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Journal of Drug Delivery and Therapeutics

Open Access to Pharmaceutical and Medical Research

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Open Access  Full Text Article                                                                                           Review Article

Roles of Herbals in Paracetamol Induced Hepatotoxicty

Monika Devi, Kapil Kumar Verma, Inder Kumar*

Minerva College of Pharmacy, Indora, Kangra, HP, India

Introduction 

Many contemporary medications have been proven to have negative side effects on the human body despite being mostly based on synthetic chemical substances. In the area of herbal medicine, this has led to a great deal of research and development. In the majority of industrialized and developing nations today, there is a rising need for herbal medicine.¹ The most common form of liver disease varies by country and may be impacted by local factors. Infection with viruses and exposure to specific chemicals are two causes of liver diseases. An important health issue is a chemical that damages the liver cells in some individuals and results from substantial liver damage brought on by medications and by the concoction of pharmaceuticals and other substances. It is difficult to find effective treatments for common liver conditions such as cirrhosis, fatty liver, and chronic hepatitis.² Effective therapeutics with few adverse effects are needed by patients and doctors. There aren't many therapeutic drugs that work well and rarely cause side effects. Few plants can effectively treat liver disorders, so there is a lot of interest in researching the many plant therapies that can help with liver diseases.³   The present review is aimed at compiling the data on promising herbal extracts from the plant that have been tested in the hepatotoxicity model using the modern scientific system.

The liver is the body portion with the highest rate of metabolic activity in addition to being the largest organ in terms of size. One of the most important organs, it serves as a common hub for nutrient metabolism, digestion, product storage, and excretion. Additionally, the liver plays a crucial role in the metabolism of drugs and the elimination of xenobiotics from the body, protecting the body from foreign chemicals by detoxifying and removing them. Hepatic toxicity may result from some compounds like CCL4, PCM used in laboratories, lead, and arsenic used in industries, or naturally occurring poisons (microcystins).⁴ A study found that 50% of all hospitalizations and 50% of all cases of acute liver failure are due to drug-induced hepatic toxicity. One of the most frequent reasons why drugs are taken off the market is drug-induced hepatotoxicity.⁵ Liver damage is also brought on by metabolic syndrome (which includes obesity, diabetes, hypertension, and hyperlipidemia), insulin resistance, alcohol use, and oxidative stress.⁶ Hepatocytes are damaged by these hepatotoxic agents, which also activate the innate immune system and result in the production of pro-inflammatory markers such as TNF, IL, and gamma interferon (Fig. 1).^6,7 

Figure 1: Induction of hepatotoxicity by various agents.

Some hepatotoxic substances frequently cause mitochondrial damage, which inhibits the electron transport pathway and results in oxidative stress. The antipyretic and analgesic medication paracetamol (PCM), which is frequently used for medical and therapeutic purposes, is also known to cause liver damage. The function and morphology of the liver mitochondria were reported to have been changed by hazardous doses of PCM in various investigations.⁸ The substances known as hepatoprotective agents lessen liver damage brought on by hepatotoxic substances. Alcohol, CCl4, beta galactosamine, thioacetamide (TAA), paracetamol (PCM), nimesulide, anti-tubercular medications like isoniazid, rifampicin, and other substances that cause hepatotoxicity in rats and mice are used to study the hepatoprotective effects of plant medicines and herbal formulations.⁹ Herbs are crucial in the treatment of a variety of liver problems because allopathic medicine lacks effective liver-protecting medications. However, numerous native plants have been employed in Ayurveda as hepatoprotective agents. Many native plants, though, have been used in Ayurveda as hepatoprotective remedies.¹⁰  The utilization of plant materials is a major component of Indian traditional medicine such as Ayurveda, Siddha, and Unani. Because of their efficacy, safety, and affordability, herbal medications have grown in importance and appeal in recent years. In some circumstances, the relationships that medicinal plants have with other plants in their habitat have an impact on their medical efficacy. The hepatoprotective properties of plant products are one of its significant and well-established uses. Consequently, safe hepatoprotective medication is constantly needed.¹¹ Natural treatments for liver illnesses have a long history, and they are still employed in some capacity worldwide in the form of medicinal plants and their derivative.¹⁰ Scientific analysis of plants has frequently demonstrated that their active principles are what make treatments effective. Many medicinal plants have been tested, and it has been discovered that many of them contain active ingredients with healing effects for a wide range of illnesses.¹² Numerous chemical components, including phenols, coumarins, lignans, essential oils, monoterpenes, carotenoids, glycosides, flavonoids, organic acids, lipids, and alkaloids, are present in liver-protective plants.¹³

