|Year : 2017 | Volume
| Issue : 3 | Page : 87-94
Ursolic acid: A natural preventive aesculapian for environmental hepatic ailments
Gunja Srivastava1, Manjul Pratap Singh1, Anurag Mishra2
1 School of Pharmacy, Babu Banarasi Das University, Lucknow, Uttar Pradesh, India
2 Faculty of Pharmacy, Ashoka Institute of Technology and Management, Varanasi, Uttar Pradesh, India
|Date of Submission||04-Jul-2017|
|Date of Acceptance||18-Sep-2017|
|Date of Web Publication||11-Oct-2017|
Faculty of Pharmacy, Ashoka Institute of Technology and Management, Varanasi - 221 007, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
Hepatic diseases are a major problem of worldwide proportions, and liver damage is very common since the liver has to encounter several toxic substances during their metabolism. Pollution is also one of the major causes of hepatic dysfunctioning, high level of pollutant in blood enhances the risk for abnormal liver enzyme level. Increased industrialization has prone workers to confront the several harmful chemicals in their day-to-day life that affect liver adversely; several studies have been published in the evidence of this fact; people cannot avoid their exposure to such environmental conditions but can counter with its harmful effects. Thus, to overcome this loophole, there is a demand of such agents that has the capability to fight against such toxins and pollutants. Ursolic acid (UA), a natural pentacyclic triterpenoid carboxylic acid, has established its identity as a very potent hepatoprotective agent in recent years. It is one of the strongest natural healers that are present in several medicinal plants. Its antioxidant effect makes it a potent antihepatotoxic agent as it modulates mitogen-activated protein kinases and nuclear factor-kappa B signaling pathway. UA has anticholestatic property that enhances its effectiveness somewhere equal to or in some cases better than silymarin (a well-known potent hepatoprotective agent). In recent years, it has attracted considerable attention due to its double-edged sword effect on the liver, defined in terms of prevention and cures both.
Keywords: Antihepatotoxic, antioxidant, hepatoprotective, hepatotoxicity, high performance thin-layer chromatography, liver, triterpenoids, ursolic acid
|How to cite this article:|
Srivastava G, Singh MP, Mishra A. Ursolic acid: A natural preventive aesculapian for environmental hepatic ailments. Environ Dis 2017;2:87-94
| Introduction|| |
Herbal medicines are the amalgam of restorative experience of generations of practicing physicians of aboriginal system of medicine since 10 decades, and they are known to be oldest medical care products that have been used by human race all over the world in the form of ethnic therapy. The use of natural products and supplements has enhanced staggeringly over the past 30 years; 80% of people worldwide rely on them for one or other part of primary health care.
The Greek word for liver is hepar, and medicinal terms correlating with liver often start with hepato or hepatic. Liver has significant functions such as metabolism, secretion, storage, and often referred as the “great chemical factory” of the body as liver synchronizes, manufactures, stores, and secretes many important proteins, nutrients, chemicals, and detoxifies the body. The bile released by the liver plays an important role in digestion. The exposure of environment to the toxins, pesticides, and frequently used chemotherapeutics has recently increased the risk of the liver intoxication. The liver is a key organ and survival without it is impossible, being a silent organ it damages without sending any signals or symptoms at initial stage due to which several people survive with liver disease for a long time without ever knowing it. Liver disease affects individuals of all age groups including neonates and children, people of all ethnicities, and socioeconomic backgrounds. Liver diseases such as hepatitis C, nonalcoholic fatty liver disease, and liver cancer are on the rise. Many of the chronic liver diseases even in advanced stages may cause no prominent clinical signs and symptoms. They either go undiagnosed or are found incidentally during general checkups, investigation for other diseases, or surgery. Regular intake of alcohol between 40–80 g increases the liver weight and frequency of fatty change in the liver. A clinical study (2011) conducted on 108 subjects suffering from liver disease, statistical result revealed that out of 108 cases 75.9% were male and 24.07 % were female.
| Hepatotoxicity|| |
Toxic liver injury induced by drugs and chemicals can cause any kind of naturally existing liver ailment. In fact, any patient suffering with hepatic ailment or unexplained jaundice is asked about the history of medication or persisting hepatotoxicity due to subjection of chemicals and drugs, which is the very common form of iatrogenic disease.
