Review Article Open Access
A Review on Drug Induced Hepatotoxicity and Alternative Therapies
Tejaswi C Chavan1* and Aniket A Kuvalekar1
1Interactive Research School for Health Affairs (IRSHA), Bharati Vidyapeeth Deemed University, Pune-Satara Road, Pune, 411043, Maharashtra,India
*Corresponding author:Tejaswi Chavan, Nutrigenomics and Functional Foods Laboratory IRSHA, Bharati Vidyapeeth Deemed University, Pune- Satara Road, Pune, Maharashtra 411043, India; E-mail: @
Received: 23 July, 2019; Accepted: 16 August, 2019; Published: 23 August, 2019
Citation: Chavan TC, Aniket AK (2019) A Review on Drug Induced Hepatotoxicity and Alternative Therapies. J Nutrition Health Food Sci 7(3):1-29. DOI: 10.15226/jnhfs.2019.001160
AbstractTop
In today’s world, liver diseases are serious health problem. Liver plays key role in regulating the nutritional state and the energy balance in the body. Nutritional supplements and traditional medicinal plants can provide many invaluable drugs to the modern drug industry. Hepatoprotective agents, nutritional supplements and herbal formulations with scientifically documented hepatocellular proliferation activities can be included in treatment for liver diseases. Due to their efficacy and safety, these therapies are in great demand in the developed world for primary health care. With the availability of modern techniques, it is now possible to standardize, optimize, and test these herbal plants and nutritional supplements clinically, for their effective use. Many medicinal plants and nutritional supplements are being used since ancient time owing to their spectrum of activities like antimicrobial, cytotoxic, anti-diabetic, antiinflammatory etc. Treatment of liver disorders can be revitalised by developing standardized and clinically tested alternative medicines with high safety and efficacy profile. This review provides up-to-date information about drug-induced hepatotoxicity and hepatoprotective effects of different interventions (Nutritional supplements, Medicinal plants and Herbal formulations) for liver disease or hepatotoxicity.

Keywords: Hepatoprotection; Herbal Drugs; Liver Disorders; Nutritional Supplements
IntroductionTop
Liver is the largest gland in the body weighing about 1500g in an adult and accounts for approximately 2.5% of total body weigh [1]. Liver is called as the metabolic “engine-room of the body” [2]. Liver performs vital role in wide range of functions such as metabolism of nutrients like amino acids, carbohydrates, lipids, minerals, vitamins; it also helps in blood clotting through synthesis and secretion of plasma proteins; eliminates dead red blood cells from blood circulation; eliminates bacteria; detoxifies chemicals, drugs, xenobiotics, helps in digestion and fat metabolism by excretion of bile salts; and excretion of end products of metabolism through urine [3]. Liver plays role in both metabolism as well as biochemical transformation [4]. Therefore, it is vital to maintain a healthy liver for overall health and well-being. But liver is continuously and variedly exposed to exogenous substances like environmental toxins, drugs and alcohol which can ultimately lead to various liver disorders, generally presenting as a distinct pattern of diseases such as hepatocellular, cholestasis (obstructive), or mixed type of liver disorders [5]. Liver injuries may lead to hepatic failure and finally death. Liver diseases today are one of the most fatal diseases globally [6]. Due to high cost and severe adverse effects of modern drugs and surgical procedures, there is no suitable cure for liver disorders [7]. The artificial drugs used in the treatment of liver diseases are sometimes inadequate and can have serious adverse effect [3]. Due to these important issues, it is necessary to search for alternative drugs for treatment of liver diseases [8]. Number of different medicinal plants and herbal formulations are being used for liver disorders in ethno-medical practices and in traditional medicine system [9-14]. Herbs play a major role in the management of various liver disorders as evidenced by several research articles based on experimental and clinical studies [4, 15-17].
HepatotoxicityTop
Hepatotoxicity is damage to the liver that is related with compromised liver function due to chemicals (Alcohol, Carbon tetrachloride, Beta galactosamine, Thioacetamide) and drugs (Paracetamol, Nimusalide, Anti tubercular drugs like Isoniazid, Rifampicin etc.)[18,19]. The serious drug-related hepatotoxicity is incapacitating as well as life-threatening [20]. The real rate of drug-related hepatotoxicity is difficult to determine owing to complex market structure of over-the-counter drugs. Several chemicals may enter the body as therapeutic drugs or from the environment [21]. Some may be toxic to the liver whereas others only cause damage when converted into toxic metabolites [22]. Several key issues like, nature of metabolites or metabolic profile of the drug, enzymes involved in the metabolism of drug, drugdrug interactions and indirect enzyme activation etc., need to be addressed to study drug induced liver injury (DILI) [22].
Hepatotoxicity classificationTop
The FDA (Food and Drug Administration) working group for drug-induced hepatotoxicity has defined hepatotoxicity or liver injury where Alanine Amino Transferase (ALT) level in the serum increases threefold, Serum Alkaline Phosphatase (ALP) level increases two-fold and/or Serum Bilirubin (SBLN) level is elevated twofold [20,23]. Hepatotoxicity can be classified as

• Hepatocellular injury: Elevated levels of serum ALT or ALP [23];
• Cholestatic injury: Serum ALP and bilirubin levels increase [23];
• Mixed injury: Both serum ALT and ALP levels increase [23].
Drug Induced Liver InjuryTop
Many drugs have intracellular, organellar targets like mitochondria. Mitochondrial dysfunction causes excessive amount of oxidants which in turn injures hepatic cells [18]. The exact mechanism of drug induced liver injury remains largely unknown, but it appears to involve two pathways – direct hepatotoxicity and adverse immune reaction. Direct hepatotoxicity is also known as intrinsic or predictable drug reaction [19, 22]. Drug or one of its metabolites that fall into this category may either cause reproducible, direct toxicity to liver or lowers the host defense mechanisms e.g. paracetamol, alcohol. The adverse effects in most individuals are seen in a dose-dependent manner. Adverse immune reaction is also known as unpredictable idiosyncratic drug reactions. Such drugs cause immune mediated toxicity, which is independent of drug concentration [19, 22]. The drug or one of its metabolites may induce hypersensitivity in the host. The drugs causing particular type of liver disease are tabulated in Table 1 [19].
Table 1:Drug induced liver diseases (adapted from [19])

Liver disease

Agents

Acute fatty liver infiltration

Adrenocortical steroids, Phenothiazines, Sulfonamides, Antithyroid drugs, Phenytoin, Tetracyclines, Isoniazid, Salicylates, Valproic acid, Methotrexate

Acute viral hepatitis

Acebutolol, Indomethacin, Phenylbutazone, Allopurinol, Isoniazid, Phenytoin, Atenolol, Ketoconazole, Piroxicam, Carbamazepine, Quinine, Diltiazem, Naproxen, Ranitidine, Enflurane, Para-aminosalicylic acid, Sulfonamides, Ethambutol, Penicillins, Sulindac, Labetalol, Probenecid, Cimetidine, Maprotiline, Pyrazinamide, Dantrolene, Metoprolol, Quinidine, Diclofenac, Mianserin, Ethionamide, Phenelzine, Tricyclic antidepressants, Halothane, Phenindione, Valproic acid, Ibuprofen, Phenobarbital, Verapamil

Cholestasis jaundice

Actinomycin D, Chlorpropamide, Erythromycin, Amoxicillin/Clavulanate, Cloxacillin, Flecainide, Azathioprine, Cyclophosphamide, Flurazepam, Captopril, Cyclosporine, Flutamide, Carbamazepine, Danazol, Glyburide, Carbimazole, Diazepam, Gold, Cephalosporins, Disopyramide, Griseofulvin, Chlordiazepoxide, Enalapril, Haloperidol, Ketoconazole, Norethandrolone, Sulfonamides, Mercaptopurine, Oral contraceptives, Tamoxifen, Methyltestosterone, Oxacillin, Thiabendazole, Nifedipine, Penicillamine, Tolbutamide, Nitrofurantoin, Phenothiazines, Tricyclic antidepressants, Nonsteroidal, Phenytoin, Troleandomycin, Anti-inflammatory drugs, Propoxyphene, Verapamil

Chronic active hepatitis

Acetaminophen, Dantrolene, Methyldopa, Isoniazid, Nitrofurantoin

Chronic cholestasis

Chlorpromazine/valproic acid (combination), Imipramine, Thiabendazole, Phenothiazines, Tolbutamide, Chlorpropamide/Erythromycin (combination), Phenytoin

Liver cirrhosis or fibrosis

Methotrexate, Terbinafine HCI, Nicotinic acid

Liver granulomas

Gold, Phenytoin, Aspirin, Hydralazine, Procainamide, Carbamazepine, Isoniazid, Guinidine, Chlorpromazine, Quinidine, Nitrofurantoin, Sulfonamides, Diltiazem, Penicillin, Tolbutamide, Disopyramide, Phenylbutazone

