A REVIEW ON MECHANISTIC ASSESSMENT OF HEPATOTOXICITY AND MEDICINAL PLANTS WITH HEPATOPROTECTIVE POTENTIAL

A REVIEW ON MECHANISTIC ASSESSMENT OF HEPATOTOXICITY AND MEDICINAL PLANTS WITH HEPATOPROTECTIVE POTENTIAL

Krishn Kumar Agrawal ^{1, 2} and Yogesh Murti ^{* 1}

Institute of Pharmaceutical Research ¹, GLA University, Mathura – 281406, Uttar Pradesh, India.

Faculty of Pharmacy ², R.B.S. Engineering Technical Campus Bichpuri Agra – 283105, Uttar Pradesh, India.

ABSTRACT: The liver is the most important organ in the body that plays a central role in the detoxification and excretion of many exogenous and endogenous compounds. Due to these functions, hepatic diseases continue to be among the main threats to public health, and that challenges health care professionals. Many liver diseases are chronic, meaning they last for years and may never go away. But even chronic liver diseases can usually be managed. The drugs that work on the liver are generally classified into two categories, one is antihepatotoxic agents, which generally antagonize the effects of any hepatotoxins causing any liver disease and another is hepatoprotective agents which prevent various types of liver infections prophylactically. Plants are the paramount source of herbal medicines. A plethora of data from the medicinal plants is available in literature. The present review is aimed at compiling data on promising herbs in concise manner, which are experimentally proved by the scientists as hepatoprotective.

Keywords:  Liver disease, medicinal plants, hepatotoxicity, hepatoprotective activity

INTRODUCTION: The liver is a large glandular organ that plays an important role in maintaining vital functions such as maintenance, performance, and regulating the homeostasis of the body. The human liver comprising two main lobes; the right lobe is larger than the left. The liver involved in almost all biochemical pathways like carbohydrate, fat, protein, hormone and drug metabolism, production of bile and bile acid, synthesis of clotting factors and plasma protein, storage of minerals, vitamins and glycogen Fig. 1 ¹.

A liver normal function may alter by the number of factors such as viruses, alcohol, toxins and drug that can ultimately lead to hepatitis and cirrhosis ². Herbal drugs are still the mainstay of health care in several developing countries. The widely used herbal remedies and health care preparations as described in ancient texts such as the Vedas and the Bible are obtained from commonly used traditional herbs and medicinal plants.

The medicinal properties of these botanicals are being better understood and are attributable to the phytochemicals that specific plants contain. The efficacy and safety of herbal products, therefore, rely on the quality and proper identification of the raw material or the original plant source. According to Gurib-Fakim there are four basic ways in which plants that are used by tribal peoples are valuable for modern medicine:

Plants used as sources of direct therapeutic agents. Plants are also used as sources of starting points for the elaboration of semi-synthetic compounds. Plants can serve as sources of substances that can be used as models for new synthetic compounds. Plants can also be used as taxonomic markers for the discovery of new compounds ³.

FIG. 1: DIFFERENT FUNCTIONS OF LIVER

METHODS: There is a plethora of medicinal plant data available that shows hepatoprotective activity. In the present article, we have searched and reviewed relevant studies on liver disease and hepatoprotective plants along with few isolated compounds through electronic searches of Pub med, Science Direct, Wiley, Scopus, Google Scholar, and EMBASE between the year 1992 and 2020. Based on this literature survey, the mechanism of liver diseases and medicinal plants with hepatoprotective potential are discussed in this review.

Diseases Associated with Liver Dysfunction: Liver disease is a general term that refers to any condition affecting your liver. These conditions may develop for different reasons, but they can all damage your liver and impact its function.

Liver dysfunction is broadly divided into two i.e., hepatitis and cirrhosis ¹. Hepatitis can be caused by viruses, alcohol, toxins, and drugs that basically mean inflammation in a liver cell or hepatocytes. Viral hepatitis is an infection that occurs by different viruses, known as hepatitis A, B, C, D, and E. The characteristics features of viral hepatitis are shown in Table 1. Liver cell dysfunction leads to progressive cell death that initiates immunological reaction which is characterized by the release of signals.

