REVIEW ON HEPATO-TOXICITY, HEPATOTOXICANTS AND LIVER PROTECTIVE PLANTS

ABOUT AUTHORS:
Mr. Gunjegaonkar shivshankar M., Mr. T.T. shelke
Dept. of Pharmacology, JSPMs Charak College of pharmacy and research,
Wagholi, Pune, Maharashtra
*gunjeshiv@gmail.com

1.  ABSTRACT
The 21st century has a paradigm shift from allopathic medicinal system to homeopathic and Ayurvedic medicinal system as it is been proved that the adverse effects or unwanted effects associated with the modern synthetic medicines are more than the herbal medicines. Worldwide acceptance of herbal medicine is increasing day by day and its beneficial effects are focused by scientific researches. The herbs play important role in management of diverse group of diseases ranging from acute fever to cardiac complications. The current review is taken with interest to gather the scientific information of plant which shows the hepatoprotective activity. Various scientific research reveals that these medicinal plant did not shows any acute toxicity even in high doses. The preliminary phytochemical studies show the presence of important secondary metabolites like flavonoids, alkaloids, tannins, rutin and rotenoids. Triterpenoid etc.

Chronic hepatic diseases stand as one of the foremost health troubles worldwide, with liver cirrhosis and drug induced liver injury accounting ninth leading cause of death in western and developing countries. Therapies developed along the principles of western medicine are often limited in efficacy, carry the risk of adverse effects, and are often too costly, especially for the de-veloping world. Therefore, treating liver diseases with plant-derived compounds which are accessible and do not require laborious pharmaceutical synthesis seems highly attractive. In this review article, an attempt has been made to compile the reported hepatoprotective plants from India and abroad and may be useful to the health professionals, scientists and scholars working the field of pharmacology and therapeutics to develop evidence-based alternative medicine to cure different kinds of liver diseases in man and animals.

Popularity of herbal remedies is increasing globally and at least one quarter of patients with liver diseases use ethnobotanicals. More efforts need to be directed to-wards methodological scientific evaluation for their safety and efficacy by subjecting to vigorous pre-clinical studies followed by clinical trials to unravel the mysteries hidden in the plants. This approach will help exploring the real therapeutic value of these natural pharmacotherapeutic agents and standardized the dosage regimen on evidence-based findings to become more than a fashionable trend. Many herbals are on the market to support health, relieve symptoms and cure diseases. However, most of these products lack scientific pharmacological validation. In experimental hepatotoxicity models in laboratory or higher animals, several herbals exerted hepatoprotective/curative effects that warrants their clinical testing. Due to lack of scientific-based pharmacological data, most of the herbal formulations cannot be recommended for the treatment of liver diseases

REFERENCE ID: PHARMATUTOR-ART-1787

2. INTRODUCTION:
Liver is the largest organ in the body carrying out most of the biochemical synthesis and secretary functions. Living in a world of inadequately controlled environment, pollution and exposed to variety of xenobiotics and therapeutic agents resulting in its structural or functional changes. Liver toxicity is one of the leading causes of mortality due to availability of hepatotoxic drugs over the counter and alcohol consumption in both developed and developing countries. The well known example of drug induced toxicity is Paracetamol. Paracetamol is extensively used as an over the counter analgesic and antipyretic drug and, though safe when used at therapeutic doses, but is associated with significant hepatotoxicity when taken in multiple doses or ingestion of a large single dose. ¹

Excessive alcohol consumption is the leading cause of liver disease throughout the world, especially in most western countries. More than 10 million Americans are alcoholics and alcohol abuse causes 200,000 deaths annually. In India also there is drastic increase in the consumption of alcohol from 29% in 1990 to 52% in 2006.Chronic alcohol consumption causes liver diseases such as hepatic steatosis, alcoholic hepatitis and cirrhosis collectively called as alcoholic liver disease.² In addition to the factors mentioned above malnutrition, anemia, infection and some chemicals also causes severe liver damage ³. The conventional drugs used in the treatment of liver diseases like Corticosteroids, anti-viral, immunosuppressant etc. agents are sometimes inadequate and may lead to serious liver toxicity hence it is imperative to search for better drugs to treat liver diseases.