Liver tumors

Anabolic steroids, Oral contraceptives, Thorotrast, Danazol, Testosterone

Alternative Therapies for HepatotoxicityTop
There are many therapies available for liver diseases like surgical procedures, hepatoprotective agents, nutritional supplements medicinal plants and herbal formulations.
Surgical procedures
To treat end-stage liver disease, liver transplantation has become an acceptable means with excellent long-term outcomes but it’s very costly. Liver failure secondary to viral hepatitis (especially hepatitis B and C) is a common indication for liver transplantation [24].
Hepatoprotective agents
Hepatoprotective agents have been given attention due to their role in treatment of liver disease [25-28]. These products include both prescription drugs and nutraceuticals. A drug is defined as “any substance, food, or non-food, that is used to treat, cure, mitigate, or prevent a disease and any non-food substance that is proposed to affect the structure or function of man or animals” [29]. Apart from modern drugs, there are several hepatoprotective agents like L-carnitine, Vitamin C, N-acetylcysteine and Milk thistle (Silymarin) and anti-oxidants, natural products, minerals etc. are used as hepatoprotective agents [25, 30-33, 35, 41-43]. The details of the hepatoprotective agents are arranged systemically in Table 2.
Table 2:List of hepatoprotective agents

Sr. no

Product

Mechanism of action

References

1

L-carnitine

Essential cofactor for transport of fatty acids into mitochondria for oxidation.

[36]

2

Milk Thistle (Silymarin)

Antioxidant; anti-inflammatory; anti-fibrotic; protects against Amanita mushroom toxicity (experimental) in dogs

[37]

3

N-acetylcysteine

Glutathione precursor

[38]

4

SAMe
(S- Adenosylmethionine)

Intermediary metabolite: indirect glutathione precursor (antioxidant); choleretic (cats); detoxification; supports membrane function.

[39]

 

 

5

Ursodiol

Hydrophilic bile acid shifts bile acid pool to less toxic hydrophilic bile acids. Choleretic in dogs (cats unknown). Protects hepatocyte membranes, modulates immune response.

[40]

6

Vitamin C

Free radical scavenger; functions in converting Vitamin E back to active form. Acts as prooxidant in the presence of high Fe, Cu levels.

[31, 41]

7

Vitamin E

Membrane associated antioxidant, protects liver against oxidative injury.

[42]

8

Zinc

Induces intestinal metallothionein, which
preferentially binds Cu and decreases
absorption. Zinc has anti-oxidant and anti-fibrotic effects; supports cell membrane function and immune response.

[43]

 

Nutritional Supplements
It is very important for patients with liver disease, to have balanced diet with suitable calories, carbohydrates, fats and proteins and with good nutritive value helps in regeneration of liver cells [44, 46]. Dietary supplements contain herbal products, vitamins, minerals, and any product that is not a drug (medication) [45]. Several Asian nations use numerous food and nutrition supplements, in routine diet that possess hepatoprotective activity. Several phytochemicals present in nutritional supplements possess potential ability to prevent or reverse different kinds of liver injuries [46]. Recent reports indicate that nutraceuticals like omega-3 fatty acids have hepatoprotective activity [47]. Omega-3 fatty acids are also known to offer significant benefits as nutritional supplement or dietary supplement for hepatoprotection [47-50]. Through pioneering epidemiological studies in early 1970s, Bang and Dyerberg proposed the hypothesis that long chain highly unsaturated Omega-3 fatty acids occurring in the fish oil and other marine animals which the Eskimos consumed, produced beneficial effect [50]. Marine life is rich source of a special class of polyunsaturated fatty acids known as omega-3 fatty acids. Scientific evidence proved that a diet with rich long chain omega-3 fatty acid content helps in the development of healthy brain, heart and immune system [51]. The list of nutritional supplements used in liver disorders is given in Table 3. In above studies, different vegetables and fruits are used as nutritional supplements
Table 3:List of nutritional supplements
Sr. No Name of the Nutritional supplement Sources Hepatotoxicity inducing agents Extracts studied Mechanism of action Reference
1 Allium flavum (Amaryllidaceae) Peels Carbon tetrachloride Ethanol Decreased levels of ALT, ALP and  improved blood cholesterol profiles [52]
2 Camel Milk Paracetamol Milk SGOT, SGPT, ALP, TC, TG levels decreased and total protein, albumin levels increased [53]
3 Cocos nucifera  (Arecaceae) coconut Paracetamol Dried- and Fermented-Processed
Virgin Coconut Oil
ALT, AST, ALP levels decreased [54]
4 Honey Honey Paracetamol Honey Prevented the increase in the serum levels of hepatic enzyme markers, and reduced both oxidative stress and inflammatory cytokines [55]
5 Linum usitatissimum L. Seeds Carbon tetrachloride Flaxseed chutney Reduces the elevated levels of SGOT, SGOT, ALP, cholesterol and hepatic lipid peroxidation [48]
(Linaceae)  
6 Linum usitatissimum Linn (Linaceae) Flaxseed Carbon tetrachloride n-butanol Effective in restoration of increased activities of liver function enzymes [56]
7 Malus domestica Borkh (Rosaceae) Peel Carbon tetrachloride Aqueous Inhibits lipid peroxidation,  increases the activities of  antioxidant enzyme i.e. SOD, MDA, GSH, Strong free radical scavenging activity [57]
8 Myristica fragrans (Myristicaceae) Seeds Carbon tetrachloride 70% methanol Reduce the levels of AST, ALT, ALP and TBS. Histology showed degenerative changes, bile duct proliferation, necrosis of hepatocytes. [58]
9 Nigella sativa Linn (Ranunculaceae) Seeds Isoniazid,  Rifampicin,
Pyrazinamide
Oil Reverses serum enzyme activity i.e. ALT, AST, ALP, TBS, total protein. [59]
10

Omega -3 polyunsaturated

fatty acids

Fish Cisplatin Oil Intrinsic biochemical antioxidant property [60]
11

Omega -3 polyunsaturated

fattyacids

Fish Galactosamine Oil Reduce the levels of SGOT, SGPT, SLP. Preventive agents for Hepatic cirrhosis in Mus musculus [61]
Sunflower  
12 Omega-3fatty acids Fish Paracetamol (Cod) liver oil Decreased level of MDA [62]
13 Punica granatum Linn (Lythraceae) Fruits Carbon tetrachloride Peel
Powder
Restore the biochemical parameters (ALS, AST TBARS and GSH).  Improved histological alteration [63]
14 Spirulina platensis Spirulina Carbon tetrachloride Powder extract Antioxidant property, radical scavenging, and metal chelatin activities [64]
15 Vigna radiata (Fabaceae) Seed Ethanol Aqueous Improved antioxidant levels (SOD, MDA), serum markers (ALT, AST, TG, cholesterol), NO level and histopathological [65]
16 Vitis vinifera (Vitaceae)
(Grape)
Seed Carbon tetrachloride Oil Reduces the levels of ALT, AST, ALP, liver MDA and hydroperoxides. Improved in glutathione, SOD, CAT, and TP [66]
Note: S: Serum; SGOT: Serum glutamic oxaloacetic transaminase; SGPT: Serum glutamic pyruvic transaminase; ALT Alanine aminotransferase; AST: Aspartate aminotransferase; ALP: Alkaline phosphatase; BIL (TB): Total bilirubin; SOD: Superoxide dismutase; CAT: Catalase; MDA: Malondialdehyde; TBARS; Thiobarbituric acid reactive substances; LPO; Lipid hydroperoxide GSH: Reduced glutathione TC: Total cholesterol; TG: Triglycerides; NO: Nitric oxide
Hepatoprotective Medicinal Plants
Medicinal plants play an important role in human health care [67]. Minimizing side effects and increasing therapeutic efficacy of medicines is the basic need of today. Alternative system specifies a broad range of natural health care practices including folk/tribal practices as well as Ayurveda, Siddha and Unani has been proved to be effective with minimum side effects [68, 69]. Management of liver diseases is still a challenge for modern medicine [67]. As per WHO report, around three quarters of the world’s population uses herbs and other traditional medicines to cure various diseases, including liver disorders [68-70]. Even the developed countries are now looking for time-tested traditional and alternative medicines as a remedy for liver diseases [68]. To a large extent these medical practices, originated from time immemorial, have developed gradually based on practical experiences [4, 67]. Many medicinal plants extract exhibit significant hepatoprotective activity as indicated from studies in animal models [47, 71]. The hepatoprotective activity is probably due to the presence of flavonoids in few herbal plants [47, 71- 73]. The literature till date indicates that extracts of leaves, stems, fruits, roots or even whole plants have significant potential towards treatment of hepatic diseases. These plants and their parts used for treatment are arranged systemically in Table 4.
Table 4:List of hepatoprotective plants

