of the polyherbal formulations are verified for their hepatoprotective action against chemical induced liver damage in experimental animals54,55,56 : Liv.5240,57, Liv.42, Liver cure, Tefroli 51,58, Livol , Hepatomed59 , Jigrine40 , Stimuliv44 , Koflet40  and Icterine60 .

Antioxidants can protect experimental animals and humans from oxidant mediated liver damages. This effect can be seen even in certain common vitamins, spices and vegetables (e.g. Vitamin-E and turmeric).Efficacy of the traditional and new herbal products should be tested by standard experimental methods. Also, there should be adequate data from in vivo and in vitro studies to validate the therapeutic potential claimed61.

Several plants have been reported  to have hepatoprotective acvity among those, a few plants tested against different experimental models  are listed  in below table.

2 . LIST OF HEPATOPROTECTIVE ACTIVITY HAVING MEDICINAL  

PLANTS:

BOTANICAL NAME

  FAMILY

PLANT PARTS USED

SCREENING METHODS

REFERENCES

Acacia catechu

Leguminosae

Powdered pale catechu

Carbontetra chloride induced

      62

Acacia confuse

Leguminosae

Bark

Carbon tetra chloride

      63

Aegle marmelos Correa

Rutaceae

Leaves

Paracetamol Induced

      64

 Aerva lanata

Amaranthaceae

Coarce powder Plant

Paracetamol Induced

      65

Alchornea cordifolia

Euphorbiaceae

Leaves

Paracetamol Induced

      66

Alocasia indica Linn

Araceae

Leaves

Paracetamol Induced

       67

Aloe barbadensis

Liliaceae

Dried aerial parts

Carbontetra chloride

       68

Amaranthus spinosus

Amaranthaceae

Whole plant

Carbontetra chloride

       69

Amaranthus caudatus Linn

Amaranthaceae

Whole plant

Carbontetrachloride Induced

       70

Anisochilus carnosus Linn

Lamiaceae

Stems

Carbontetrachloride Induced

71

Apium graveolens

Apiaceae

Seeds

Paracetamol and thioacetamide

72

Arachiodes exilis

Dryppteridaceae

Rhizomes

Carbontetra chloride

73

Argemone mexicana

Solanaceae

Plant material

Carbontetra chloride

74

Asparagus racemosus Linn

Asparagaceae

Roots

Paracetamol induced

75

Azadirachta indica

Meliaceae

Leaf

Paracetamol Induced

76

Azitetracantha

Salvadoraceae

Leaves

Paracetamol induced

77

Baliospermum montanum

Euphorbiaceae

Roots

Paracetamol induced

78

Boerhaavia diffusa

Nyctaginaceae

Roots

Thioacetamide

79

Bupleurum kaoi

Umbelliferar

Dried roots

Carbontetra chloride

80

Byrsocarpus coccineus

Connaraceae

Leaf

Carbontetra chloride

81

Bixa orellana

Bixxaceae

Plant material

Carbontetra chloride

82

Cajanus cajan Linn

Leguminosae

Pigeon pea leaf

D-galactosamine

83

Cajanus scarabaeoide

Fabaeceae

Whole plant

Paracetamol induced

84

Carissa carindas Linn

Apocyanaceae

Root

Carbontetrachloride Induced

85

Carum copticum

Apiaceae

Seed

Carbontetra chloride,paracetamol

86

Calotropis procera

Asclepediaceae

Root bark

Carbontetrachloride Induced

87

Cassia  fistula

Leguminosae

Leaf

Carbontetrachloride Induced

88

Cassia tora

Caesalpiniaceae

Leaves

Carbontetra chloride

89

Cassia Occidentalis

Caesalpiniaceae

Leaves

Paracetamol and Ethyl alcoho

90

Chamomile capitula

Asteraceae

Fresh natural mature capitula

Paracetamol

91

Clerodendrum inerme

Verbenaceae

Leaves

Carbontetra chloride

92

Clitoria ternatea Linn

Fabaceae

Leaves

Paracetamol induced

93

Cleome viscose Linn

Capparidaceae

Leaf powder 

Carbon tetra chloride

94

Cochlospermum planchoni

Coclospermaae

Rhizomes

Carbontetra chloride

95

Cichorium intybus

Asteraceae

Leaves

Thioacetamide

96

Cordia Macleodii

Boraginaceae

Leaves

Carbontetra chloride

97

Cuscuta chinensis

Convolvulaceae

Seeds

Acetaminophen

98

Decalepis hamiltonii

Asclepiadaceae

Roots

Carbontetra chloride

99

Elephrantopus scaber Linn

Asteraceae

Whole plant

D-galactosamine and acetaminophen

100

Equisetum arvense

equisetaceae

Aerial parts

Carbontetra chloride Induced

101

Embelia ribes

myrsinaceae

Fruits

Paracetamol induced

102

Enicostemma axillare

Gentianaceae

Whole plant

D-galactosamine

103

Euphorbia fusiformis

Euphorbiaceae

Tubers

Rifampicin

104

Ficus religiosa Linn

Moraceae

Stem bark

Paracetamol induced

105

Fructus schisandrae

Magnoliaceae

Dried fructus

Carbontetra chloride Induced

106

Fumaria indica

Papaveraceae