The stimulation of the immune system activates the Kupffer cells and natural killer cells. These cells are responsible for the release of inflammatory mediators like cytokines, tumor necrosis factor (TNF-α), interferon-γ, and interleukin-1β that causes liver injury ⁴.

TABLE 1: CHARACTERISTICS FEATURES OF VIRAL HEPATITIS ¹

Overconsumption of alcohol leads to alcohol hepatitis that is the second most common cause of total human death every year. It consists of fatty liver, steatosis, alcoholic hepatitis, steatohepatitis, chronic hepatitis, liver fibrosis, and hepatocellular carcinoma. Ethanol is metabolized by enzymes catalyzed oxidative process. Alcohol dehydro-genase converts the alcohol into acetaldehyde after the chronic consumption of alcohol. The acetaldehyde is further metabolized to acetic acid by the enzyme acetaldehyde dehydrogenase, which is then converted to carbon-di-oxide and water molecules via a citric acid pathway. NADH is generated during the citric acid pathway triggers oxidative stress, which leads to the generation of reactive oxygen species (ROS), causing peroxidation of lipid and decreasing the endogenous antioxidant. The active acetaldehyde induces fatty acid synthesis via an increase in NADH/NAD⁺ ratio. This converts the glycerol to triglycerides and accumulates in the hepatocytes. This leads to disruption of the integrity of the cell. Other mechanisms of liver necrosis by ethanol chronic consumption include ATP depletion and intracellular Ca⁺² accumulations ⁵. The mechanism involved in alcohol-induced hepatitis includes shown in Fig. 2.

FIG. 2: MECHANISM OF ALCOHOL-INDUCED HEPATITIS

Drug-induced hepatitis is the major concern of acute liver failure and a major reason for liver transplantation. There are various pharmacological classes of drugs that cause liver injuries like anticancer, NSAIDs, anti-tuberculer, antiviral drugs and antibiotics. The liver metabolized the drug into inactive compounds via phase-II metabolism. The cytochrome P450 is the main enzyme system in the liver for the metabolism of drug metabolites. These metabolite bind ith the protein of cellular membrane to form an adduct. This adduct causes oxidative hepatocyte damage via a different mechanism like mitochondrial damage, ER stress, DNA damage, and bile acid accumulation. The injured hepatocyte release DAMPs molecules that stimulate the immune response. Activated immune systems release pro-inflammatory cells and sensitize T-lymphocytes, causing hepatocyte necrosis ². The mechanism or pathogenesis involved in drug-induced liver disease ⁶ is shown in Fig. 3.

FIG. 3: PATHOGENESIS OF DRUG-INDUCED LIVER DISEASE

Cirrhosis is a formation of regenerative nodules in liver parenchymal cells by fibrous septa due to chronic liver injury. The mechanism behind liver cirrhosis includes the overproduction of insoluble collagen in the formation of connective tissues that reduces the hepatic blood flow and impairs the liver's metabolic function, and increased portal vein pressure ^{7, 8}. Cirrhosis is caused by a number of factors shown in Fig. 4.

FIG. 4: CAUSES OF DIFFERENT TYPE OF CIRRHOSIS

Medicinal Plants with Hepatoprotective Activity: Liver failure due to inappropriate use of drugs such as paracetamol (PCM) and excessive alcohol consumption depends on age, gender, lifestyle, and nutritional deficiency. In addition, hepatotoxicity can also be caused by toxic substances such as thioacetamide (TAA), chemo-therapeutic agents such as carbon tetrachloride (CC1₄), some organic and inorganic compounds, aflatoxin, microbes, and viral infections. Several reports have shown that oxidative stress triggered by free radicals is the main causative agent of liver damage. Various mechanisms are involved in the toxicity of liver like generation of reactive oxygen species (ROS), increased lipid peroxidation and biochemical parameters, depletion of glutathione (GSH), and leads to alteration of membrane fluidity and permeability ⁹. Folkloric plants play an indispensable role in improving the quality of life of rural dwellers, especially in developing countries where contemporary health facilities are not available to all. The plants are always being the starting material for the synthetic as well as for the semi-synthetic molecule. They are the rich source of bio active phyto-chemicals like alkaloids, glycosides, tannins, protein, carbohydrates, mucilage, flavonoids and phenolic compounds.  The evaluation of efficacy and safety of medicinal plants as hepatoprotective are depended on the phytochemicals present in the extract. There is a need to prepare appropriate formulations of extracts and bioactive molecules to facilitate their physiological target and pharmacological activity. With increasing interest in traditional herbal medicines, the researchers are trying to explore the potential of herbal molecules as hepato-protective ¹⁰. There is an abundance of research had been conducted on the plants and their isolated molecules to evaluate their hepatoprotective potential. Details of the most promising herbs having hepatoprotective potential in their different parts are discussed here. The results of the investigations of hepatoprotective activity conducted on many other plants are also summarized in Table 2.