Mechanism of hepatotoxicity
There are several conditions which are responsible for liver toxicity; that may be psychological distress, environmental exposure to hepatotoxins (organic solvents used in different industrial processes may be associated with hepatotoxicity), genetic factors, interaction with medication, alcohol abuse, nutritional conditions, age etc. all these conditions directly or indirectly damages the hepatocytes.
The very first step of this damaging process includes opening of mitochondrial permeability transitional pore (MPTP), MPTP openings lower the structural and functional integrity of mitochondrial membrane of hepatocytes due to which ATP (adenosine triphosphate) synthesis get impaired. Such impairment increases the intercellular calcium level via activation of plasma membrane calcium ATPase. Enhanced calcium level causes release of preapoptotic proteins such as caspases, cytochrome C, and apoptosis-inducing factors;, these proteins have the ability to bind with apoptotic protease-activating factor, after binding with Apaf caspase-9 and caspase-3 get activated and initiate apoptosis pathway., It can be said that MPTP opening serves as one of the major causes of liver impairments, and some hepatotoxic agents that induce MPTP opening are xenobiotic, or some endogenous byproducts like calcium, fatty acid of bile salt.
There is another possible mechanism of hepatotoxicity that is generation of “reactive oxygen species” (ROS) through activity of mitochondrial respiratory chain. Normally, ROS can be detoxified through glutathione peroxidase using glutathione as cofactor. Glutathione depletion causes H2O2 accumulation, and this entire process results in the upshot of the MPTP opening, c-Jun N-terminal kinase activation, and arousal of p38 hP22 apoptotic pathway., This enhanced level of ROS can also destruct oxidative phosphorylation protein, cardiolipin, and mitochondrial DNA which leads to cytosolic hepatitis., Glutathione depletion is associated with drugs, exogenous compounds, ethanol consumption, fasting, and various viral diseases. Some drugs as well as ethanol toxicity can also limit mitochondrial beta-oxidation that can result in microvesicular steatosis that is accumulation of triglycerides in hepatocytes., There are several hepatic disorders that affect the millions of people; a summarized data of such liver disorders are given in [Table 1].
| Natural Liver Protective Agents|| |
Plants are known to be good sources of antihepatotoxic drugs; nearly 160 constituents from 101 plants are having hepatoprotective activity. India reports to have more than 87 plants which are active parts of 33 patented and proprietary polyherbal formulations. In spite of the colossal advances, very less antihepatotoxic agents are available in modern era of therapeutics. Thus, much importance has been given globally to elaborate plant-origin hepatoprotective drugs effectual against assortment of liver disorders. Herbal drugs have broad historical framework in curing several hepatic ailments; systems of traditional medicines such as Ayurveda, system of traditional Chinese medicine, European system of medicine, and other systems have strong ethnical evidence to justify their vast hepatoprotective potentials. The 21st century has been the era that demands the researcher to pharmacologically and therapeutically evaluate the herbals for their antihepatotoxic potential, by carefully applying the concept of synergism so as to enhance the strengths of the traditional medicine along with the modern concept of evidence-based medicinal evaluation or the reverse pharmacological approach. Standardization is the basic need for the herbals, and randomized placebo-controlled clinical trials are done to support clinical efficacy of such herbal products.
The Indian traditional medicinal systems such as Ayurveda, Siddha, and Unani are based on the use of plant materials. Natural products have gained importance and popularity in recent years because of their safe, efficacious, and cost-effective values.
Classification of liver protective agents
Such agents are classified into three categories without any strict delineation among them.
- Antihepatotoxic agents: Such compounds generally antagonize the toxic effect of any hepatotoxin that causes hepatitis or any other liver diseases
- Hepatotropic agents: Such agents generally support or promote the healing process of the liver. Practically, it is difficult to distinguish between these two activities
- Hepatoprotective agents: Such agents prevent different types of liver diseases prophylactically. In general, any hepatoprotective agent can act as an antihepatotoxic or hepatotropic agent, but the vice versa is always not true.
Thus, generation of hepatoprotective agents can be better tool for treatment of the liver as they can antagonize the toxicity as well as synergies, the healing process.
| Ursolic Acid: A natural Hepatic Aesculapian|| |
Triterpenoids are ubiquitous throughout the plant kingdom as free acids or aglycones of saponins and possess various biological activities. More than 80 triterpenoids have been isolated from plants, and the number of researches describing their bioactive effects has enhanced sharply during the last decade.