Hepatoprotective Herbs 

Leading pharmaceutical companies have helped make herbal-based treatments for liver problems popular all over the world. They have been used for a long time in India to treat liver disorders. Even though many herbal remedies are extremely popular overall and for treating liver illnesses in particular, they are still unsuitable therapy options.¹⁴ The impediments to this inevitability include (i) the lack of standardization of herbal treatments; (ii) the inability to identify the active ingredient(s) or principle(s); (iii) the absence of randomized controlled clinical trials (RCTs); and (iv)the absence of toxicological examination. Natural liver disease treatments have a long history, dating back to the Ayurvedic system and extending to the Chinese, European, and other traditional medical systems.¹⁵ In the 21st century, there has been a paradigm shift towards the therapeutic evaluation of herbal products in liver disease models by carefully combining the benefits of traditional medical systems with the contemporary concept of evidence-based medicinal evaluation, standardization, and randomized placebo-controlled clinical trials to support clinical efficacy.¹⁶ Hepatoprotective properties of numerous plants and formulas have been asserted. It has been asserted that around 160 phytoconstituents from 101 plants have liver-protective properties. 33 patented and unique multi-ingredient plant compositions contain more than 87 plants from India.¹⁰ Despite the enormous progress gained, there are still no substantial and safe hepatoprotective drugs used in modern treatments.¹⁶ The development of plant-based hepatoprotective medicines that are effective against a range of liver illnesses has therefore received the proper attention on a global scale. The role of medicinal plants is crucial since they not only preserve human and animal health and vigor but also treat several diseases, such as liver disorders, without posing any danger to humans or other animals. India, which is aptly referred to as the "Botanical Garden of the World," is the world's largest producer of medicinal herbs.¹⁷ The purpose of this study is to gather information about promising phytochemicals from medicinal plants that have been studied in hepatotoxicity models based on published studies.

Table 1: List of Some Hepatoprotective Plants.

Some Herbal plants are used as hepatoprotective  

To date, available modern drugs have not been able to come up with a satisfactory answer for liver disorders because of high costs and additional adverse effects. It is therefore necessary to search for alternative drugs for the treatment of liver diseases to replace the currently used drugs of doubtful efficacy and safety. There are numerous plants and polyherbal formulations claimed to have Hepatoprotective activity. Nearly phytoconstituents from 101 plants have been claimed to possess liver-protecting activity.¹⁵ Thus there are some marketed products in India [Silybon (microlabs), LIV 52(Himalaya)] that are available as hepatoprotectives. At the same time surprisingly, we do not have readily available plant drugs/formulations to treat liver diseases. However, several medicinal plants have been advocated in traditional system of medicine, especially in Ayurveda, for treating liver disorders.¹⁶

Curcuma longa 

Curcumin, often known as turmeric's yellow pigment, has anti-carcinogenic, anti-inflammatory, hepatoprotective, and antioxidant activities. Curcumin's liver-protective qualities are mostly related to its antioxidant capabilities. Curcumin consumption causes a decrease in liver structural changes and total bilirubin, as well as a drop in the activities of ALT, AST, ALP, LDH, GGT, and a rise in serum proteins. It demonstrated promising results in the treatment of cholestasis, hepatic fibrosis, and hepatic malignancies.⁶²

