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6 Bedi, Bijjem, Kumar and Gauttam Indian J Physiol Pharmacol 2016; 60(1)

Review Article

Herbal Induced Hepatoprotection and Hepatotoxicity :A Critical Review

Onkar Bedi1, Krishna Reddy V. Bijjem1, Puneet Kumar1

and Vinod Gauttam2*

Departments of 1Pharmacology & 2Pharmacogonosy,I.S.F. College of Pharmacy,Moga – 142 001, Punjab, India

Abstract

Traditional herbal drugs are wonderful remedies for the treatment of various devastating disorders. Recently,there has been a change in a universal fashion from synthetic to herbal medicine, which is like homecomingto nature. In the present situation, the dietary changes lead to liver disorders like non-alcoholic and alcoholicfatty liver disorders. India is one of the world’s twelve leading biodiversity centers with the presence of over45,000 diverse plant species, out of this about 15,000-20,000 plants have good medicinal and therapeuticproperties of which only about 7,000-7,500 are being used by traditional practitioners. Hepatic injury accountsfor 3.5%-9.5% of all adverse drug reaction reports and up to 14.7% of fatal adverse reaction. Hepaticdisorders/toxicity can occur by several mechanisms like Cytochrome P450 activation, lipid peroxidation,Induction of nitric acid synthase, mitochondrial dysfunction, activation of pro-inflammatory mediators andBile acid-induced liver cell death. There are a number of drugs or therapies available for the treatment ofhepatic disorders, but still there is a need for the novel drug discovery which can target multiple diseasepathways. Traditional medicines have exhaustive ancient and scientific literature for curing a lot of lifethreatening disorders with less or no side effects. There are number of scientifically proved hepatoprotectiveherbal drugs like Andrographis paniculata, Ocimum sanctum, Solanum nigrum, Silybum marianum, Phyllanthusniruri etc. which are widely used for the treatment of liver disorders. However, there are various herbal plantsand phytoconstituents, which are found to be hepatotoxic like Lanata camra Linn, Symphytum officinale,Azadirachta indica, Amantia phalloides etc. This review emphasizes on both sides of the coin like crucialaspects of phytoconstituents with reference to their hepatoprotective as well as hepatotoxic effects linkedto use of herbal preparations.

Indian J Physiol Pharmacol 2016; 60(1) : 6–21

*Corresponding author :

Dr. Vinod Gauttam, M. Pharm., PhD (Pharmacognosy), Associate Professor, Department of Pharmacognosy, I.S.F College ofPharmacy, Moga (Punjab) India; E-mail [email protected], Mobile number: 09876499479, Phone number: 01636-324200,324201, Fax number: 01636-239515

(Received on April 12, 2015)

Indian J Physiol Pharmacol 2016; 60(1) Herbal Induced Hepatoprotection And Hepatotoxicity 7

and bile acid, etc. (2, 3). Liver disorders (LD) are aterm used in any conditions, diseases, and infectionsthat affect the structures, or functions of the liver.LD causes a lot of pathophysiological changes likecirrhosis, nonalcoholic hepatic steatosis, hepatitis,Biliary cirrhosis, alcoholic hepatitis, liver, cancer etc.

The global crude annual incidence rate for LD was14 per 100000 populations and the standardizedannual incidence rate was estimated to be 8.1 per100000 populations. In industrialized nations such

Introduction

The liver is considered as major organ involved inthe body’s defense against bacteria and foreignmacromolecules (1). It has the highest level ofenzymatic systems capable of transforming foreignchemicals, hencemetabolize, detoxify and activateexogenous (drugs, insecticides, etc.) or endogenouscompounds (steroids, fatty acids etc.). Liver containsa system of well-developed organelles that participatein the synthesis of albumin, fibrinogen, cholesterol

Graphical Abstract :


as the United States, ADRs account for up to 13%of cases of acute hepatic failure, while it is lesscommon (5%) in tropical countries such as India (4).The damage of liver cells can occur by severalmechanisms l ike oxidat ive stress, ant ioxidantdepletion, nitric oxide synthase activity, etc. Liverdisorders are of various types and due to the changingdiet style of the people there is gradually increasingof different types of hepatic disorder with theinvolvement of different pathogenesis. Basically, thereare three types of liver disorders; one is alcoholicliver disorders (ALD), second non-alcoholic liverdisorders (NALD) and the third one is a genetic liverdisorder (GLD) (5). A literature survey was carriedout to find out the current scenario of liver disordersfrom the various sources and which compiled andshown in Table I.