TABLE 2: MEDICINAL PLANTS HAVING HEPATOPROTECTIVE ACTIVITY

Acacia Catechu Family Leguminoseae: The ethanolic extract (250 mg/kg) of Acacia catechu bark was evaluated by Sheshidhar G Bannale et al. (2013) for hepatoprotective activity against paracetamol (250 mg/kg, p.o.) induced liver injury in albino wistar rat. Silymarin was taken as positive control for the study. The hepatoprotection was assessed by biochemical (SGOT, SGPT, ALP) and histological parameters. The result of the study revealed that ethanolic extract of Acacia catechu significantly reduced the elevated level of SGOT, SGPT and ALP. The histopathology showed central vein with normal hepatocyte and portal tract with mild congestion ¹¹. Further, the aqueous slurry of powder Acacia catechu (400 mg/kg) was analysed for the hepatoprotective activity against carbon tetra chloride (0.7 cc/kg, oral) induced hepatic injury in Wistar albino rat. Decreased level of biochemical parameters (SGPT, SGOT, TB, GGT, ALP) and histological results supported its hepatoprotective potential ¹². Jayashekhar et al. (1997) used ethyl acetate extract of Acacia catechu (250 mg/kg) and investigated hepatoprotective activity against CCl₄ induced toxicity (4 mL/kg, s.c. in olive oil) in albino rat. The result revealed that ethyl acetate extract significantly decrease the SGOT, SGPT, ALP and TB level. The histopathology showed slightly improvement in hepatocytes architecture ¹³.

Adhatoda vasica Family Acanthaceae: The hepatoprotective activity of aqueous extract of Adhatoda vasica leaves was evaluated against CCl₄ (0.1 mL/kg, i.p.) induced hepatotoxicity in albino rats. Kumar et al. (2015) reported that aqueous extract at doses of 250 and 500 mg/kg showed significant decrease in serum biochemical parameters and total protein level was increased ¹⁴. The ethanolic extract of Adhatoda vasica leaves was investigated by Chauhan et. al. (2008) for hepatoprotective activity. The extract was mixed with 1% gum tragacanth for oral administration in CCl₄ (0.1 mL/kg) induced liver injury in Wistar albino rat. The result revealed that plant extract significantly decreased the AST, ALT, ALP and TB level ¹⁵.

Allium sativum Family Amaryllidaceae: The ethanolic extract of Allium sativum raw bulblets was evaluated for the hepato-protection against thioacetamide (50 mg/kg, s.c.) induced hepato-toxicity in Wistar albino rat. The study was conducted by Chinnala et al. (2018) at the dose of 200 and 400 mg/kg/p.o. A significant (p<0.001) reduction in elevated biochemical parameters like AST, ALP, ALT and TB confirmed the hepato-protective activity ¹⁶. Tsai et al. (2019) evaluated the hepatoprotective activity of n-butanol and water fermented Allium sativum (200 & 500 mg/kg), against the CCl₄ (10 mL/kg, p.o.) induced liver toxicity. The results revealed that n-butanol and water extracts significantly reduced the serum AST, ALP and ALT level.  The antioxidant parameters like hepatic MDA, GSH-Px and GSH-Rd level were increased and the reduced level of TNF-α and IL-1β showed the improvement in the histopathology ¹⁷.

