HEPATOPROTECTIVE MEDICINAL HERBS AND ANIMAL MODELS FOR THEIR SCREENING – A REVIEW

HEPATOPROTECTIVE MEDICINAL HERBS AND ANIMAL MODELS FOR THEIR SCREENING - A REVIEW

Qadrie Z. L. ^{*1, 2}, B. Rajkapoor ³ and S. Kavimani ⁴

Prist University ¹, Centre for Research and Development, Vallam, Thanjavur, TN, India

Department of Clinical Pharmacology ², SKIMS, Srinagar J & K, India

Department of Pharmacology ³, Faculty of Medicine, Sebha University, Sebha, Libya

College of Pharmacy ⁴, Mother Theresa Post Graduate and Research Institute of Health Science, Pondicherry, TN, India

ABSTRACT: The liver is a vital solid organ in the upper abdomen that helps in digestion, detoxification and has other synthetic, metabolic and storage functions. Liver diseases are a major problem worldwide; viral hepatitis, alcohol, malnutrition, autoimmune and drugs being most important causes.  Currently there is no way to compensate for the absence of liver function in the long term and liver transplant is the only option for those with irreversible loss of hepatic function. The scientific basis for the statement that plants and their active constituents play an important role in the prevention of diseases is continuously advancing. In this review some of the plants with their phyto-constituents studied for protective effect in liver diseases are reviewed.

Liver, Hepatotoxic agents, Hepatoprotective, Medicinal herbs, Phytoconstituents

INTRODUCTION: The liver plays an astonishing array of vital functions in the maintenance, performance and regulating homeostasis of the body. It is involved with almost all the biochemical pathways to growth, fight against disease, nutrient supply, energy provision and reproduction. And it functions as a centre of metabolism of nutrients such as carbohydrates, proteins and lipids and excretion of waste metabolites. The bile secreted by the liver has, among other things, plays an important role in digestion. Therefore, maintenance of a healthy liver is essential for the overall well being of an individual ¹.

Liver cell injury caused by various toxicants such as certain chemotherapeutic agents, carbon tetrachloride, thioacetamide, chronic alcohol consumption and microbes are common. Enhanced lipid per oxidation during metabolism of ethanol may result in development of hepatitis leading to cirrhosis ².

Herbal drugs have gained importance and popularity in recent years because of their safety, efficacy and cost effectiveness. The association of medical plants with other plants in their habitat also influences their medicinal values in some cases. Since time immemorial, mankind has made the use of medicinal plants in the treatment of various ailments. Recently, various medicinal plants and their phytoextracts/active bioactive compounds have shown plenty of medicinal properties including antioxidant ^{3, 4}, anti-inflammation⁵, anti-cancer ⁵, anti-microbial ^{6, 7}, anti-diabetes ^{5, 8}, anti-nociceptive action ⁹ etc. The Indian Traditional Medicine like Ayurveda, Siddha and Unani are predominantly based on the use of plant materials. The association of medical plants with other plants in their habitat also influences their medicinal values in some cases.

One of the important and well documented uses of plant products is their use as hepatoprotective agents. Hence, there is an ever increasing need for safe hepatoprotective agent¹⁰. In spite of tremendous strides in modern medicine, there are hardly any drugs that stimulate liver function, offer protection to the liver from damage or help regeneration of hepatic cell. Many formulations containing herbal extracts are sold in the Indian market for liver disorders ¹¹. But management of liver disorders by a simple and precise herbal drug is still an intriguing problem. Several Indian medicinal plants have been extensively used in the Indian traditional system of medicine for the management of liver disorder. Some of these plants have already been reported to posse’s strong antioxidant activity ^{12, 13}.