Sr.
No

Name of the plant

Plant
parts used

Hepatotoxicity inducing agents

Extracts studied

Mechanism of action

Reference

1

Acalypha racemose
(Euphorbiaceae)

Leaves

Carbon tetrachloride

Methanol

Reduced the levels of serum ALT, AST,  total protein and albumin and  MDA

[11]

2

Achillea millefolium (Asteraceae)
Cichorium intybus
(Asteraceae)
Capparis spinosa (Capparaceae)

Aerial,

Seeds,
Fruit

Carbon tetrachloride,
Paracetamol

Aqueous,
methanol and chloroform

Antihepatotoxic property

[74]

3

Actinidia deliciosa Chev
(Actinidiaceae)

Roots

Carbon tetrachloride

Ethanol

ALT, AST serum levels decreased. MDA decreased  and GSH increased in liver  homogenate

[75]

4

Adina cordifolia
(Rubiaceae)

Leaves

Ethanol

Acetone and aqueous

SGOT, SGPT, ALP, total bilirubin serum levels decreased and increased the levels of total protein in liver

[76]

5

Aegle marmelos Corr
(Rutaceae)

Leaves

30%Ethanol

Ethanol

Enhanced level of TBRS, GSH, SOD, CAT and  in both plasma and liver samples

[77]

6

Aerva lanata Linn
(Amaranthaceae)

Fresh bulbs

Paracetamol

Ethanol: Water

Reduces the levels of serum ALT, AST, ALP and bilirubin

[78]

7

Allium ascalonicum (Amaryllidaceae)

Whole

Paracetamol

Aqueous

Decreased level of ALT and  % of liver lesion (Micro vesicular steatosis, Necrosis area and  Lymphocytic infiltration)

[79]

8

Allium sativum (Amaryllidaceae)

Garlic

N-nitrosodiethylamine

Aqueous

Reduced the liver toxicity (ALT, AST,ALP, LPO, SOD,GSH)

[80]

9

Alocasia indica (Araceae)

Tuber vegetable

Carbon
tetra chloride

80% Ethanol

Strong antioxidant property

[81]

10

Aloe barbadensis Mill
(Xanthorrhoeaceae)

Aerial

Carbon tetrachloride

Aqueous

Restore the levels of  serum ALT, ALP, TBP, triglycerides, MDA,  glutathione, glucose-6-phosphatase, microsomal aniline hydroxylase and amidopyrine N-demethylase and  integrity of hepatocytes

[82]

11

Amaranthus caudatus Linn
(Amaranthaceae)

Whole plant

Carbon tertrachloride

Methanol

Decreased levels of  ALT AST, ALB, TP, TB, DB
Prevents the elevation of MDA, GSH, CAT and TT

[83]

12

Andrographis paniculata
(Acanthaceae)

 

Ethanol

Aqueous

Decreased levels of  ALT, AST, ALP and Bilirubin

[84]

13

Anisochilus carnosus Linn(Lamiaceae)

Stems

Carbon tertrachloride

Ethanol

Prevents the elevation of all liver marker enzyme

[85]

14

Annona squamosa
(Annonaceae)

Leaves

Isoniazid,
Rifampicin

Ethanol

Significant decrease in ALP, AST, ALT and γ-GT

[86]

15

Anthrodia comphorata
(Incertae sedis)

Mycelium
and Sporocarp

Alcohol

Aqueous

Decreased the activity of SGOT, SGPT, glucose in serum. Increased the activities of hepatic TBARS, SOD and catalase in liver tissue

[87]

16

Artemisia bsinthium (Asteraceae)

Whole

Acetaminophen,
carbon tetrachloride

Aqueous-methanol

Prevents the elevation of SGOT and SGPT

[88]

17

Artemisia campestris
(Asteraceae)

 

Carbon tetrachloride

Aqueous

Strong scavenging action of 1,1-diphenyl-2-picrylhydrazyl (DPPH), hydroxyl and superoxide anion radicals in liver
Reduced the SGOT, SGPT levels

[89]

18

Artemisia maritime (Asteraceae)

Whole

Acetaminophen,
carbon tetrachloride

aqueous-methanolic

Prevents the elevation of SGOT and SGPT

[90]

19

Aspalathus linearis
(Fabaceae)

Leaves

Carbon tetrachloride

Aqueous

Inhibits MDA triacylglycerols and cholesterol in liver tissue. suppressed mainly the increase in ALT, AST, ALP and  bilirubin in plasma

[91]

20

Asparagus racemosus Linn(Asparagaceae)

Roots

Paracetamol

Ethanol

Significantly altered serum marker enzymes and antioxidant levels

[92]

21

Azadirachta indica
(Meliaceae)

Leaves

Acetaminophen

Fresh juice

Decreased levels of  SGOT, SGPT, acid phosphatase and ALP

[93]

22

Azadirachta indica
(Meliaceae)

Leaf

Paracetamol

Aqueous

Reduced elevated levels of AST, ALT and  γ-GT

[94]

23

Azima tetracantha
(Salyadraceae)

Leaves

Paracetamol

Ethanol

Restore the levels of serum SGOT, SGPT, ALP,  TBS and TC

[95]

24

Ballota glandulosissima
(Lamiaceae)

Aerial

Carbon tetrachloride,

Aqueous

Significantly ameliorated the levels of AST, ALT, ALP and bilirubin in serum, decreased the ballooning degeneration in  histopathological examination and significant reduction in rat paw oedema

[96]

25

Bauhinia varlegate Linn
(Fabaceae)

Stem bark

Carbon tetrachloride

Ethanol

Reduces the levels of serum marker enzymes, i.e. AST, ALT, ALP and and liver protein and lipids

[97]

26

Berberis tinctoria
(Berberidaceae)

Leaves

Acetaminophen

Methanol

Decreased the levels of serum SGOT, SGPT, ALP bilirubin and MDA and significantly increased the levels GSH, CAT and SOD in liver

[98]

28

Boswellia serrate Roxb.
(Burseraceae)

Oleo gum resin

Carbon tetrachloride

Chloroform

Significantly reduced the elevated levels of serum marker enzymes, prevented the increase in liver weight and supported by changes in histopathology

[99]

29

Butea superba Roxb.
(Euphorbiaceae)

Stem bark

Carbon tetrachloride

Ethanol

Decrease in the levels of serum markers, indicating the protection of hepatic cells.

[100]

30

Cajanus cajan Linn
(Fabaceae)

Pigeon pea leaf

D-galactosamine

Ethanol

Significantly reduced in serum enzyme such as ALT, AST and increase in reduced MDA and normalized level of SOD, CAT, GSH, and GPx also histopathological improvement in liver tissue.

[101]

31

Cajanus cajan Linn
(Fabaceae)

Whole

Carbon tertrachloride

70% ethanol

Significantly reduced in SGOT and SGPT and increased in hepatic total protein.

[102]

32

Cajanus indicus Linn
(Fabaceae)

Leaves

Acetaminophen

Protein Fraction

Significantly reversed  SGPT, ALP,  creatinine and blood urea nitrogen  and  antioxidant enzymes (namely, MDA,  SOD, CAT, GSH almost normal  in both liver and kidney homogenates and protects hepatic and renal tissues against oxidative damages

[103]

33

Cajanus scarabaeoides Linn
(Fabaceae)

Whole plant

Paracetamol

n-butanol,
ethanol

significantly and dose dependently decreased the liver marker enzyme activity i.e. SGPT, SGPT, TBS, ALP, total protein, total bilirubin and an almost normal architecture of liver

[104]

34

Calotropis procera
(Asclepiadaceae)

Aerial

Paracetamol

Chloroform

Normalize all biochemical parameter

[105]

35

Calotropis procera Ait
(Asclepiadaceae)

Latex

Carbon tetrachloride

Dried latex

Significantly and dose-dependent reduction in the serum levels of liver enzymes and inflammatory mediators and attenuated the necro-inflammatory changes in the liver

[106]

36

Capparis Spinosa Linn
(Capparaceae)

Roots

Carbon tetrachloride

Ethanol

decreased in the levels of serum markers AST, ALT and  duration of sleep, indicating the protection of hepatic cells

[107]

37

Careya arborea
(Lecythidaceae)

Stem bark

Carbon tetrachloride

Methanol

Reduced the activity of serum maker enzymes i.e. SGOT, SGPT, ALP, bilirubin, uric acid, and Liver marker enzymes i.e. decreased lipid peroxidation and significantly increased the levels of SOD, CAT, GSH, vitamin C, vitamin E and protein in a dose dependent manner.

