REVIEW ON HEPATO-TOXICITY, HEPATOTOXICANTS AND LIVER PROTECTIVE PLANTS

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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.

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