The nature has bestowed some plants with the property to prevent, treat and cure hepatic disturbances with interception of fewer side effects. Hepatoprotectives are a class of therapeutic agents that includes synthetic as well as natural product which offer protection to liver from damage or help in regeneration of hepatic cells. Medicinal herbs are significant source of hepatoprotective drugs. It has been reported that about 170 phytoconstituents isolated from 110 plants belonging to 55 families do possess hepatoprotective activity.¹⁴ Liver protective herbal drugs contain a variety of chemical constituents like phenols, coumarins, curcuminoids, lignans, essential oils and terpenoids. Clinical research has also shown that herbals have genuine utility in the treatment of liver diseases. Only a small portion of hepatoprotective plants as well as formulations used in traditional medicine are pharmacologically evaluated for its efficacy.¹⁴

According to world health organization (WHO) more than 80% of the world’s population relies on traditional medicines for their primary health care needs¹⁵. In India, about 40 polyherbal commercial formulations reputed to have hepatoprotective action are being used. It has been reported that 160 phytoconstituents from 101 plants have hepatoprotective activity.^{16, 17} 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 xanthines.¹⁸

Modern medicines have little to offer for alleviation of hepatic diseases and it was chiefly the plant based preparations, which were employed for their treatment of liver disorders. But there was not much drug available for the treatment of liver disorders^{19, 20}. Therefore; many folk remedies from plant origin were tested for its potential antioxidant and hepatoprotective liver damage in experimental animal model.

Liver Functions: ²¹

Various functions of liver are as follows:

1. A large part of amino acid synthesis.

2. The liver performs several roles in carbohydrate metabolism:

1. Gluconeogenesis (the synthesis of glucose from certain amino acids, lactate or glycerol)
2. Glycogenolysis (the breakdown of glycogen into glucose)
3. Glycogenesis (the formation of glycogen from glucose)(muscle tissues can also do this)
4. The liver is responsible for the mainstay of protein metabolism, synthesis as well as degradation

3. The liver also performs several roles in lipid metabolism:

1. Cholesterol synthesis
2. Lipogenesis, the production of triglycerides (fats).

4. The liver produces coagulation factors I (fibrinogen), II (prothrombin), V, VII, IX

5. X and XI, as well as protein C, protein S and antithrombin.

6. In the first trimester foetus, the liver is the main site of red blood cell production. By the 32^nd week of gestation, the bone marrow has almost completely taken over that task.

7. The liver produces and excretes bile (a yellowish liquid) required for emulsifying fats.

8. Some of the bile drains directly into the duodenum, and some is stored in the gallbladder.

9. The liver also produces insulin-like growth factor 1 (IGF-1), a polypeptide protein hormone that plays an important role in childhood growth and continues to have anabolic effects in adults.

10. The liver is a major site of thrombopoietin production. Thrombopoietin is a glycoprotein hormone that regulates the production of platelets by the bone marrow.

11. The liver stores a multitude of substances, including glucose (in the form of glycogen), vitamin A (1–2 years' supply), vitamin D (1–4 months' supply), vitamin B₁₂ (1-3 years' supply), iron, and copper.

12. The liver is responsible for immunological effects- the reticulo-endothelial system of the liver contains many immunologically active cells, acting as a 'sieve' for antigens carried to it via the portal system.

13. The liver produces albumin, the major osmolar component of blood serum.

14. The liver synthesizes angiotensinogen, a hormone that is responsible for raising the blood pressure when activated by renin, an enzyme that is released when the kidney senses low blood pressure.

Breakdown of Chemical Constituents: ²¹

1. The liver helps in the breakdown of insulin and other hormones.

2. It breaks down hemoglobin, creating metabolites that are added to bile as pigment (bilirubin and biliverdin).

3. It modifies toxic substances (e.g., methylation) and most medicinal products in a process called drug metabolism. This sometimes results in toxicities, when the metabolite is more toxic than its precursor. Preferably, the toxins are conjugated to avail excretion in bile or urine.

4. The liver converts ammonia to urea.

List of Hepatotoxic Agents: ²¹

1. Various Cshemical agents those causes hepatotoxicity are shown in Table 1
2. TABLE 1: VARIOUS CHEMICAL AGENTS THOSE CAUSES HEPATOTOXICITY.

1. Various Medicinal agents those causes hepatotoxicity are shown in Table 2 below

TABLE 2: VARIOUS MEDICINAL AGENTS THOSE CAUSES HEPATOTOXICITY.