[108]

38

Carica papaya
(Caricaceae)

Fruits

Carbon tetrachloride

Ethanol and Aqueous

Reduced all liver damage marker enzyme

[109]

39

Carissa carandas Linn (Apocynaceae)
Pergularia daemia (Forsk.) Chiov. (Asclepiadaceae)

Root

Carbon tertrachloride,
Paracetamol,
Ethanol

Ethanol

Significantly reduced in the levels of SGOT, SGPT, ALP, total bilirubin, and total cholesterol, significantly maintained the levels of GSH, MDA, and a normal architecture of the liver

[110]

40

Cassia fistula
(Fabaceae)

Leaves

Carbon tetrachloride

n-Heptane

Protects against increased serum markers such  SGOT, SGPT, bilirubin and ALP

[111]

41

Cassia auriculata
(Fabaceae)

Leaves

Alcohol

Aqueous

Significantly reduced in serum enzyme markers

[112]

42

Cassia occidentalis
(Fabaceae)

Leaves

Paracetamol, ethanol

Aqueous-ethanol

Normalized in the levels of serum SGOT, SGPT, ALP, cholesterol, total lipids and histopathological alterations.

[113]

43

Cassia occidentalis Linn
(Gentianaceae)

Roots

Carbon tetrachloride

Aqueous

Decreases AST, ALT and gamma glutamyl

[114]

44

Cassia roxburghii (Fabaceae)

Seeds

Ethanol, carbon tertrachloride

Methanol

Inhibit the enhanced SGOT, SGPT, ALP, TB, TP  albumin and  TC

[115]

45

Casuarina equisetifolia (Casuarinaceae),
Cajanus cajan (Fabaceae), Glycosmis pentaphylla (Rutaceae),
Bixa orellana
(Bixaceae)
Argemone mexicana
(Papaveraceae)
Physalis minima
(Solanaceae),
Caesalpinia bonduc (Caesalpiniaceae)

 

Leaf and bark,
Whole,
leaf and bark,
seeds,

Whole,
leaf and
flower,
leaf and bark.

 

Carbon tertrachloride

 

Methanol

The four plants extract significantly, and dose dependently decreased in the levels of serum markers, indicating the protection of hepatic

 

[116]

46

Chamomile
(Asteraceae)

Capitula flower

Acetaminophen

50% ethanol

Suppresses the elevated levels of  Na+ K+- ATPase activity, serum marker enzymes, glycogen and TBARS in blood and liver, normalized impair membrane function activity.

[117]

47

Chenopodium album Linn.
(Chenopodiaceae)

Aerial

Alcohol

Petroleum ether

Restore physiological integrity of hepatocytes

[118]

48

Silybam marianum
(Asteraceae)
Cichorium intybus (Asteraceae)

Seeds

Thioacetamide

Ethanol

Significantly decreased in the activity of ALT, AST, ALP and bilirubin, significantly altered the level of Na+, K+ and liver weight

[119]

49

Cichorium intybus
(Asteraceae)

Leaves

Carbon tetrachloride

Ethanol

Prevents the elevation levels of  serum ALT, AST and ALP,  and significant hepatoprotection

[120]

50

Cichorium intybus
(Asteraceae)

Root and root callus

Carbon tetrachloride

Aqueous

SGOT, SGPT, ALP  and bilirubin levels decreased

[121]

51

Cleome viscosa Linn
(Cleomaceae)

Seeds

Carbon tetrachloride

Aqueous

Prevents the elevation of all liver marker enzyme

[122]

52

Clerodendrum inerme Linn
(Lamiaceae)

Leaves

Carbon tetrachloride

Ethanol

SGOT, SGPT, ALP, TG, TC serum levels decreased, significantly increased the glutathione level

[123]

53

Clitoria ternatea Linn (Fabaceae)

Leaves

Paracetamol

Methanol

Antioxidant property

[124]

54

Commiphora opobalsamum
(Burseraceae)

Aerial

Carbon tetrachloride

Ethanol

significantly protected SGOT, SGPT, ALP and  bilirubin

[125]

55

Cryptolepis buchanani
(Asclepiadaceae)

Leaves

Acetaminophen

Ethanol

Hepatoprotective and antioxidant property

[126]

56

Cucumis trigonus Roxb (Cucurbitaceae)

Fruit

Carbon tertrachloride

Ether, chloroform, alcohol, aqueous

High significantly decreased in the levels of serum markers, indicating the protection of hepatic cells

[127]

57

Curculigo orchioides
(Hypoxidaceae)

Rhizomes

Carbon tetrachloride

Methanol

Antioxidant property

[128]

58

Curcuma longa
(Zingiberaceae.)
Allium sativum
(Amaryllidaceae) 

Rhizomes

7-12 Dimethylbemzamthracene

Aqueous

Antioxidant property, reverse ALT, AST, ALP,  bilirubin  urea and creatinine levels 

[129]

59

Curcuma longa
(Zingiberaceae)

Rhizomes

Acetaminophen, isoniazid,
pyrazinamide,
rifampicin

Ethanol

Lowered serum liver enzyme activities, normal histology

[130]

60

Curcuma longa
(Zingiberaceae)

Rhizomes

Carbon tetrachloride

Aqueous

Decreased antioxidant enzyme activities such as SOD, CAT, GPx, GST, GSH, total TSH, protein (PSH), non-protein (NPSH) thiols and ascorbic acid in the liver, decreased  ALT, AST, Glucose-6-phosphatase (G6Pase) and the membrane bound ATPase activities

[131]

61

Cuscuta chinensis Linn.
(Convolvulaceae)

Seeds

Acetaminophen

Ethanol

Reduce SGPT, SGPT, ALP levels, prevent hepatic injuries

[132]

62

Cyperus articulatus Linn.
(Cyperaceae)

Whole rhizome

Paracetamol

Methanol

SGPT, SGOT, ALP, total protein and total bilirubin levels decreased in serum.  Improvement or  normalized the level of MDA, SOD, CAT, GSH in liver  homogenate

[133]

63

Diospyros malaborica
(Ebenaceae)

Bark

Carbon tetrachloride

Methanol

Hypoglycemic activity, antioxidant activity,  antidiabetic activity

[134]

64

Eclipta alba
(Asteraceae)

Whole

Acetaminophen,

Ethanol

Significantly reduced in serum marker enzyme

[135]

65

Eclipta alba
(Asteraceae)

 

Carbon tetrachloride

Ethanol, water

Hepatoprotective activity, Reduced in serum marker enzymes

[136]

66

Enicostema axillare Lam
(Gentianaceae)

Leaves

Carbon tetrachloride

Ethanol

Decrease in the levels of serum markers, indicating the protection of hepatic cells.

[137]

67

Epaltes divaricata Casso
(Asteraceae)

Whole

Carbon tetrachloride

Aqueous

Improved liver marker enzyme

[138]

68

Ervatamia coronaria
(Apocynaceae)

Leaves

Carbon tetrachloride

Methanol

Hepatoprotective activity

[139]

69

Euphorbia antiquorum
(Euphorbiaceae)

Aerial

Carbon tetrachloride

Aqueous

Hepatoprotective and antioxidant property

[140]

70

Euphorbia hirta Linn
(Euphorbiaceae)

Whole

Carbon tetra chloride

Ethanol

Enhanced level of  SGPT, SGOT, ALP, bilirubin in the dose dependent manner

[141]

71

Ficus carica Linn
(Moraceae)

Leaves

Carbon tetrachloride

Methanol

Lowed the serum levels of ALT,AST, ALP, total bilirubin, and malondialdehyde

[142]

72

Ficus religiosa Linn
(Moraceae)

Stem bark

Paracetamol

Methanol

Significantly reduced serum enzyme levels.

[143]

73

Foeniculum vulgare
(Apiaceae)

Seeds

Carbon tetrachloride

Essential oil

Decreased levels of serum AST, ALT, ALP and bilirubin.

[144]

74

Garcinia indica Linn
(Clusiaceae)

Fruit

Carbon tertrachloride

Ethanol

Antioxidant and hepatoprotective activity

[145]

75

Ginkgo biloba
(Ginkgoaceae)

Leaves

Carbon tetrachloride

Dry extract

AST, ALT, ALP,  and TP, albumin levels  decreased

[146]

76

Glycyrrhiza glabra
(Fabaceae)

Roots

Lipopolysaccharide /
D-galactosamine

 

Prevents inflammatory responses and IL-18 production,  significantly inhibited IL-18 production in liver injury

[147]

77

Gmelina asiatica Linn (Lamiaceae)

Aerial

Carbon tertrachloride

Ethanol chloroform

Antioxidant and hepatoprotective activity

[148]

78

Hibiscus rosa-sinensis
(Malvaceae)

Petals

Carbon tetrachloride

Ethanol

Antidiabetic and antioxidant property, therapeutic
Application

[149]

79

Hyptis suaveolens Linn
(Lamiaceae)

Leaves

Acetaminophen

Aqueous

Significantly reduced in the levels of albumin, TP, total globulin,
ALT, AST and catalase in the blood plasma and liver were

[150]

80

Ichnocarpus frutescens Linn
(Apocynaceae)

Whole

Acetaminophen

Chloroform
Methanol

Decreased  the activity of serum enzymes, bilirubin, and lipid peroxidation, significantly increased the levels of GSH, SOD, CAT, in a dose dependent manner.