Metabolism of drugs and chemicals takes placelargely in the liver, which accounts for the organ’ssusceptibility to metabolism-dependent hepatic injury(3). The pathogenesis of liver injury are initiated bythe participation of a toxic agent or by the bioactivation to chemically reactive metabolites (6).These metabolites can be electrophilic chemicals orfree radicals, that either elicits an immune responseor protein dysfunction, l ipid peroxidation, DNAdamage, oxidative stress and depletion of reducedglutathione (7, 8). The pathogenesis of the liverdamage involve all cells (hepatocytes, kupffer, stellateand endothelial cells) present in the l iver viaapoptosis, necrosis, ischemia and regeneration, allprocesses leading to altered gene expression asshown in Fig. 1.

Allopathic medicine is widely used to refer to thebroad category of medical practice that is sometimescalled Western medicine, biomedicine, evidence-based medicine, or modern medicine. Ayurvedacomparatively takes a long period of time to cure,whereas in most of the cases allopathic treatmentcures the diseases within a short span of time. Thereare lot of allopathic hepatoprotective formulations ina market which is widely used by physicians, butdue to their serious ADR shown in table 2 and toxicityeffect they lose their identity in the market. But nosuch side effects can really be found in Ayurvedictreatment (9, 10). Scientific data have demonstratedthat there are numerous well known hepatoprotectiveherbal drugs with less ADR, which has beenpracticed in various traditional medical systems.Numerous ethno medicinal plants, which have beenproved to be hepatoprotective in the Ayurveda,Siddha, Unani and Amchi medicinal systems as wellas in other traditional medicinal practices aroundthe globe, are successfully tested in vivo for theirtherapeutic potential. On the other hand herbal drugsalso produce hepatic toxicity which raises someconcerns regarding herbal safety. Therefore, in thisreview, our main face has been made to highlightabout the present scenario of herbal drugs with theirharmful and beneficial effects.

Historical background of Liver disorders

This peculiar transformation of the liver was identifiedby the first anatomic pathologist, Gianbattista

TABLE I : Description of several types of Hepatic disorders.

Liver disorders Sub-type of liver disorders

1. Hepatitis • Viral hepatitis• Autoimmune hepatitis• Alcoholic hepatitis

2. Cirrhosis

3. Fatty liver • NASH• Vascular• Budd-Chiari syndrome• Hepatic Veno-occlusive disease• Portal hypertension• Nutmeg liver

4. Alcoholic liver disease

5. Liver failure

6. Hepatic encephalopathy

7. Acute liver failure

8. Liver abscess • Pyogenic• Amoebic

9. Hepatorenal syndrome

10. Peliosis hepatis

11. Metabolic Disorders • Wilson’s Disease• Hemochromatosis

12. Gallbladder • Cholecystitis• Gallstones/Cholecystolithiasis• Cholesterolosis• Rokitansky-Aschoff sinuses• Postcholecystectomy syndrome• Porcelain gallbladder

13. Bile duct/Other biliary tree • Cholangitis• Secondary sclerosing cholangitis• Cholestasis/Mirizzi’s syndrome• Biliary fistula• Haemobilia• Gallstones/Cholelithiasis

14. Common bile duct • Choledocholithiasis• Biliary dyskinesia

15. Sphincter of Oddidysfunction


Fig. 1: Pathophysiology of hepatic injury (Nonalcoholic steatohepatitis (NASH), Cirrhosis) including oxidative stress, increaseinflammatory cytokines, impaired mitochondrial electron transport chain with protective DNA BER pathways for liverprotection. (AP-1 Activator protein-1, BER base excision repair, APE/Ref-1Human apurinic (apyrimidinic) endonuclease/redox-factor 1, TNFα tumor necrosis factor, IL-1 Interleukin).