Natural resources such as plants are explored in the search of new molecules to be used as medicines. In the Indian System of Medicine (ISM), the plants are classified in various groups on the basis of experience and ethno medicinal uses. Medicinal plants have been traditionally used for treating liver diseases since centuries. Several leads from plant sources have been found as potential hepatoprotective agents with diverse chemical structures ⁴. The 21st century has seen a paradigm shift towards therapeutic evaluation of herbal products in liver diseases by carefully synergizing the strengths of the traditional systems of medicine with that of the modern concept of evidence-based medicinal evaluation⁵.

3. HEPATOTOXICITY AND TOXINS:
Toxic liver injury produced by drugs and chemicals may virtually mimic any form of naturally-occurring liver disease. Hepatoprotective effect were studies against chemicals and drugs induced hepatotoxicity in rats like alcohol, CCl4, galactosamine, Paracetamol, isoniazid, rifampicin etc.

Classification of hepatotoxins
A) Intrinsic:
It consists of agents that are predictable hepatotoxins. They are recognized by high incidence of hepatic injury in exposed individuals and in experimental animals. There is a consistent latent period between exposure to a particular agent and the development of hepatic injury and the injury appeared to be dose related.

There are two types of intrinsic hepatotoxins:
1. Direct hepatotoxin:
It may be so called because they (or their metabolic products) produce direct injury to hepatocytes and its organelles, especially the endoplasmic reticulum. CCl4, the prototype, produces peroxidation of the membrane lipids that lead to degeneration of the membranes.
Ex: CCl4 induced hepatotoxicity 12

The drug is metabolized in endoplasmic reticulum and mitochondria with the formation of CCl3O - the reactive oxidative free radical intermediate generated by cytochrome P-450, the nascent oxygen O - resulted via lipoperoxidation causes rise in intracellular reactive Fe+2 ions, aldehyde and depletion GSH, and calcium sequestration. Oxidative CCl3O- also by direct covalent interaction induces degeneration of Ca+2 sequestrations. Failure into sequestration results in increased intracellular Ca+2, aggregation by proteolytic enzyme and causes an increase in Fe+2 ions, which in turn by lipoid peroxidation precipitates aldehyde cytotoxicity.

CCl₄-----------------------------> CCl₃O- + O

2. Indirect hepatotoxin
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 derangement 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 necrosis, or may be mainly cholestasis, interfering only or mainly with biliary secretion.

Ex. A) Paracetamol induced hepatotoxicity 13
The liver damage associated with Paracetamol overdose is due to the formation of a hepatotoxic metabolite. Therapeutic doses of Paracetamol are metabolized mostly by sulphate and glucuronide conjugates. The rest is metabolized to a reactive intermediate which is detoxified by conjugation with glutathion. In overdose, the sulphate and glucuronide conjugation pathways are saturated and most of the part of drug is converted to the reactive metabolite. The glutathione available for its detoxification is rapidly depleted and the metabolites accumulated and 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 protected13.

B) Alcohol induced hepatotoxicity 13, 15
Ethanol produces dose- related deleterious effects in the liver. The primary effects are fatty infiltration of the liver, hepatitis and cirrhosis. Because of its intrinsic toxicity, alcohol can injures the liver in the absence of dietary deficiencies. The accumulation of fat in the liver is an early event and can occur in normal individual after the ingestion of relatively small amount of ethanol. This accumulation results from inhibition of both the Tricarboxylic acid cycle and oxidation of fat, in part owing to the degeneration of excess NADH produced by the action of alcohol dehydrogenase and aldehyde dehydrogenase. Fibrosis resulting from tissue necrosis and chronic inflammation is the underlying cause of alcoholic cirrhosis. Normal liver tissue is replaced by fibrous tissue. Alcohol can affect directly stellate cells in the liver; causing deposition of collagen around terminal hepatic venules. Chronic alcohol use is associated with transformation of stellate cells into collagen- producing myofibroblast-like cells. The histologic hallmark of alcoholic cirrhosis is the formation ofMallory bodies, which are thought to be related to an altered cytokeratin intermediate cytoskeleton. A number of underlying molecular mechanism have been proposed