[151]

81

Indigofera trita Linn
(Fabaceae)

Whole

Carbon tetrachloride

Ethanol

Significantly and dose dependent decreased in the levels of SGOT, SGPT, ALP and TBARS and significantly increased in the levels of albumin, TP, SOD and CAT

[152]

82

Kalanchoe pinnata
(Crassulaceae)

Leaves

Carbon tetrachloride

Fresh juice

Hepatoprotective Activity

[153]

83

Lannea coromandelica Linn.
(Anacardiaceae)

Bark

Thioacetamide

Aqueous and ethanol

Hepatoprotective and antioxidant activity

[154]

84

Launaea pinnatifida
(Asteraceae)

Leaves and roots

Carbon tetrachloride

Ethanol

Significantly restored all the serum and liver parameters near to the normal levels

[155]

85

Lawsonia alba
(Lythraceae)

Bark

Carbon tetrachloride

50% Ethanol

Reduced GSH level and inhibits the production of free radicals and peroxidation of microsomal lipids in a dose-dependent manner.

[156]

86

Lawsonia inermis
(Lythraceae)

Roots

Paracetamol and anti-tubercular drugs

Alcoholic and aqueous

Significantly reversed  the levels of cytosolic enzymes, a marker of oxidative damage to hepatocytes and significantly increased the levels SOD, GSH

[157]

87

Leucas cilita Linn
(Lamiaceae)

Whole

Carbon tertrachloride

Ethanol

Strong free radical scavenging and hepatoprotective activity.

[158]

88

Leucas lavandulaefolia Rees
(Labiatae)

Aerial

Carbon tetrachloride

Chloroform

Hepatoprotective activity

[159]

89

Leucophyllum frutescens Berl. (Scrophulariaceae)

Aerial

Carbon tetrachloride

Methanol

ALT, AST levels decreased

[160]

90

Luffa echinata
(Cucurbitaceae)

Fruit

Carbon tetrachloride

Petroleum ether, acetone, methanol

Hepatoprotective activity

[161]

91

Lycium chinense (Solanaceae)

Fruits

Carbon tetrachloride

Aqueous

AST, ALT and ALP levels decreased, strong free radical scavenging activity in a dose-dependent manner, significantly decreased in the level of cytochrome P450 2E1 (CYP2E1) mRNA and protein in liver

[162]

92

Lygodium flexuosum Swartz
(Lygodiaceae)

Whole

D-galactosamine

n-Hexane

Prevents the elevation of AST, ALT, LDH, hepatic MDA and GSH levels and normal histological index

[163]

93

Momordica subangulata
(Cucurbitaceae)
Naragamia alata
(Meliaceae)

Leaves,

whole
plant

Acetaminophen

Aqueous

Hepatoprotective and choleretic activities

[164]

94

Melia azadiracta Linn
(Meliaceae)
Piper longum (Piperaceae)

Leaves

Carbon tetra chloride

Ethanol

Restore the levels of biochemical parameters like total protein, total bilirubin, total cholesterol, triglycerides, and urea

[165]

95

Melia azedarach Linn
(Meliaceae)
Catharanthus roseus
(Apocynaceae)
Brassica oleracea (Brassicaceae)

Leaves

Simvastatin

Ethanol

Hepatoprotective activity

[166]

96

Mentha arvensis
(Lamiaceae)

Whole

Alcohol and carbon tetra chloride

Aqueous

Restored all biochemical parameters in serum and liver

[167]

97

Momordica dioica
(Cucurbitaceae)

Leaves

Acetaminophen

Aqueous

Hepatoprotective, antioxidant and anti-inflammatory property

[168]

98

Morinda citrifolia Linn
(Rubiaceae)

Fruit

Streptozotocin

Aqueous

Hypoglycemic and hepatoprotective property

[169]

99

Mussaenda frondosa Linn
(Rubiaceae)

Leaves

20% alcohol

Petroleum ether, chloroform, alcohol

Decreased the level of AST, ALP, ALT, bilirubin, cholesterol, triglyceride, VLDL, MDA in serum and increased the level of protein, HDL and antioxidants (SOD, GSH and CAT)  in liver

[170]

100

Myrtus communis
(Myrtaceae)

Leaves

Paracetamol

Aqueous

Significant reduction in serum hepatic enzymes

[171]

101

Nelumbo nucifera Gaerth
(Nymphaeaceae)

Flowers

Carbon tetrachloride

Ethanol

Protects against hepatocytic necrosis, fatty changes and oxidative damage

[172]

102

Nigella sativa
(Ranunculaceae)

Seeds

Carbon tetrachloride

Ethanol

Prevents MDA, increase anti-oxidant defense system activity and also prevent liver damage

[173]

103

Ocimum gratissimum
(Lamiaceae),
Vernonia amygdalina
(Asteraceae)
Tridax procumbens
(Asteraceae)
Parkia biglobosa
(Fabaceae)
Bridelia ferruginea, (Phyllanthaceae)

Leaves

2-Acetylaminoflourene

Aqueous

Hepatoprotective potential

[174]

104

Ocimum sanctum
(Lamiaceae)

Leaves

Carbon tetrachloride isoniazid,
pyrazinamide,
rifampicin

Ethanol

Hepatoprotective action,  antioxidant activity and  revers the biochemical and histological changes

[175]

105

Parkinsonia aculeata Linn
(Fabaceae)

Leaves

Carbon tetrachloride

Ethanol

Potential therapeutic and preventive, antioxidative  property

[176]

106

Pergularia daemia Forsk (Apocynaceae)

Aerial

Carbon tetrachloride

Ethanol

Hepatoprotective activity

[177]

107

Phoenix dactylifera
(Arecaceae)

Pits and flesh

Carbon tetrachloride

Aqueous

Effective prophylactic or treatment against liver cytotoxicity

[178]

108

Phyllanthus  longiflorus (Phyllanthaceae)

Leaves

Acetaminophen

Ethanol

Reduced the necrosis and swelling of the hepatocytes in liver histology, ALT, AST, ALP, TP, albumin and total bilirubin levels in serum.

[179]

109

Phyllanthus maderaspatensis
(Phyllanthaceae)

Whole

Acetaminophen

n-Hexane

Antihepatotoxic activity

[180]

110

Phyllanthus niruri
(Phyllanthaceae)

Leaves

Acetaminophen

Alcohol

Regenerative changes, presence of
binucleated cells, anisonucleosis and anisocytosis, reduced SGPT level

[181]

111

Phyllanthus polyphyllus Willd(Phyllanthaceae)

Leaves

Acetaminophen

Methanol

Significantly altered serum marker enzymes and antioxidant levels to near normal

[182]

112

Phyllanthus rheedi  (Phyllanthaceae)

Whole

D-galactosamine

Ethanol

Antioxidant and choleretic activity

[183]

113

Platycodon grandiflorum
(Campanulaceae)

Roots

Acetaminophen

Aqueous

Inhibits P450 lA2-dependent methoxyresorufin O-deethylase activities and the P450 2E1-dependent p-nitrophenol and aniline hydroxylase, blocked P450-mediated APAP bioactivation.