Azima tetracantha Lam Family Salvadoraceae L The anti-hepatotoxic effect of hydroalcoholic extract of Azima tetracantha leaves were evaluated against the ferrous sulphate (100 mg/kg, p.o.) induced liver toxicity in albino rat by Manikandaselvi et al. (2013). Various biochemical parameters like globulin, albumin, HDL, vitamin E, superoxide dismutase, LDL, VLDL, bilirubin, cholesterol, triglycerides, ALP, and TBARS were determined. The result of the study showed significant hepatoprotective activity ¹⁸. Prakash et al. (2015) compared the hepatoprotective activity of Azima tetracantha leaf aqueous extract with silver nanoparticles (100, 200 & 300 µg/mL) through CCl₄ (1 % v/v, p.o.) induced liver toxicity. Biochemical variables such as protein, ALP, SGOT and SGPT were evaluated and results showed that extract with silver nanoparticles treated animals reversed the variables near to normal compared with Azima tetracantha leaf extract ¹⁹.

Curcuma longa Family Zingiberaecae: Hepato-protective activity of ethanolic extract (250 & 500 mg/kg) of Curcuma longa rhizome was evaluated against the thioacetamide (200 mg/kg, i.p.) induced liver cirrhosis in Sprague-dawley rats. Salama et al. (2013) designed the study for 8 weeks. The hepatoprotective activity was evaluated by hepatic cytochrome P450 2E1, serum TGF-β1, and TNF-α. The result of the study revealed that the extract treated group improved the to pathological result, immune his to chemistry and liver biochemistry parameters compared to control group ²⁰. The ethanolic extract (0.187 mg/kg/day) of Curcuma longa rhizome was evaluated against the bleomycin (0.069 U/mL; 0.29 U/kg) induced chronic liver damage in males IRC mice. Bleomycin was injected intraperitoneally for a period of 4 weeks. Karamalakova et al. (2019) reported that crude drug extract significantly reduced the plasma bilirubin, gamma glutamyltranspeptidase (GGT) and lipid peroxidation level ²¹.

Ficus religiosa L Family Moraceae: The aqueous and methanolic extract of Ficus religiosa at a dose of 200 mg/kg leaves were evaluated for the hepatoprotective activity on paracetamol (500 mg/kg, i.v.) and CCl₄ (1.5 mg/kg, oral) induced liver injury in Wistar rat. Selvan et al. (2017) reported that ALT and AST level was significantly decreased at the same dose ²². The petroleum ether, ethyl acetate, methanolic and aqueous extract of stem bark of Ficus religiosa at a dose of 200 mg/kg was evaluated for the hepatoprotective activity against the paracetamol (2 g/kg, oral) induced liver toxicity in male Wistar albino rat. The hepatoprotective effect as assessed by Suryawanshi et al. (2011) revealed that biochemical variables like SGOT, SGPT, ALP, total bilirubin, and histological results improved by methanolic extract, significantly ²³.

Foeniculum vulgare Mill Family Umbelliferae: The hepatoprotective activity of hydroalcoholic extracts (80%) (250 & 500 mg/kg) of Foeniculum vulgar seeds was evaluated against the paracetamol (2 g/kg, p.o.) induced toxicity in a rabbit model.  Nazir et al. (2020) reported that hydroalcoholic extract significantly decreased the biochemical variables like AST, ALT, and ALP level, and the histopathology showed no evidence of fibrosis and steatosis ²⁴. Agrawal et al. (2018) used hexane and methanolic extract of Foeniculum vulgare seeds to evaluate hepatoprotective activity against CCl₄ (1 mL/kg, s.c.) induced liver injury in Wistar albino rat. Silymarin (100 mg/kg) was used as a standard drug. The hexane seed extract at dose of 400 mg/kg significantly reduced the biochemical variables like ALT, AST, ALP, and total & direct bilirubin ²⁵.