3. Host idiosyncrasy 15
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 period.

Ex. Galactosamine induced hepatotoxicity 16
It resembles to that caused by acute human viral hepatitis. The cholestasis caused by galactosamine may be from its damaging effects on bile ducts or ductless or canalicular membrane of hepatocytes. Collagen- producing myofibroblast-like cells. The histological hallmark of alcoholic cirrhosis is the formation of Mallory bodies, which are thought to be related to an altered cytokeratin intermediate cytoskeleton. A number of underlying molecular mechanisms have been proposed.

TABLE NO.3.1 CLASSIFICATION OF HEPATOTOXINS.

4. HEPATOPROTECTIVE PLANTS

1.      Plant name: Amaranthus caudatusLinn.
Botanical name:Amaranthus caudatus Linn.
Family:  Amaranthaceae.
Habitat:Grown as vegetable in northern India & other asian countries.
Part used:Whole plant.
Solvent used:  Methanol.
Chemical constituents:  Flavonoids, Saponins, Glycosides.
Method of induction:Carbon tetra chloride.
Use:Blood Purifier, Diuretic, Used in piles, Dropsy & Anasarea, Tea has been used in pulmonary conditions, Ulcers, Diarrhoea As well as inflammation of mouth.

2.      Plant name: Anisochilus carnosus Linn.
Botanical name:Anisochilus carnosus Linn.
Family:Lamiaceae.
Habitat:Tirumala gardens of chittor disrict of A.P, India; Western Ghats & it is annual herb.
Part used:Stems.
Solvent used:Ethanol.
Chemical constituents:  Alkaloids, Flavonoids, Glycosides.
Method of induction:Carbon tetra chloride.
Use:  Gastrointestinal disorder, Cough, Cold, Fever, Hepatoprotective and Anti-ulcer activity

3.      Plant name: Asparagus Racemosus Linn.
Botanical name:Asparagus racemosus Linn.
Family:Asparagaceae.
Habitat:Shatavari is a branched, sppinous under shrub found growing in tropical & sub-tropical parts of India & other countries.
Part used:Roots.
Solvent used:Ethanol.
Chemical constituents:  Phenols, coumarins.
Method of induction:Paracetamol.
Use:Anti-Oxidant, Immuno-modulatory, Anti-Ulcer, Anti-Abortifacient, Prevent Ageing, Anti-Diarrheal, Anti-Diabetic.

4.      Plant name: Azima Tetracantha.
Botanical name:Azima tetracantha.
Family:Salvadoracaeae.
Habitat:Peninsular India Orissa, West bengal.
Part used:Leaves. Root, bark
Solvent used:Ethanol.
Chemical constituents:  Flavonoids, Triterpenoids.
Method of induction:Paracetamol induced.
Use:-Diurectic, Antirheumatic, Expectorants, Anti-Spasmodic, Anti Periodic, Astringent

5.      Plant name: Calotropis procera R.Br
Botanical name:Calotropis procera R.Br.
Family:Asclepediaceae.
Habitat:An evergreen shrub distributed in west & central India.
Part used:Root, bark, Leaves.
Solvent used:Methanol.
Chemical constituents:Terpinoids, Glycosides,Flavonoids.
Method of induction:Carbon tetra chloride.
Use:Used in Bronchial asthma, used in dyspepsia, used in external swelling, Anti-tussive activity.

6.      Plant name: Cajanus cajan Linn.
Botanical name:Cajanus cajan Linn.
Family:Leguminosae.
Habitat:Cultivated on pulse crop, chiefly in M.P, Bihar, A.P, Maharashtra, U.P, karnataka.
Part used:leaf.
Solvent used:ethanol.
Chemical constituents:  Flavonoids, stibenes.
Method of induction:D-galactosamine.
Use:Hypocholesterolaemic leaves used in diseases of mouth, topically for treating measles & other eruptions and jaundice.