[184]

114

Pleurotus ostreatus
(Pleurotaceae)

Whole

Carbon tetrachloride

Ethanol

SGOT, SGPT and ALP levels reverted,  GSH, CAT, SOD and Gpx  levels increased and MDA significantly lowered

[185]

115

Polygala arvensis Wild
(Polygalaceae)

Leaves

D-galactosamine

Chloroform

Normalized the levels of SGOT, SGPT, ), ALP, lactate dehydrogenase TC, TGL, albumin, TP

[186]

116

Pterocarpus santalinus Linn
(Fabaceae)

Stem bark

Carbon tetrachloride

Aqueous

Decrease in levels of liver enzyme markers,  significantly increased in total protein, indicating the recovery of hepatic cells, revealed normal hepatic cords without any cellular necrosis and fatty infiltration

[187]

117

Raphanus sativus Linn (Brassicaceae)

Seeds

Carbon tetrachloride

Aqueous, methanol

Inhibits increased SGOT, SGPT, bilirubin and histopathological changes

[188]

118

Rhodococcum vitis
(Ericaceae)

Leaves

D-galactosamine

Aqueous

Antioxidant activity

[189]

119

Rhododendron arboretum
(Ericaceae)

Leaves

Carbon tetrachloride

Ethanol

Hepatoprotective property, anti-oxidant activity

[190]

120

Ricinus communis
(Euphorbiaceae)

Leaves

Carbon tetrachloride,
acetaminophen,
thioacetamide

n-Hexane chloroform

Protects against hepatotoxicity

[191]

121

Rubia cordifolia
(Rubiaceae)

Roots

Thioacetamide

Methanol

Hepatoprotective property

[192]

122

Saccharum officinarum (Poaceae)

Cane

20% Ethanol

Juice

Significantly prevented the physical, biochemical, histological and functional changes

[193]

123

Saponaria officinalis Linn
(Caryophyllaceae)
Punica granatum Linn.(Lythraceae)
Syzygium aromaticum Linn (Myrtaceae)

Carbon tetrachloride

Powdered

Ameliorated the histopathological alteration in liver section

[194]

124

Sarcostemma brevistigma
(Asclepiadaceae)

Stem

Carbon tetrachloride,

Ethyl acetate

Hepatoprotective property

[195]

125

Schisandra chinensis
(Schisandraceae)

Seeds

Carbon tetrachloride

Alcoholic

Reduced in the levels of ALT, AST, and GGT, glucose, triglycerides, and cholesterol in serum,  found new flavonoids

[196]

126

Sida cordifolia
(Malvaceae)

Leaves

Ethanol

Petroleum ether, chloroform

Analgesic, anti-inflammatory, hypoglycemic activities

[197]

127

Sida cordifolia
(Malvaceae)

Whole

Carbon tetrachloride, paracetamol and
Rifampicin

Methanol
Aqueous

Immunomodulator and pharmacological properties

[197]

128

Sida veronicaefolia (Malvaceae)

Leaves

Ethanol

Aqueous and ethanol

SGPT, SGOT, ALP, total bilirubin levels decreased and increased the levels of total protein.

[198]

129

Smilax chinensis (Smilaceae)  

Roots

Acetaminophen

Ethyl acetate

Hepatoprotective and antioxidant activities

[199]

130

Solanum nigram Linn
(Solanaceae)
Cichorium intybus
(Asteraceae)

Fruits

Carbon tertrachloride

Ethanol

Reduce the serum biochemical indicators like AST, ALT, TB, TP and oxidative stress like GSH, SOD, LPO levels decreased

[200]

131

Solanum trilobatum
(Solanaceae)

Whole

Carbon tetrachloride

Ethanol

Antioxidant and hepatoprotective

[201]

132

Swertia longifolia Boiss
(Gentianaceae)

Aerial

Acetaminophen

Ethanol

Significantly reduced AST, ALT ALP

[202]

133

Syzgium aromaticum Linn
(Myrtaceae)

Flowers buds

Acetaminophen

Ethanol

Antioxidant activity

[203]

134

Tecomella undulate
(Bignoniaceae)

Leaves

Alcohol and paracetamol

Methanol

Hepatoprotective potential and presence of flavonoids, quinones and other bioactive constituents

[204]

135

Tectona grandis Linn.
(Lamiaceae)

Leaves

Carbon tetra chloride

Hydroalcoholic

Significantly and dose dependently decreased the levels SGOT, SGPT  and  ALP

[205]

136

Tephrosia purpurea (Fabaceae)

Aerial

Arsenic

Aqueous

ALT, AST, ALP levels decreased and reduced necrosis and inflammation in liver section

[206]

137

Terminalia bellerica Roxb
(Combretaceae)

Fruits

Alcohol

Aqueous
Ethanol

Prevents the physical and biochemical changes against hepatotoxins

[207]

138

Terminalia catappa
(Combretaceae)

Leaves

Carbon tetrachloride

Chloroform

Protects against liver mitochondrial damage

[208]

139

Teucrium polium
(Lamiaceae)

Aerial

Carbon tetrachloride

Ethyl acetate

Restore the normal histomorphology pattern of liver cells

[209]

140

Thespesia lampas Dalz and Gibs (Malvaceae)

Roots

Carbon tertrachloride

Methanol

Revealed normal liver section without any  hepatic steatosis, centrilobular necrosis, and swelling of the hepatic cytoplasm

[210]

141

Tinospora cordifolia
(Menispermaceae)

Stem, leaves

Carbon tertrachloride

Aqueous

Antioxidant or free radical scavenger property and  hepatic regeneration ability

[211]

142

Tinospora cordifolia (Menispermaceae)

Leaf, stem, roots

Carbon tertrachloride

Pet  ether, Ethanol, Aqueous

Biologically and hepatoprotective activity

[212]

143

Tinospora cordifolia (Menispermaceae)

Stem

Carbon tetrachloride

Aqueous

Liver function and  immune functions

[213]

144

Tinospora cordifolia (Menispermaceae),
Aloe vera (Xanthorrhoeaceae),
Mangifera indica (Anacardiaceae)

Stem and bark
leaf
pulp

Carbon tertrachloride

Aqueous

Restoration of improved level of SOD, CAT, MDA

[214]

145

Tinospora sinensis (Menispermaceae)
Tinospora cordifolia
(Menispermaceae)
Neem guduchi
(Menispermaceae)

 

Stem

 

Acetaminophen

 

Satwa

Improved hepatic function normalized the lipid profile in the serum and liver, and improvements in the levels of antioxidant enzymes and oxidative-stress markers.
Restore and strengthen the liver functions

[215]

146

Tinospora cordifolia Wild.
(Menispermaceae)
Ocimum sanctum L(Labiatae)
Zizyphus mauritiana Lam
(Rhamnaceae)
Curcuma longa
(Zingiberaceae)

Roots

Isoniazid,
rifampicin and pyrazinamide

Ethanol

Hepatoprotective potential and prevents immunosuppression

[216]

147

Trianthema portulacastrum
(Aizoaceae)

Leaves

Acetaminophen,

Ethanol

Significant hepatoprotective activity

[217]

148

Tridax procumbens
(Asteraceae)

Aerial

D-galactosamine

Ethanol

Alteration in biochemical marker enzymes

[218]

149

Trigonella foenum-graecum Linn (Fabaceae)

Seeds

Carbon tetrachloride

Diethyl ether

Anti-inflammatory and hepatoprotective

[219]

150

Tylophora indica
(Apocynaceae)

Leaves

Ethanol

Aqueous

Significantly prevented the physical (liver weight and volume), biochemical (ALT,AST, ALP, TP,TBP, TC,  triglycerides), histological (damage to hepatocytes) and functional changes (thiopentone-induced sleeping time) histological (damage to hepatocytes)

[220]

151

Uetica parviflora Roxb.
(Urticaceae)

Leaves

Carbon tetrachloride

Ethanol

Restore of the levels of serum bilirubin, proteins and hepato protective enzymes, revealed the centrilobular necrosis in a dose dependent manner

[221]

152

Veronica ciliata (Plantaginaceae,)

Herbs

Carbon tetra chloride

Petroleum ether, ethyl acetate

Antioxidant

[222]

153

Vetiveria zizanioides
(Poaceae)

Root

Paracetamol

Methanolic

Antioxidant

[223]

154

Vetiveria zizanioides Linn (Poaceae)

Roots

Alcohol

Methanol

Hepatoprotective property

[224]

155

Vicia calcarata Desf
(Leguminosae)

Aerial

Carbon tetrachloride

Ethanol

Inhibits lipid peroxidation, revealed the flavanol glycosides of F-2 protect against hepatic damage

[225]

156

Vitex negundo Linn (Lamiaceae)

Fresh bark

Paracetamol

Methanol

Significantly altered in all biochemical and histopathological sections

[226]

157

Xylopia phloiodora Mildbr.
(Annonaceae)

Stem bark

Carbon tetrachloride,
acetaminophen

Crude extract
Ether extract
Essential oil

Antihepatotoxicity activity

[227]

158

Zizyphus mauritian Lamk

Seed

Isoniazid, Pyrazinamide

Ethanol

Hepatoprotective, strong antioxidant property and  indicated probable presence of flavonoids, phenolic compounds, tannins and saponins

            [228]

159

Zizyphus mauritian Lamk

Seed

Isoniazid, Pyrazinamide

Ethanol

Hepatoprotective, strong antioxidant property and  indicated probable presence of flavonoids, phenolic compounds, tannins and saponins

            [228]

 

Note: S: Serum; SGOT: Serum glutamic oxaloacetic transaminase; SGPT: Serum glutamic pyruvic transaminase; ALT Alanine aminotransferase; AST:Aspartate aminotransferase ALP: Alkaline phosphatase; BIL (TB): Total bilirubin; SOD: Superoxide dismutase; CAT: Catalase; MDA: Malondialdehyde;TBARS; Thiobarbituric acid reactive substances; LPO; Lipid hydroperoxide GSH: Reduced glutathione TC: Total cholesterol; TG: Triglycerides; NO:Nitric oxide; TT: Thrombin time: γ-GT: Gamma-Glutamyl Transferase; GPx: Glutathione peroxidase
Herbal formulations used in liver disorder
There are numerous medicinal plants and their formulations used to treat liver disorders in ethno-medicine practice as well as traditional system of medicine in India [229, 230]. There are about 600 commercial herbal formulations available in market all over the world, which are claimed to have hepatoprotective activity [231, 246]. In India, about 40 patented polyherbal formulations representing a variety of combination of 93 medicinal plants from 44 families are available [232].