Glycyrrhiza glabra Family Papilionaceae Fabaceae: The hydro-methanolic (50%) root extract of Glycyrrhiza glabra was evaluated for the hepatoprotective potential against CCl₄ induced oxidative stress mediated hepatotoxicity in albino mice. CCl₄ (1.5 mL/kg) was injected i.p. for 7 days by Sharma et al. (2014). The result revealed that crude extract at doses of 300 and 600 mg/kg significantly decreased the LPO level and increased the GSH and CAT level ²⁶. The histopathology showed reduction in necrosis patterns. Huo et al. (2011), studied the hepatoprotective activity of aqueous extract (100, 150 & 300 mg/kg) of Glycyrrhiza glabra root against CCl₄ (2 mL/kg in 1:1 with groundnut oil, oral) induced liver injury in Wistar rat. After the treatment with the Glycyrrhiza glabra aqueous extract, the elevated level of serum biochemical parameters (AST, ALT and ALP) becomes inhibited. The result also showed that hydroxyproline and TNF-α increased levels also reversed ²⁷. The aqueous and ethanolic extract Glycyrrhiza glabra root was evaluated against CCl₄ (1 mL/kg, i.p. in olive oil) induced hepatopathy in male Wistar albino rat. The treatment dose was selected by Laylani et al. (2016) for both extracts (250 and 500 mg/kg). The result showed a significant reduction in AST, ALT, and improvement in SOD level ²⁸.

Melia azedarach L Family Meliaceae: The hepatoprotective activity of ethanolic extract of Melia azedarachleaves at the dose of 300 & 500 mg/kg was evaluated for the simvastatin (20 mg/kg, p.o.) induced liver injury in Wistar albino rat. Rao et al. (2012) reported a significant reduction in the serum SGPT, SGOT, ALP and TB level ²⁹. Ahmed et al. (2012) evaluated the hepatoprotective activity of Melia azadarach leaves ethanolic extract at the dose of 500mg/kg against the CCl₄ (1 mL/kg, p.o.) induced liver damage in Wistar albino rat. The study was designed for four days. The result of the study revealed that extract significantly decreased the level of SGOT, SGPT, and ALP level ³⁰.

Punica granatum Family Punicaceae: The study was planned by Khan et al. (2015), to investigate the hepatoprotective activity of ethanolic extract of Punica granatum peel at the dose of 200 & 400 mg/kg against the CCl₄ (1 mL/kg, i.p.) induced liver injury in Wistar albino rat. The results of biochemical analysis showed the decreased AST, ALT, ALP and TB level ³¹. The histopathology showed a decrease in the extent of centrilobular necrosis. The further in-vitro study was also conducted on the hydroalcoholic, ethyl acetate and n-hexane (1-10000 µg/mL) extracts of Punica granatum seeds against CC_l4 (100 mM) induced HepG2 cell line damage. Jamshidzadeh et al. (2012) reported that the percentage cell viability of HepG2 cells was increased by hydroalcoholic extract ³². Khalil et al. (2004) was evaluated the aqueous extract (0.43 g/kg) of the rind of Punica granatum for hepato-protective activity against acetaminophen (0.5 g/kg, i.p.) induced liver damage in the male albino rat. The result showed decreased AST, ALT, and LDH levels. The histopathology showed a reduction in fatty droplets, vacuolization, and necrotic area after the treatment with extract ³³.

CONCLUSION: Despite advances in pharmacology, the demerits associated with synthetic drugs have outshone the merits. The benefits of herbal treatments in human health is still a productive area of research and offer great confidence to researchers for finding the prevention tools for chronic disorders of human body. One major obstacle that might impair the potential use of traditional medicine as medicine of choice is the lack of standardization. The present paper is an attempt to review the hepatoprotective activities of traditional drugs reported in the recent literature.  Isolation and characterization of the bioactive compounds from the active extract is a crucial step to find out the active principles within. There is a need to conduct experimental and clinically controlled studies on plant extracts and bioactive compounds.  It is anticipated that different studies on hepatoprotective activities of herbal drugs will open new avenues for further bio-prospection and will certainly lead to new pharmaceutical agents for the treatment of hepatic diseases.

ACKNOWLEDGMENT: The authors are thankful to Central Library, GLA University, Mathura for providing literature through DELNET service.

CONFLICTS OF INTEREST: The authors declare that they have no conflicts of interest concerning this article.

AUTHORS’ CONTRIBUTIONS: Krishn Kumar Agrawal conceived of and wrote the manuscript. Yogesh Murti edited the paper. Both authors read and approved the final manuscript.

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     How to cite this article:
     Agrawal KK and Murti Y: A review on mechanistic assessment of hepatotoxicity and medicinal plants with hepatoprotective potential. Int J Pharm Sci & Res 2021; 12(9): 4549-79. doi: 10.13040/IJPSR.0975-8232.12(9).4549-79.

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