UA (3-beta-hydroxy-urs-12-en-28-oic acid) is a natural pentacyclic triterpenoid carboxylic acid [Figure 1] which possesses several biological activities. Chemically, UA is known as merotaine, urson, prunol, micromerol, and malol, which has white, light green, yellow, and sometimes creamy yellow depending on the source from which it is obtained. UA is a main phytoconstituent of some traditional medicinal herbs, foods, and other plants that have significant biological activities. UA being a triterpenoid is well known for its hepatoprotective effect. It is effective against thioacetamide-, galactosamine-, and carbon tetrachloride-induced hepatotoxicity. Seeing to its wide range of effect on liver several data from organized literature reveals that pretreatment of the liver with UA increases the viability of hepatocytes. In large doses, it significantly produces choleretic effect and has hepatoprotective activity comparable to silymarin. Bile salts have a pivotal role in hepatobiliary and intestinal homeostasis and digestion, primary bile salts (cholic acid and chenodeoxycholic acid) are formed by the liver from cholesterol (CHL) and may be modified by intestinal flora to form secondary and tertiary bile salts. Under physiological conditions, the bile salt pool is tightly regulated, but adaptive capacity may fall shorter under cholestatic conditions. Hepatobiliary disease with cholestasis is allied with elevated level of serum bile acid. Raised serum and tissue levels of potentially toxic hydrophobic bile salts during cholestasis may cause mitochondrial damage, apoptosis, or necrosis in vulnerable cell type. UA pretreatment normalizes the bile flow and its contents in a dose-dependent manner. UA has anticholestatic property as it increases the bile flow, bile salts, and bile acids, which possibly may be due to induction of bile salt-dependent fraction or repair of bile duct. UA pretreatment provides a significant protection of the altered biochemical parameters that signifies the liver damage and brings them back toward the normal limit along with increase in the percentage of viable hepatocytes. It has antagonistic effect against toxic behavior of several chemicals such as galactosamine, thioacetamide, and carbon tetrachloride which indicates that UA might protect the liver by increasing protein synthesis, stabilizing the cell membrane, and inhibiting the toxin including free radical generation.
|Figure 1: Different positions in ursolic acid responsible for cytotoxic activity|
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Role of ursolic acid as a hepatocytotoxic moiety
Structural activity relationship
UA is one of the potent natural compounds that have apoptotic effects on human cancerous hepatocytes. Not only several attempts have been made to synthesize UA in laboratories, but also its various derivatives are also generated, such attempts resulted in the development of such UA derivatives that inhibit interferon-induced nitric oxide production capacity; also, these activities would be significantly increased by inducing methoxycarbonyl, carbonyl, or cyano-functional groups.,, Literature says that esterification at C-3 is essential for the pharmacological activities of pentacyclic triterpenes, and incorporation of a hydrogen donor group at either C-3 position and/or C-28 position of UA is essential for its cytotoxic activity; cytotoxic activities of UA derivative have been evaluated in vitro against liver cancer cell line (HeLa). The results showed that acetylation of the alcohol at C-3 along with coupling of a substituted amino group at C-28 results in derivatives possesses much stronger cell growth inhibitory effect than UA. Furthermore, introducing carbonyl group on C-11 of UA can significantly inhibit tumor cell growth. These structural modifications are represented in [Figure 1].
Mode of action of ursolic acid in liver cytotoxicity
UA antioxidant activity and its ability to modulate the mitogen-activated protein kinases (MAPK) and nuclear factor-kappa B (NF-κB) signaling pathway provide it outstanding hepatoprotective activity. It significantly decreases the activation of MAPK, which, in turn, inactivates the immunoregulatory transcription factor NF-κB, that is responsible for regulating gene expression that encodes the products involved in tissue damage and inflammation; this protects the liver against CCl4-induced oxidative stress and inflammation by the MAPK/NF-κB pathway.