More than 700 mono and poly-herbal preparations from more than 100 plants are in clinical use as hepatoprotective agents in the form of decoction, tincture, tablets and capsules [232, 233]. In recent years, the use of herbal drugs for the treatment of liver diseases has increased all over the world [233]. The herbal drugs are easily available and believed to be harmless and free from serious adverse reactions [234]. The usage of alternative medicine, including herbal preparations, has increased due to limited therapeutic options and disappointing success of modern medicine in treating liver ailments [235]. Several commercial hepatoprotective herbal formulations are known to be effective in liver diseases and are used to treat different types of liver disorders [236-255].

The synchronous activity of ingredients from polyherbal formulation is believed to be responsible for hepatoprotective activities of these formulations mention in Table 5.

The mechanism of action of promising hepatoprotective therapies (Hepatoprotective agents, nutritional supplement, medicinal plants, herbal formulation) is shown in Figure 1.
Table 5:List of herbal formulations

Sr.
No

Name of the formulation

Plants used in
the formulation

Hepatotoxicity inducing agents

Mechanism of action

Reference

1

Blood wort
(Herb pharma,
Nigeria)

Rumex acetosa L. (Polygonacease; bark)
Cinchona succirubra Pav. (Rubiaceae; bark).

Carbon tetrachloride

Hepatoprotective property

[236]

2

BR-16A (Mentat)
Himalaya Drug Company

Bacopa monnieri (Scrophulariaceae),
Asparagus racemosus (Asparagaceae),
Acorus calamus (Acoraceae),
Withania somnifera (Solanaceae),
Tinospora cordifolia (Menispermaceae),
Emblica officinalis (Euphorbiaceae),
Evolvulus alsinoides (Convolvulaceae),
Saurssurea lappa (Compositae),
Terminalia chebula (Combretaceae),
and T.bellirica (Combretaceae)

Ethanol

Anxiogenic response

[237]

 

 

 

3

Clearliv polyherbal formulation
(Apex Laboratories Ltd., Chennai)

Phyllanthus niruri (Phyllanthaceae),
Eclipta alba (Asteraceae),
Boerhaavia diffusa (Nyctaginaceae)
Tinospora cordifolia (Menisperemacea),
Tribulus terrestris (Zygophyllaceae),
Tephrosia purpurea (Fabaceae),
Indigofera tinctoria (Fabaceae),
Aconitum heterophyllum (Ranunculaceae),
Andrographis paniculata (Acanthaceae),
Rubia cordifolia (Rubiaceae), Terminalia chebula (Combretaceae), Curcuma longa (Zingiberaceae),
Ricinus cummunis (Euphorbiaceae)

Thioacetamide D-Galactosamine and
carbon tetrachloride,

Reduces plasma liver markers, and elevated antioxidants levels.

[238]

4

DHC-1
(Himalaya Drug Company)

Bacopa monnieri Linn. (Scrophulariaceae; whole),
Emblica officinalis Gaertn. (Euphorbiaceae; fruit),
Glycyrrhiza glabra Linn. (Papilionaceae; roots),
Mangifera indica Linn. (Anacardiaceae; bark),
Syzygium aromaticum Linn. (Myrtaceae; flower bud)

Carbon tetrachloride

Reduces the levels of serum markers and decreased in tissue MDA levels and increased in SOD, catalase, GSH and membrane bound enzymes indicated the hepatoprotective and antioxidant property

[239]

5

HD-03
(Himalaya Drug company.)

Solanum nigrum L. (Solanaceae;whole plant),
Cichorium intybus L. (Asteraceae; seeds),
Picrorrhiza kurroa Benth. (Plantaginaceae; roots),
Tephrosia purpurea L. (Fabaceae; whole plant) Andographis paniculata Nees (Acanthaceae;leaves)

D-Galactosamine

Hepatoprotective property

[240]

6

Hepax, a polyherbal formulation,
(Anglo-French drug industries, Bangalore)

Plumbago zeylanica (Chitraka, Plumbaginaceae),
Picrorrhiza kurroa (Katuka, Plantaginaceae),
Piper nigrum (Maricha, Piperaceae),
Zingiber officinale (Ardraka, Zingiberaceae),
Sodii carbonas impure (Sajikakshara),
Phyllanthus embilica (Amalaki, Euphorbiaceae), Terminalia chebula (Haritaki, Combretaceae), Calcii oxidum (chuna),
Potassii carbonas impure (Yavakshara)

Carbon tetrachloride, paracetamol and thiocetamide

Decreased the levels SGPT, SGOT, ALP and total bilirubin
Strongly hepatoprotective effect

 

 

[241]

7

Herbal formulation

Andrographis paniculata (Acanthaceae; leaves),
Boerhavia diffusa (Nyctaginaceae; root), Eclipta alba (Asteraceae; whole plant)and Picrorhiza kurroa (Plantaginaceae; rhizome)

Carbon tetrachloride and ethanol

Restores the cellular integrity of liver architecture,
strongly indicated  the herbal formulation has potential hepatoprotective action

[242]

8

Herbal Preparation (HP-4)

Aloe vera (Xanthorrhoeaceae; leaves),
Bacopa monnieri (Scrophulariaceae; leaves), Moringa oleifera (Moringaceae; Leaves)and Zingiber officinale (Zingiberaceae;rhizome)

D-Galactosamine

Free radical scavenging properties, Antioxidants property, Hepatoprotective activity, Synergistic protection

[243]

9

HPN-12

Glycyrrhiza glabra (Papilionaceae),
Picrorrhiza kurroa (Plantaginaceae),
Berberis aristata (Berberidaceae),
Piper longum (Piperaceae),
Phy1lanthus niruri (Phyllanthaceae),
Solanum dulcamara (Solanaceae),
Zingiber officianale (Zingiberaceae),
Curculigo orchioides (Hypoxidaceae),
Elettaria cardamomum (Zingiberaceae),
Tinospora cordifolia (Menispermaceae), Desmodium triflorum (Fabaceae),
Saccharum officinarum(Poaceae)

Carbon tetrachloride

Improved serum, liver function marker such as AST, ALT, ALP

[244]

10

Jigrine
(an Unani polypharmaceutical herbal formulation)

Cichorium intybus Linn. (Asteraceae),
Tamarix dioica Roxb. (Tamaricaceae),
Solanum nigrum Linn. (Solanaceae),
Rheum emodi Wall. (Polygonaceae),
Rubia cordifolia Linn. (Rubiaceae),
Vitex negundo Linn. (Lamiaceae),
Cassia occidentalis Linn. (Fabacea),
Foeniculum vulgare Mill. (Apiaceae),
Cuscuta reflexa  Roxb. (Convolvulaceae),
Careya arborea Roxb. (Lecythidaceae),
Phy1lanthus niruri Linn Hook. (Euphorbiaceae), Plantago major Linn.( Plantaginaceae),
Rosa damascena Linn.(Rosaceae),
Solanum  xanthocarpum (Solanaceae),

Alcohol, carbon tetrachloride and paracetamol

Hepatoprotective activity of Jigrine and antioxidant property

[245]

11

Liv 52
(Himalaya Drug Company)

Achillea millefolium (Asteraceae),
Capparis spinosa (Capparaceae),
Cassia occidentalis (Fabaceae)
Cichorium intybus (Asteraceae),
Solanum nigrum (Solanaceae),
Tamarix gallica (Tamaricaceae),
Terminalia arjuna (Combretaceae)

Carbon tetrachloride and
Paracetamol

all the six herbal formulations (Ayurvedic medicine) showed marked beneficial effects in the studied pharmacological, biochemical and histological parameters.
Protects liver against different  hepatotoxins, promotes appetite and growth

[246]

12

Livergen
(Standard Pharamcuticals Serampore, West Bengal)

Andrographis paniculata (Acanthaceae),
Apium graveolens (Apiaceae),
Asteracantha longifolia (Acanthaceae),
Cassia angustifolia (Fabaceae),
Trachyspermum ammi (Apiaceae),
Trigonella foenum-graecum (Fabaceae)