The Table 3 shows Various Medicinal/Herbal plants having Hepatoprotective Activity.

TABLE 3: VARIOUS MEDICINAL/HERBAL PLANTS HAVING HEPATOPROTECTIVE ACTIVITY ²⁵

The Table 4 shows Various Phytoconstituents showing Hepatoprotective Activity below.

TABLE 4: VARIOUS PHYTOCONSTITUENTS SHOWING HEPATOPROTECTIVE ACTIVITY¹¹²

The Table 5 shows Medicinal Plants in Ayurveda showing Hepatoprotective activity below.

TABLE 5: MEDICINAL PLANTS IN AYURVEDA SHOWING HEPATOPROTECTIVE ACTIVITY¹¹².

The Table 6 shows Database of retrospective studies on Medicinal herbs showing hepatoprotective activity below.

TABLE 6: DATABASE OF RETROSPECTIVE STUDIES ON MEDICINAL HERBS SHOWING HEPATOPROTECTIVE ACTIVITY.¹⁶⁷

Screening Models for Hepatotoxic Studies:

Various models needed for the screening of hepatoprotectives can be classified as follows:

1. In vivo models
2. In vitro studies

These are briefly described as:

1. In Vivo Models:
2. Carbon Tetrachloride (CCl₄) induced hepatotoxicity:

Liver injury due to carbontetrachloride in rats was first reported in 1936 and has been widely and successfully used by many investigators. Carbontetrachloride is metabolized by cytochrome P-450 in endoplasmic reticulum and mitochondria with the formation of CCl₃O^-, a reactive oxidative free radical, which initiate lipid peroxidation. Administration of a single dose of CCl₄ to a rat produces a centrilobular necrosis and fatty changes within 24 hrs. The poison reaches its maximum concentration in the liver within 3 hrs of administration. Thereafter, the level falls and by 24 hrs there is no CCl₄ left in the liver. The development of necrosis is associated with leakage of hepatic enzymes into serum.^249-254

1. Galactosamine induced hepatotoxicity:

D-Galactosamine induced liver damage has been extensively used as an experimental model. Galactosamine produces diffuse type of liver injury simulating viral hepatitis. It presumably disrupts the synthesis of essential uridylate nucleotides resulting in organelle injury and ultimately cell death. Depletion of those nucleotides would impede the normal synthesis of RNA and consequently would produce a decline in protein synthesis.

This mechanism of toxicity brings about an increase in cell membrane permeability leading to enzyme leakage and eventually cell death. The cholestasis caused by galactosamine may be from its damaging effects on bile ducts or ductules or canalicular membrane of hepatocytes. Galactosamine decreases the bile flow and it’s content i.e. bile salts, cholic acid and deoxycholic acid. Galactosamine reduces the number of viable hepatocytes as well as rate of oxygen consumption.²⁵⁵

1. Thioacetamide induced hepatotoxicity:

Thioacetamide interferes with the movement of RNA from the nucleus to cytoplasm which may cause membrane injury. A metabolite of thioacetamide is responsible for hepatic injury. Thioacetamide reduce the number of viable hepatocytes as well as rate of oxygen consumption. It also decreases the volume of bile and it’s content i.e. bile salts, cholic acid and deoxycholic acid.²⁵⁵

1. Alcohol induced hepatotoxicity:

Among the organs liver is most susceptible to the toxic effects of ethanol. Alcohol consumption is known to cause fatty infiltration, hepatitis and cirrhosis. Fat infiltration is a reversible phenomenon that occurs when alcohol replaces fatty acids in the mitochondria. Hepatitis and cirrhosis may occur because of enhanced lipid peroxidative reaction during the microsomal metabolism of ethanol. It is generally accepted that alcohol can induce in vivo changes in membrane lipid composition and fluidity, which may eventually affect cellular functions. Among the mechanisms responsible for effects of alcohol, an increase in hepatic lipid peroxidation leads to alteration in membrane phospholipid composition. The effects of ethanol have been suggested to be a result of the enhanced generation of oxyfree radicals during its oxidation in liver.