Trigonella foenumgraecum

Trigonella foenumgraecum seeds have been shown to protect against hepatic diseases caused by ethanol, aluminum chloride, and diabetes. Irradiated rats were given 1g Trigonella foenumgraecum seed powder/kg body weight/day via gavage for 7 days before irradiation. Trigonella foenumgraecum therapy considerably reduced hepatic oxidative stress caused by radiation, as seen by considerable improvements in serum aminotransferase enzymes and ALP activity.⁶³

Olea europaea

Olea europaea leaves contain maslinic acid, ursolic, oleanolic, quercetin, apigenin, luteolin, tannins, and caffeic acid Treatment of experimental animals with Olea europaea leaves extract caused a reduction in blood glucose prevention of hepatotoxicity.⁶⁴

Figure 2: Herbal plants (a) turmeric (b) Fenugreek (c) Olive

Petroselinum crispum

Parsley leaves were used to cure colic, jaundice, constipation, flatulence, edema, and rheumatism. It was used to treat impotence, blood pressure regulation, lumbago, and nosebleeds. Chemical research has been conducted on the contents of parsley, which include ascorbic acid, carotenoids, flavonoids, coumarins, apiole, different terpenoid chemicals, phenylpropanoids, phthalides, furanocoumarins, and tocopherol. It is immunosuppressive, antioxidant, anti-diabetic, cytoprotective, and hepatoprotective.⁶³

Caesalpinia crista 

Caesalpinia crista is a Fabaceae family, genus of flowering plants in the legume family, also known as Karanja in Hindi, a large shrubby perennial climber found throughout India in the plains, wastelands, and coastal areas, up to an elevation of 1000 m in the hills. Saponins, flavonoids, alkaloids, and glycosides are among the bioactive chemicals found in C. crista.⁶⁵ This plant contains anti-inflammatory, antimalarial, anti-jaundice, anthelmintic, antidiabetic, antiperiodic, and antipyretic properties. Mishra et al. studied the hepatoprotective efficacy of ethanolic C. crista leaf extracts in PCM-induced hepatotoxicity in rats. Compared to the positive control group, the treatment with ethanolic extract (200 and 400 mg/kg) resulted in a significant decrease in higher levels of TB, serum marker enzymes, and TGA. Based on these findings, it was determined that ethanolic C. crista leaf extracts exhibited favorable hepatoprotective qualities in rats against PCM-induced liver damage.⁶⁶

Cyathea gigantea 

Cyathea gigantea is a tree fern that is usually distributed in the moist open areas of Thailand, Sri Lanka, Northeastern to Southern India, Western Java, and Nepal. This plant can grow up to 20 m  have reported on the hepatoprotective effect of methanolic of C. gigantean leaf extract in PCM‑induced toxicity in Wistar Albino rats. It was noted that the PCM intoxication led to histological and biochemical hepatic damage in the experimental rats.⁶⁷ On the other hand, the treatment with methanolic C. gigantean leaf extract decreased the elevated levels of ALP, serum glutamic oxaloacetic transaminase, TB, and serum glutamate‑pyruvate transaminase; in addition, it also reversed the hepatic damage by restoring the structural integrity of the plasma membrane. The phytochemical screening showed that the leaf extract of C. gigantean comprises flavonoids, triterpenes, phenols, sterols, and saponins. These bioactive compounds might be responsible for its hepatoprotective potential. The findings from this study revealed the hepatoprotective potential of C. gigantean in PCM-induced‑hepatotoxicity model in rats.⁶⁶