7.      Plant name:Cajanus scarabaeoides Linn.
Botanical name:Cajanus scarabaeoides Linn.
Family:Fabaeceae.
Habitat:Widely distributed species, Its native of South-east Asia,China, Japan, india, pakisthan, Papua & Australia.
Part used:Whole plant.
Solvent used:N-Butanol, Ethanol.
Chemical constituents:  Flavonoids.
Method of induction:Paracetamol.
Use:Wound healing, Anti-diabetic, Anti-inflammatory, Hepatoprotective, Anti-diarrheal, Anthalmintic & Anti-bacterial activity.

8.      Plant name: Carissa carindas Linn.
Botanical name:Carissa carindas Linn.
Family:Apocyanaceae.
Habitat: The plant is native & common throughout India, Sri-Lanka, Java, Malaysia & Pakisthan.
Part used:Root.
Solvent used:Ethanol.
Chemical constituents:  Alkaloids, Tannins, Steroids.
Method of induction:Carbon tetra chloride.
Use: Anthelmintic, Astringent, Appetizer, Anti-Pyretic, Stomach Disorders, Rheumatism, Diseases of Brain, Anti-Viral Activity.

9.      Plant name: Cucumis trigonus Roxb.
Botanical name:Cucumis trigonus Roxb.
Family:Cucurbitaceae.
Habitat:Wild throughout the drier uplands tracks of India.
Part used:Fruit. Seeds
Solvent used:Pet. ether, chloroform, alcohol, aqueous.
Chemical constituents:  Flavonoids.
Method of induction:Carbon tetra chloride.
Use: Pulp of fruit drastic purgative, Astringent Effect, Useful in bilious disorders, Analgesic & Anti-Inflammatory Activity.

10.  Plant name: Garcinia indica Linn.
Botanical name:Garcinia indica Linn.
Family:Clusiaceae.
Habitat:Evergreen forests of west-Bengal from konkan southwards & in goa, also cultivated in southern districts of Maharashtra & on lower slopes of nilgiris.
Parts used:Fruit rind.
Solvent used: Ethanol.
Chemical constituents:  Benzophenones, Garcinol.
Method of induction:Carbon tetra chloride.
Use:Astringent, Antifungal, Antibacterial, used in cystitis, diseases of the genitourinary tract, diarrhoea, tropical dysentery and fevers. Used externally for eczema and other skin diseases.

11.  Plant name: Ficus religiosa Linn.
Botanical name:Ficus religiosa Linn.
Family:Moraceae.
Habitat: Sub-Himalayan tracts, West-Bengal, central & South India, planted throughout India as an avenue tree.
Parts used:Stem bark, fruits
Solvent used:Methanol.
Chemical constituents:  Glycosides, steroids, tannins.
Method of induction:Paracetamol induced.
Use:Astringent, Anti-Septic, Laxative, Haemostatic, Vaginal disinfectant, applied externally on unhealthy ulcers & wounds, used as a uterine tonic, Anti-Bacterial activity.

12.  Plant name: Gmelina asiatica Linn
Botanical name:Gmelina asiatica Linn.
Family:Verbenaceae.
Habitat:South India; planted in gardens in Maharashtra and West Bengal.
Parts used: Aerial parts.  
Solvent used:Ethanol, chloroform.
Chemical constituents:Flavonoids.
Method of induction:Carbon tetra chloride
Use: Demulcent, Alterative, Blood Purifier, Anti-Catarrhal, Astringent, Anti-Rheumatic.

13.  Plant name: Hyptis Suaveolens Linn.
Botanical name:Hyptis Suaveolens Linn.
Family:Lamiaceae.
Habitat:Native to tropical America and distributed throughout India.
Parts used:Leaves.
Solvent used:Aqueous.
Chemical constituents: Flavonoids.
Method of induction:Acetaminophen induced.
Use:Carminative, Antispasmodic, Anti-Soporific, Anti-Rheumatic, Used in catarrhal and uterine affections, Hepatoprotective.