Carbon tetrachloride and paracetamol

Gastrointestinal and hepatic regulator

[246]

14

Livokin
(Herbo-med, Kolkata)

Andrographis paniculata (Acanthaceae),
Apium graveolens (Apiaceae),
Berberis lyceum (Berberidaceae),
Carum copticum (Apiaceae),
Cichorium intybus (Asteraceae),
Cyperus rotundus (Cyperaceae),
Eclipta alba (Asteraceae),
Ipomoea turpethum (Convolvulaceae),
Oldenlandia corymbosa (Rubiaceae),
Picrrorhiza kurroa (Plantaginaceae),
Hygrophila spinosa (Acanthaceae),
Plumbago zeylanica (Plumbaginaceae),
Solanum nigrum (Solanaceae),
Tephrosia purpurea (Fabaceae),
Terminalia arjuna (Combretaceae),
Terminalia chebula (Combretaceae),
Trigonella foenum-graecum (Fabaceae)

Carbon tetrachloride and paracetamol

Herbal formulation, for hepatic dysfunction

[246]

15

Octogen
(Plethico Pharamcuticals Ltd., Indore)

Arogyavardhini rasa,
Phyllanthus niruri (Phyllanthaceae)

Carbon tetrachloride and paracetamol

Highly potent hepatoprotective

[246]

16

Stimuliv
(Franco-Indian Pharamcuticals Pvt. Ltd., Mumbai)

Andrographis paniculata (Acanthaceae),
Eclipta alba (Asteraceae),
Phyllanthus niruri (Phyllanthaceae),
Justicia procumbens (Acanthaceae)

Carbon tetrachloride and paracetamol

Liver stimulant and tonic

[246]

17

Tefroliv
(TTK Pharma Pvt. Ltd., Chennai)

Andrographis paniculata (Acanthaceae),
Eclipta alba(Asteraceae),
Ocimum sanctum (Lamiaceae),
Phyllanthus niruri (Phyllanthaceae),
Picrrorhiza kurroa (Plantaginaceae),
Piper longum (Piperaceae),
Solanum nigrum(Solanaceae),
Tephrosia purpurea (Fabaceae),
Terminalia chebula (Combretaceae)

Carbon tetrachloride and paracetamol

Standardized liver formulation for effective hepatic regeneration

[246]

18

Liv. 100
(Himalaya Drug company)

Cichorium intybus (Asteraceae),
Solanum nigrum (Solanaceae),
Phyllanthus amarus (Phyllanthaceae),
Picrorrhiza kurroa (Plantaginaceae),
Emblica officinalis (Euphorbiaceae)

Isoniazid, rifampicin, and
Pyrazinamide

Decreased in the activity of Na+K+ ATPase Ca2+ ATPase and Mg2+ ATPase, restores antioxidant enzymes and scavenge reactive oxygen species

[247]

19

Liv. 52
(Himalaya Drug Company)

Achillea millefolium (Asteraceae),
Capparis spinosa (Capparaceae),
Cassia occidentalis (Fabaceae),
Cichorium intybus (Asteraceae),
Solanum nigrum (Solanaceae),
Tamarix gallica (Tamaricaceae),
Terminalia arjuna (Combretaceae)

Carbon tetrachloride

Significantly decreased  in MDA

[248]

20

Mandur bhasma
(Himalaya’s herbs)

Ferric oxide/hematite or red iron oxide

Carbon tetrachloride

Prevents the paraffin mediated and CC14 mediated changes in the enzyme activities,
hepatoprotective role

[249]

21

Panchagavya ghrit.
(Go-Vigyan
Anusandhan Kendra, Deolapar).

cow milk,
ghee, urine, dung and curd in equal proportions

Carbon tetrachloride

Prevents elevated levels of serum GPT, GOT, ACP and ALP, normal architecture and reduced the CCl4 induced hepatotoxicity

[250]

22

Polyherbal formulation

Curcuma longa (Zingiberaceae; rhizomes), Emblica officinalis (Phyllanthaceae; fruit), Terminalia chebula (Combretaceae;fruit), Terminalia belirica (Combretaceae; fruit) and Myrica nagi (Myricaceae; fruit)and bees wax.

Paracetamol

Hepatoprotective property

[251]

23

Polyherbal formulation

Emblica officinalis (Euphorbiaceae;leaves), Phyllanthus acidus (Phyllanthaceae; leaves),
Moringa oleifera (Moringaceae; leaves)

Paracetamol

 

Inhibits against various hepatotoxicants, SGPT, SGOT, ALP, DB and LDH levels decreased

[252]

25

Polyherbal formulation tablets
(TulsiAmrit Pvt. Ltd., Indore, India)

Andrographis paniculata (Acanthaceae), Phyllanthus niruri Linn. (Euphorbiaceae),
Phyllanthus emblica Linn. (Euphorbiaceae)

Alcohol, carbon tetrachloride and paracetamol

[252]

24

Polyherbal formulation

Acacia catechu (Fabaceae),
Allium sativum (Amarylidaceae),
Andrographis paniculata (Acanthaceae),
Azadirachta indica (Meliaceae),
Boerhaavia diffusa (Nyctaginaceae),
Curcuma longa (Zingiberaceae),
Eclipta alba (Asteraceae),
Emblica officinalis (Euphorbiaceae),
Luffa echinata (Cucurbitaceae),
Picrorrhiza kurroa (Plantaginaceae),
Phyllanthus amarus (Phyllanthaceae)

Carbon tetrachloride and paracetamol

Prophylactic and therapeutic efficacy
Strong biochemical parameters, morphological, pentobarbitone sleeping time and histopathological

[253]

26

Polyherbal formulation tablets

Phyllanthus niruri (Phyllanthaceae),
Eclipta alba (Asteraceae),
Cichorium intybus (Asteraceae),
Boerhaavia diffusa (Nyctaginaceae),
Embelia ribes (Myrsinaceae),
Berberis aristata (Berberidaceae),
Picrorhiza kurroa (Plantaginaceae)

Carbon tetrachloride

Antioxidant activity

[254]

27

Rhinax
(Hindustan Antibiotics Limited, Pune)

Withania somnifera L. (Solanaceae; root), Asparagus racemosus Wild. (Liliaceae; root), Mucuna pruriens Baker non-DC (Papilionaceae; root),
Phyllanthus emblica Gasertn. (Euphorbiaceae; fruit),
Glycyrrhiza glabra L.(Papilionaceae; root), Terminalia chebula Retz.(Combretaceae; fruit),
Myristica fragrans Houtt. (Myristicaceae; seed)

Carbon tetrachloride

Anti-hepatotoxic activity, increased activity of cytochrome P450,

[255]

 

 

Note: S: Serum; SGOT: Serum glutamic oxaloacetic transaminase; SGPT: Serum glutamic pyruvic transaminase; ALT: Alanine aminotransferase; AST:Aspartate aminotransferase ALP: Alkaline phosphatase; BIL (TB): Total bilirubin; DB: Direct bilirubin; SOD: Superoxide dismutase; CAT: Catalase;MDA: Malondialdehyde; TBARS; Thiobarbituric acid reactive substances; LPO; Lipid hydroperoxide GSH: Reduced glutathione TC: Total cholesterol; TG: Triglycerides; NO: Nitric oxide; TT: Thrombin time: γ-GT: Gamma-Glutamyl Transferase; GPx: Glutathione peroxidase; ACP: Acid phosphatase; CCl4: Carbon tetrachloride
Figure 1: Mechanisms of action of promising hepatoprotective therapies
Note: SGOT: Serum glutamic oxaloacetic transaminase; SGPT: Serum glutamic pyruvic transaminase; ALP: Alkaline phosphatase; γ-GT: Gamma-Glutamyl Transferase; MDA: Malondialdehyde; SOD: Superoxide dismutase; GSH: Reduced glutathione; CAT: Catalase; GPx: Glutathione peroxidase; LPO; Lipid hydroperoxide; TC: Total cholesterol; TG: Triglycerides
ConclusionTop
Present review concludes the several reports recommended interventions or alternative therapies of nutritional supplements, medicinal plants, and herbal formulations showed hepatoprotective activity against drug induced hepatotoxicity with higher efficacy safety, and long-term benefits without major side effects. Several herbal plants and formulations have been used as medicine in ayurveda from ancient time. Inspite of ample literature, there are very few successfully marketed formulations with excellent hepatoprotective or hepatocorrective activities. There is a need for authentication and scientific investigations of the hepatoprotective claims of ayurvedic or traditional herbal formulations for their wider acceptance. As our review found the alternative therapies having promising effects, either experimentally in animal models or cell cultures or even in clinical trials.
AcknowledgementTop
Authors are thankful to Bharati Vidyapeeth Deemed University for providing financial support and infrastructure facilities.
ReferencesTop
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