Figure 3: Herbal plants (a) Parsley (b) Caesalpinia crista (c) Cyathea gigantea

Aquilaria agallocha 

This is a big tree growing up to 60–80 feet with thick a stem of 3–4 feet in diameter. It is native to Southeast Asia. The bark is papery thin and was sometimes used for writing just like Betula utilizing tree bark. Leaves are thin‑like leather, shiny, and up to 3‑inches long. Flowers are white and fruit is 1–2 inches long, smooth, and thin.⁶⁸ The plant Aquilaria agallocha has several pharmacological effects and shows anticancer, antioxidant, anti-inflammatory, antidiabetic, analgesic, antihistaminic, antipyretic, laxative, antidiarrheal, antidiabetic, antihistaminic, anxiolytic, antimicrobial, sedative, antibacterial, ulcer, and anticonvulsant protective activities. Alam proved the hepatoprotective role of ethanolic extract of A. agallocha (AAE) leaves (400 mg/ml) in PCM-induced hepatotoxicity in Sprague–Dawley (SD) rats. These results revealed that AAE leaves exert a hepatoprotective effect as they exhibited a protective effect contrary to PCM-induced hepatotoxicity in SD rats as shown by a substantial decrease in AST, ALP, ALT, LDH, CHL, and TB, increase in ALB and total protein concentration, and prevention of PCM‑induced histopathological changes in the liver.⁶⁶ 

Flacourtia indica 

The extracts of the aerial parts of Flacourtia indica (Burm. f.) Merr. were evaluated for hepato-protective properties. In paracetamol-induced hepatic necrosis in rat models, all extracts were found to reduce serum aspartate transaminase (AST), serum alanine transaminase (ALT), and serum alkaline phosphatase (ALP).⁶⁹ The most significant reduction of the serum level of AST and ALT was exhibited by petroleum ether and ethyl acetate extracts at a single oral dose of 1.5g/kg of body weight with a reduction of 29.0% AST & 24.0% ALT level by petroleum ether extract, and 10.57% AST & 6.7% ALT level by ethyl acetate extract compared to paracetamol (3 g/kg of body weight) treated animals. Histopathological examination also showed good recovery of paracetamol-induced necrosis by petroleum ether and ethyl acetate extracts.⁷⁰ On the other hand, the methanol extract did not show any remarkable effect on paracetamol-induced hepatic necrosis.⁶⁶ The hepatoprotective effects exhibited by petroleum ether and ethyl acetate extract might be mediated through the inhibition of microsomal drug-metabolizing enzymes. But, in this study the dose they have used is too high and it is not successful or rationale for human dose.⁷¹

Zingiber officinale

Ginger (Zingiber officinale Roscoe, Zingiberaceae) is widely used around the world in foods as a spice. For centuries, it has been an important ingredient in Chinese, Ayurvedic, and Tibb- Unani herbal medicines for the treatment of catarrh, rheumatism, nervous diseases, gingivitis, toothache, asthma, stroke, constipation, and diabetes Among the pharmacological effects demonstrated are anti-platelets, antioxidant, antitumor, anti-rhino viral, anti-hepatotoxicity, anti-arthritic and anti-inflammatory.⁷² The antioxidant activity of gingerol and other constituents of ginger has been confirmed. Different doses of ginger extract cause alterations in biochemical parameters, free radicals, antioxidant enzymes, and drug-metabolizing enzymes induced by bromobenzene in the liver of male rats and alleviating the toxicity of bromobenzene in the liver. Curcumin, another active component present in ginger, was found to be an antioxidant and anti-inflammatory agent and induced haem oxygenase-1 and protected endothelial cells against oxidative stress.⁷³ The antioxidants inhibit the reactive oxygen species (ROS), which are capable of causing DNA damage, associated with carcinogenesis, coronary heart disease, and many other health problems related to advancing age. The aqueous extract of ginger root may cause hepatoprotective effects against aspartame, which may cause hepatotoxicity and oxidative stress.⁷⁴ Ginger root extract has hepatoprotective effect against aspartame-induced hepatotoxicity and decreased liver function markers (ALT, AST, ALP, γ-GT), serum total protein, albumin and total bilirubin levels, serum LDH activity, α-fetoprotein, and tumor necrosis factor (TNF), increased levels of antioxidant enzymes, and reduced levels of malondialdehyde.⁷⁵ 

Figure 4: Herbal plants (a) Aquilaria agallocha (b) Flacourtia indica (c) Zingiber officinale

Cucurbita pepo L.