Antihepatotoxic effects of ursolic acid
- Liver damage is common under antitubercular (anti-TB) drug regimen. UA and oleanolic acid (tri-terpenic acids) were investigated against anti-TB drugs induced hepatotoxicity in mice Abti-TB drugs like rifampicin, isoniazid, and were given to mice to induce liver toxicity. Mixture of UA and oleanolic acid were given to mice under test, both of these acids significantly decreased the level of aspartate transaminase (AST) and alanine transaminase (ALT) enzymes in mice blood which were elevated due to anti-TB drugs administration. These triterpenic acids also prevented liver steatosis that occurred in mice liver due to anti-TB drugs 
- Cynomorium songaricum and its major ingredient UA protect the liver against CCl4-induced liver damage. UA significantly inhibited the plasma aspartate aminotransferase and alanine aminotransferase activities against carbon tetrachloride (CCl4)-induced hepatotoxicity, both the active fraction of plant C. songaricum as well as UA protect liver by mitochondrial pathway 
- UA isolated from methanolic extract of Barleria montana (aerial parts) has hepatoprotective activity against CCl4. The assay of the marker enzymes such as serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), alkaline phosphatase (ALKP), total bilirubin (TBL), CHL, total protein (TPTN), and albumin (ALB) was done. Methanolic extracts of B. montana (rich in UA) showed a significant decrease in all the elevated SGOT, SGPT, ALKP, TBL, and CHL and significant increase in TPTN and ALB levels when given to rats 
- Not only UA but also its derivatives show significant antihepatotoxic activity. It is new isolated derivative of Ursolic acid, an isolated active phytoconstituent from the plant Irvingia gabonensis, was screened for its hepatoprotective potential by in vitro method against CCl4-induced damage in rat hepatoma cells. It showed a significant hepatoprotective activity as this constituent has ability to prevent liver cell death and lactate dehydrogenase leakage; during CCl4 intoxication, the possible action may be due to its significant antioxidant activity as it scavenges free radical and inhibit microsomal lipid peroxidation 
- Eucalyptus tereticornis leaves possess a significant amount of UA due to which it has remarkable hepatoprotective activity (21%–l00%). Thioacetamide, galactosamine, and carbon tetrachloride was given to induce hepatotoxicity. These hepatotoxins decreased the viability of liver cells that was detected by trypan blue exclusion assay, rate of oxygen uptake test, and decrease in bile volume and bile contents. Pretreatment with UA increased the viability of rat hepatocytes significantly; also, potent dose-dependent anticholestatic activity was observed in conscious rat which was signified by increase in bile flow rate and an increase in bile content 
- Stress is one of the major causes for consumption of alcohol. High alcohol consumption causes increase in oxidative stress and decrease in antioxidant defense mechanism and liver injury that causes altered serum aminotransferase activities (aspartate aminotransferase and alanine aminotransferase) and total bilirubin levels. Effect of UA was tested on rat against ethanol-induced hepatotoxicity; when UA given to rat in dose-dependent manner, it was found to improve the antioxidant status of alcoholic rats, which was confirmed by decreased levels of lipid peroxidation markers in plasma that were thiobarbituric acid-reactive substances and lipid hydroperoxides and increased levels of circulatory antioxidants such as reduced glutathione, ascorbic acid, and alpha-tocopherol. The antihepatotoxic activity of UA was comparatively better than silymarin in certain parameters; these effects were due to the antioxidant potential of UA 
- UA acid has anticholestatic activity as well as antioxidant activity. When UA was given to rats against paracetamol-induced hepatotoxicity, it showed a dose-dependent (5–20 mg/kg) choleretic effect and significant anticholestatic activity (27.9%–100%) against cholestasis induced by paracetamol. UA also showed hepatoprotection against galactosamine-induced hepatotoxicity by reversing the altered values of viable isolated hepatocytes and the altered biochemical liver and serum parameters. Hepatoprotective effect of UA was tested for its ability to modulate activity of CYP450 enzymes in human liver microsomes; UA completely inhibited CYP2C19-catalyzed 5-mephenytoin 4'hydroxylation due to its antioxidant effect and showed the IC50 value of 119.7 (80.3) μM 
- Terminalia catappa and its chief constituent UA was tested for its possible mechanism of action on mitochondria and free radicals against hepatotoxicity; primary cultured hepatocytes were induced elevation in ALT and AST levels (19- and 21-fold) by D-GalN; this effect was blocked with whole extract of T. catappa; it showed inhibition of Ca + 2-induced mitochondrial swelling when given in dose-dependent manner (50–500 μM) at the same concentration of T. catappa, also there was superoxide anion and hydroxyl radical scavenging activity 