Whole plant

D-galactosamine

107

Ganoderma lucidum

Polyporaceae

Winter mushrooms

D-galactosamine

108

Ginkgo biloba

Ginkgoaceae

Dried extract

Carbontetra chloride Induced

109

Glyrrhiza glabra

Fabaceae

Root powder

Carbontetra chloride Induced

110

Gracinia indica Linn

Clusiaceae 

Fruit rind

Carbontetrachloride Induced

111

Gmelina asiatica Linn

Verbenaceae

Aerial parts

Carbontetrachloride Induced

112

Gundelia tourenfortii

Asteraceae

Fresh edible stalk

Carbontetra chloride Induced

113

Halenia elliptica

Gentianaceae

Whole plant

Carbontetra chloride Induced

114

Hibiscus Sabdariffa

Malvaceae

Leaves

Paracetamol induced

115

Hibiscus esculentus

Malvaceae

Roots

Carbontetra chloride

Induced

116

Hypericum japonicum

Clusiaceae

Whole plant

Carbontetra chloride Induced

117

Hygrophila auriculata

Acanthaceae

Root

Carbontetra chloride Induced

118

Hyptis suaveolens Linn

laminaceae

leaves 

Acetaminophen induced

119

Hoslundia opposite

Lamiaceae

Stem

Carbontetra chloride And paracetamol Induced

120

Juncus subulatus

Juncaceae

Powdered tubers

Paracetamol  induced

121

Kalanchoe  pinnata

 

Crassulaceae

Leaves

Carbontetra chloride

Induced

122

Lawsonia alba

Lythraceae

Whole plant

Carbon tetrachloride

123

Lactuca indica

Compositae

Aerial parts

Carbontetra chloride

Induced

124

Luffa echinata

Curcubitaceae

Fruits

Carbontetra chloride Induced

125

Laggera  pterodonta

Asteraceae

Whole herb

Carbontetra chloride

And 

D-galactosamine Induced

126

Mallotus japonicas

Euphorbiaceae

Cortex

Carbontetra chloride Induced

127

Mamoridca subangulata

Cucurbitaceae

Leaf

Paracetamol  induced

128

Melia azhadirecta Linn

Piperaceae

Leaves

Carbontetrachloride, silymarin induced

129

Morinda citrifolia Linn

Rubiaceae

Fruit

Streptozotocin induced

130

Myoporum lactum Linn

myoporaceae

Leaves

Carbontetrachloride Induced

131

Myrtus communis Linn

Myrtaceae

Leaves

Paracetamol induced

132

Nelumbo nucifera

Nelumbonaceae

Leaves

Carbontetrachloride Induced

133

Nigella sativa

Ranunculaceae

Seeds

Tert –butyl hydroperoxide

134

Ocimum sanctum

Lamiaceae

Leaf

Paracetamol induced

135

Orthosiphan stamineus

Lamiaceae

Leaves

Acetaminophen

136

Phyllanthus amarus schum

Euphorbiaceae

Aerial part

Ehanol

137

Phyllanthus amarus

Euphorbiaceae

Whole plant except root

Aflatoxin b1 induced liver damage

138

Physalis minima

Solanaceae

Plant material

Carbontetra chloride

139

Phyllanthus niruri

Euphorbiaceae

Leaves and fruits

Carbontetrachloride Induced

140

Phyllanthus polyphullus

Euphorbiaceae

Leaves

Acetaminophen

141

Picrorhiza kurrooa

Scrophulariaceae

Root and rhizomes

Alcohol –carbon tetra chloride

142

Picrorrhiza rhizome

Scrophulariaceae

Dried underground stem

Poloxamer(PX)-407

143

Piper chaba

Piperaceae

Fruit

D-galactosamine

144

Piper longum

Piperaceae

Fruits and roots

Carbontetra chloride

145

Pittosporum neelgherrense

Pittospoaceae

Stem bark

Carbontetra chloride, 

D-galactosamine and acetaminophen Induced

 

146

Plantago major

Plantaginaceae

Seeds

Carbontetra chloride

147

Pterocarpus marsupium

Papilionaceae

Stem bark

Carbontetra chloride

148

Ptrospermum acerifolium

Sterculiaceae

Leaves

Carbontetra chloride

149

Ricinus communis

Euphorbiaceae

Leaves

Carbon tetrachloride

150

Rubia cordifolia

Rubiaceae

Roots

Carbontetra chloride

151

Sarcostemma brevistigma

Asclepiadaceae

Stem

Carbontetra chloride

152

Saururus chinensis

Sauruaceae

Whole plant

Carbontetra chloride

153

Scoparia dulcis

Scrophulariaceae

Whole plant

Carbontetra chloride

154

Schouwia theebica

Arecaceae

Aerial part

Carbontetra chloride

155

Solanum nigram Linn

Solsnaceae

Fruits

Carbontetrachloride Induced

156

Tecomella undulate

Bignoniaceae

Stem bark

Thioacetamide

157

Tephrosia purpurea Linn

Fabaceae

Aerial parts

Thioacetamide

158

Thunbergia laurifolia

Acanthaceae

Leaves

Ethanol

159

Tridax procumbens

Asteraceae

Leaves

Carbontetrachloride Induced

160

Tylophora indica

Asclepiadaceae

Leaf  powder

Ethanol

161

Vitex trifolia

Verbenaceae

Leaves

Carbontetrachloride Induced

162

Vitis vinifera

Vitaceae

Leaves

Carbontetrachloride Induced

163

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