Pumpkin seeds (Cucurbita pepo L.) are a rich source of unsaturated fatty acids, antioxidants, and fibers, known to have anti-atherogenic and hepatoprotective activities. Pumpkin is one such plant that has been frequently used as functional food or medicine. Some of its common uses in most countries are for diabetes where it is used internally as well as externally for the management of worms and parasites. Treatment of spontaneously hypertensive rats with felodipine or captopril monotherapy or combined with pumpkin seed oil produced improvement in the measured free radical scavengers in the heart and kidney.⁷⁶ Pumpkin is also rich in unsaturated fatty acids especially linoleic and oleic acid and tocopherols and with very high oxidative stability. In addition to the carotenoids and gamma-aminobutyric acids (GABA) found in the fruits, there are other biologically active ingredients, which are found in pumpkins, such as sterols, proteins, peptides, polysaccharides, para-aminobenzoic acid, and fixed oils.⁷⁷ Pumpkin seed oil’s main nutrients are essential fatty acid-omega 6, omega 9, phytosterols, and antioxidants such as carotenoids, vitamin A, and vitamin E. Linoleic acid, a polyunsaturated fatty acid present in pumpkin seed oil, is known to increase membrane fluidity and allows for osmosis, intracellular and extracellular gaseous exchange.⁷⁸ Pumpkin seed oil includes fatty acids: palmitic (C 16:0), stearic (C 18:0), oleic (C 18:1), and linoleic (C 18:2). Antioxidants are the substances that when present in low concentration significantly delay or reduce the oxidation of the substrate. Pumpkin oil may play an important role in the protection against alcohol-induced hepatotoxicity and oxidative stress.⁷⁹ Pretreatment with pumpkin oil may have hepatoprotective effects, which are varied and include oxidation, anti-lipid peroxidation enhanced detoxification, and protection against glutathione depletion.⁸⁰ 

Andrographis paniculata 

Andrographis paniculata (A. paniculata), known among the Indians, is one of the most commonly used plants in the traditional systems of Unani and Ayurvedic medicines. It is called Creat in English and is known as the king of bitters. The aerial parts are most commonly used; however, the whole plant or the roots are also used for certain purposes in some manuscripts.⁸¹ A. paniculata has been reported as having antibacterial, anti-malarial, antiviral, cardioprotective, antioxidant, anti-inflammatory, antidiabetic effects and also antitumor activities.⁸² Treatment with whole plant extract of A. paniculata effectively reduced the level of lipid peroxidation and increased the status of antioxidant enzymes. This may be due to the presence of various flavonoids, phenols, and glycosides in the drug.⁸³

Allium sativum

Allium sativum contains fatty acids, proteins, carbohydrates, fiber, glycolipids, phospholipids, glycosides lectins, saponins, ajoene, allicin, diallyl trisulfide, diallyl disulfide, SAC sulfoxide, B, E, and C vitamins, which may be responsible for protection from various disorders and tissue damage.⁸⁴ Aged Allium sativum extract has a high antioxidant content. However, free radical scavenging activity has been suggested as a possible mechanism of hepatoprotective action.^85,86  

Figure 5: Herbal plants (a) Cucurbita pepo L.  (b) Andrographis paniculata (c) Allium sativum

Conclusion 

Herbal medications have the potential to be an effective treatment for liver problems. An extensive review of the literature on hepatoprotective plants clearly shows that herbal medications have significant promise for the treatment of liver ailments. We also presented the available data in the literature for different plants' phytochemical elements. As a result, we conclude that herbs are an important source of hepatoprotective and liver regeneration drugs. More study is needed, however, to identify, characterize, and standardize the active substances, beneficial compounds, and formulations for the treatment of liver illnesses. The availability of modern hepatoprotective medications with realistic clinical utility is still quite restricted, and the discovery of new compounds with similar potentials will undoubtedly encourage the drug discovery process.

Conflict of Interest: None

Funding: None

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