- UA has protective effects against three hepatotoxicants, CCl4, acetaminophen, and cadmium chloride. Hepatotoxicity was assessed by serum activities of ALT and sorbitol dehydrogenase. UA remarkably decreased the toxicity produced by all three hepatotoxicants mentioned above along with this UA also increased liver metallothionein level by 10-fold which was determined by the Cd/hemoglobin assay 
- Ethanolic extract of Hedyotis corymbosa, a traditional medicine in Bangladesh for the treatment of jaundice and other liver disorders, has a strong antihepatotoxic activity due to UA. Isolated UA from H. corymbosa was evaluated to investigate hepatoprotection against paracetamol-induced hepatotoxicity. Both UA and ethanolic extract of plant showed significant hepatoprotection which was signified by decreased level of serum enzymes such as SGPT: Serum Glutamic Pyruvic Transaminase SGOT: Serum Glutamic Oxaloacetic Transaminase SAKP: Serum Alakaline Phosphatase SBIL: Serum Bilirubin; histological parameters of the liver treated with UA and extract were normal when compared to the paracetamol-treated liver.
Partial survey on some other antihepatotoxic plant is given in [Table 2]. High performance thin-layer chromatography (HPTLC), which is a quick analytical tool for qualitative as well as quantitative analysis of herbals, gives accurate results in terms of quantification since UA being a potent hepatoprotective agent is present in plant and responsible for antihepatotoxic effect of such plants; therefore, HPTLC can be an authentic measure for the identification and quantification of UA in hepatoprotective plants. [Table 3] defines the complete HPTLC fingerprint profile of plants containing UA.
|Table 3: High performance thin-layer chromatography fingerprint profile of hepatoprotective plants containing ursolic acid|
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| Discussion|| |
UA being ubiquitous throughout the plant kingdom makes it accessible to be explored in various disease conditions such as inflammation and hepatic disorders. UA is regarded as one such compound that possesses the ability to induce apoptosis that makes it an important phytochemical that exhibits cytotoxic activity. It has gain much importance in recent days due its wide horizon of pharmacological activities combined with relatively less toxicity. On the basis of data available on its hepatoprotective action, it can be said that it is a very important antihepatotoxic agent and has much more scope to be explored in the field of hepatology. This review article is also an effort to explore the hepatoprotective profile of UA and the plants that contain it; the HPTLC profile of such hepatoprotective plants confirms the presence of UA as one of the main phytoconstituents that list these plants in the dictionary of hepatoprotection. Still, the mode of action of UA in relation to its hepatoprotective activity has a question mark to some extent while few evidences say that it has the ability to modulate the MAPK and NF-κB signaling pathway and exert hepatoprotection by its antioxidant effects. Nothing in nature is perfect so with UA in spite of having several positive effects on entire body, UA is associated with some adverse effect too. A systemic application of UA in the treatment of heart diseases seems to be unfavorable as it possesses the DNA damaging activity; UA has ability to induce cell death in endothelial cells when the concentration exceeded 12.5 μM. Thus, consideration must be taken while deciding the dose of UA. Despite having certain negative aspects which are dose dependent, still, UA can be anticipated to be used as a potent agent to generate a comprehensive component strategy to cure as well as prevent several health disorders. This review gives a scope for the development of hepatoprotective formulations that contain UA as an active pharmaceutical ingredient.
| Conclusion|| |
In this review, article exhaustive literature survey revealed the substantiality of UA as a potent antihepatotoxic agent, its antioxidant potential, and anti-inflammatory property act as sword to cut and deplete all the toxicity and dysfunctioning caused by free radicals generated in the liver due to altered and adverse liver physiology. Since UA is ubiquitous through the plant kingdom, thus it opens the channels for several plants which are rich in UA to be explored in hepatology and join the mainstream of hepatoprotective agents and can reduce the risk of liver impairments. It gives protection to the liver in dose-dependent manner by increasing the viable count of healthy hepatocytes and restricts the liver enzymes to normal level. This review is a confined summary of UA and its protective effect on the liver.
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Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3]
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