The peroxidation of membrane lipids results in loss of membrane structure and integrity. This result in elevated levels of ¡-glutamyl transpeptidase, a membrane bound enzyme in serum. Ethanol inhibits glutathione peroxidase, decrease the activity of catalase, superoxide dismutase, along with increase in levels of glutathione in liver. The decrease in activity of antioxidant enzymes superoxide dismutase, glutathione peroxidase are speculated to be due to the damaging effects of free radicals produced following ethanol exposure or alternatively could be due to a direct effect of acetaldehyde, formed by oxidation of ethanol.^256,257

1. Paracetamol induced hepatotoxicity:

Paracetamol, a widely used analgesic and antipyretic drug, produces acute liver damage in high doses. Paracetamol administration causes necrosis of the centrilobular hepatocytes characterized by nuclear pyknosis and eosinophilic cytoplasm followed by large excessive hepatic lesion. The covalent binding of N-acetyl- P-benzoquinoneimine, an oxidative product of paracetamol to sulphydryl groups of protein, result in lipid peroxidative degradation of glutathione level and thereby, produces cell necrosis in the liver.^{249, 257}

1. Nonsteroidal antiinflammatory drugs:

Although individual analgesics rarely induce liver damage due to their widespread use, NSAIDS have emerged as a major group of drugs exhibiting hepatotoxicity. Both dose dependent and idiosyncratic reactions have been documented. Aspirin and phenylbutazone are associated with intrinsic hepatotoxicity and idiosyncratic reaction has been associated with ibuprofen, sulindac, phenylbutazone, piroxicam, diclofenac and indomethacin.²⁵⁸

1. Glucocorticoids:

Glucocorticoids are so named due to their effect on carbohydrate mechanism. They promote glycogen storage in liver. Enlarged liver is a rare side effect of long term steroid use in childrens. The classical effect of prolonged use both in adult and paediatric population is steatosis.²⁵⁹

1. In Vitro Studies:²¹

Fresh hepatocyte preparations and primary cultured hepatocytes are used to study direct antihepatotoxic activity of drugs. Hepatocytes are treated with hepatotoxic and the effect of the plant drug on the same is evaluated. The activities of the transaminases released into the medium are determined. An increase in the activity in the medium indicates liver damage. Parameters such as hepatocyte multiplication, morphology, macromolecular synthesis and oxygen consumption are determined.

CONCLUSION: Popularity of herbal remedies is increasing globally and at least 25% of patients with liver diseases use ethnobotanicals. More efforts need to be directed towards methodological scientific evaluation for their safety and efficacy by subjecting to vigorous preclinical studies followed by clinical trials to unravel the mysteries hidden in the medicinal herbs and build scientific evidence in their favour. This approach will help exploring the real therapeutic value of these natural pharmaco-therapeutic agents and standardized the dosage regimen on evidence-based findings to become more than herbal folklore.

Liver diseases have become one of the major causes of mortality all over the world and viral hepatitis, alcohol, malnutrition, autoimmune and drug induced hepatotoxicity  appears to be the most common contributing factors. Total deaths worldwide from cirrhosis and liver cancer rose by 50 million per year over 2 decades, according to the first-ever World Health Organization (WHO) study of liver disease mortality; 1.25 to 1.75 million from 1990 to 2010 and an increasing proportion was due to liver cancer. In this review article, an attempt was made to compile the reported hepatoprotective plants from India and abroad that may be useful to the health professionals, scientists and scholars working the field of pharmacology, therapeutics, and pharmacognosy to develop evidence based alternative medicines to cure different kinds of liver diseases in man and animals.

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How to cite this article:

Qadrie ZL, Rajkapoor B and Kavimani S: Hepatoprotective Medicinal Herbs and Animal Models for Their Screening - A Review. Int J Pharm Sci Res 2015; 6(12): 5006-28.doi: 10.13040/IJPSR.0975-8232.6(12).5006-28.

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