14.  Plant name: Leucas Cilita Linn.
Botanical name:Leucas cilita Linn.
Family:Lamiaceae.
Habitat:Shrub which is frequently distributed along the ghats and in planes along forest edges in Ahmednagar, Dhule, Kolhapur, Mumbai, Satara, Sindhudurg and regions of Maharashtra in India.
Parts used: Whole plant.
Solvent used:Ethanol.
Chemical constituents:Flavonoids.
Method of induction:Carbon tetrachloride induced.
Use:wound healing and as antidote for snakebite, antibacterial and antifungal activity, antioxidant and hepatoprotective properties

15.  Plant name: Melia Azedarach Linn.
Botanical name:Melia Azedarach Linn.
Family:Piperaceae, Meliaceae.
Habitat:China, Baluchistan, Kashmir, Western Himalayas, South India.
Part used:Leaves, Fruit, Stem, Bark, Roots Bark, Seed, Gum and Flower.
Solvent used:Ethanol.
Chemical constituents:.
Method of induction:Carbon Tetra Chloride.
Use: Diuretic, anthelmintic, anti-lithic, febrifuge, sedative, anti-leprotic, deobstruent, anti-rheumatic, insecticidal, insect repellent, spleen enlargement, asthma.

5. SUMMARY
Chronic hepatic diseases stand as one of the foremost health troubles worldwide, with liver cirrhosis and drug induced liver injury accounting ninth leading cause of death in western and developing countries. Therapies developed along the principles of western medicine are often limited in efficacy, carry the risk of adverse effects, and are often too costly, especially for the de-veloping world. Therefore, treating liver diseases with plant-derived compounds which are accessible and do not require laborious pharmaceutical synthesis seems highly attractive. In this review article, an attempt has been made to compile the reported hepatoprotective plants from India and abroad and may be useful to the health professionals, scientists and scholars working the field of pharmacology and therapeutics to develop evidence-based alternative medicine to cure different kinds of liver diseases in man and animals

Popularity of herbal remedies is increasing globally and at least one quarter of patients with liver diseases use ethnobotanicals. More efforts need to be directed to-wards methodological scientific evaluation for their safety and efficacy by subjecting to vigorous pre-clinical studies followed by clinical trials to unravel the mysteries hidden in the plants. This approach will help exploring the real therapeutic value of these natural pharmacotherapeutic agents and standardized the dosage regimen on evidence-based findings to become more than a fashionable trend (Stickel and Schuppan, 2007). Many herbals are on the market to support health, relieve symptoms and cure diseases. However, most of these products lack scientific pharmacological validation. In experimental hepatotoxicity models in laboratory or higher animals, several herbals exerted hepato-protective/curative effects that warrants their clinical testing. Due to lack of scientific-based pharmacological data, most of the herbal formulations cannot be recommended for the treatment of liver diseases (Stickel and Schuppan, 2007).

In spite of the availability of more than 300 preparations for the treatment of jaundice and chronic liver diseases in Indian Systems of Medicine (using more than 87 Indian medicinal plants,) only four terrestrial plants have been scientifically elucidated while adhering to the internationally acceptable scientific proto-cols. In-depth studies have proved Sylibum marianumto be anti-oxidative, anti-lipid peroxidative, antifibrotic, anti-inflammatory, immunomodulating and liver regenerative. Glycyrrhiza glabra has been shown to be he-patoprotective and capable of inducing an endogenous interferon. Picrorhiza kurroa is proved to be anti-inflammatory, hepatoprotective and immunomodulatory. Extensive studies on Phyllanthus amarus have confirmed this plant preparation possessed anti-viral against hepatitis B and C viruses, hepatoprotective and immunomodulating effects, besides anti-inflammatory properties (Thyagarajan et al., 2002).

6. CONCLUSION:
The present study reveals plant extracts with hepatoprotective properties against toxic chemicals that cause liver injury, seeming to validate their use in folk medicine. 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. The study also identified glycosides, flavonoids, triterpenes and phenolic compounds as classes of compounds with hepatoprotective activity. The potent hepatoprotective activities of the chemically defined molecules isolated from natural origins represent an exciting advance in the search for effective liver protective agents, especially now, when there is an urgent need for new innovative drug leads. Further studies including clinical trials need to be carried out to ascertain the safety of these compounds as a good alternative to conventional drugs in the treatment of liver diseases.

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