TABLE II : Name of allopathic medicine with their adversedrug reactions.

Sr. No. Name of allopathic medicine Active constituents of allopathic medicine ADR (Adverse Drug Reactions)

1. ESSENTIALE-L (Nicholas Piramal) Essential phospholipids, linoleic acid, Nausea, stomach upset skin rash acuteunseat fatty acid, Lecithin. toxicity, contraindicated during pregnancyDose: 350 mg oral capsule

2. HEPA MERZ (Win-Medicare) L-Ornithine L-Aspartate Hyperuricaemia, Lacrimation,Dose: 5 g/10 ml Skin rashes, Sneezing

3. LIVOSIL FORTE (CENTAUR) Silymarin 140 mg, Thiamine 5 mg, Bloating, dyspepsia, nausea and irregularRiboflavin 5 mg, Pyridoxine 1.5 mg, stools, at high dose laxation.Niacinamide 7.5 mg, Pantothenic acid 25 mg,Vitamin B12.Dose : 250 mg Capsule

4. MECOLIN (STADMED) Tricholine Citrate 0.55 gm and Abdominal pain, Diarrhea, Flatulence,Sorbitol 7.15 gm in each 10 ml. Hyperuricaemia, Lactic acidosis, UrticariaDose: 10 ml syrup

5. SILYBON-70 (Micro Labs) Silymarin Nausea, stomach upset skin rash acute

Dose: 70 mg/tablet toxicity, contraindicated during pregnancy

6. SORBILINE (Franco-Indian) Sorbitol 7.15 gm, Tricholine citrate 550 mg Abdominal pain, Diarrhea, Flatulence,Dose: 200 ml Syrup Hyperuricaemia, Lactic acidosis, Urticaria


Morgagni in his 500 autopsies published in 1761 butthe name of “cirrhosis” (greek=orange color) was givenby laennec in 1826 because of the yellowish-tan colorof the cirrhotic liver. Only in 1930, one hundred yearslater, however, the first theory as to the pathogenesiso f th is d isorder was advanced by roess le :parenchymal degeneration, regeneration and scarringwhich is now understood according to the followingsequence: injury, degeneration, fibrosis, formation offibro-vascular membranes, parenchymal dissectioninto nodules, rearrangement of blood circulation andcirrhosis (11). Thomas Earl Starzl (born March 11,1926) is an American physician, researcher, and isan expert on organ transplants. He performed thefirst human liver transplants in 1963, and the firstsuccessful human liver transplant in 1967, and hasoften been referred to as “the father of moderntransplantation” (12). In 1976, Dr. Blumberg won theNobel Prize in Medicine for his discovery of thehepatitis B virus. He and his colleagues discoveredthe virus in 1967, developed the blood test that isused to detect the virus, and invented the firsthepatitis B vaccine in 1969 (13). Four years afterdiscovering the hepatitis B virus, Drs. Blumberg andMillman developed the first hepatitis B vaccine, whichwas initially a heat-treated form of the virus (14).The hepatitis C virus was initially isolated from theserum of a person with non-A, non-B hepatitis in1989 by Choo and colleagues. The US Food andDrug Administration (FDA) approved the first-evertreatment for hepatitis C in 1991 (15). HAV was firstdiscovered in 1973 by Steven M. Feinstone as anonenvoloped, spherical, positive stranded RNA virusand their vaccine was first successfully invented byMaurice Hilleman at Merck (16). In this way thevarious vaccines were invented for the treatment ofvarious viral induced liver disorders which is still goingon with time. Natural remedies represent a $1.8billion market in the United States, and a singleherbal preparation, Silymarin, which is used almostexclusively for liver diseases, amounts to $180 millionin Germany alone. Marketing of herbals tripledbetween 1992 and 1996, and nearly a third ofoutpatients attending liver clinics use these products(17). Use of herbal medicines can be traced back asfar as 2100 B.C. in ancient China (Xia dynasty) andIndia (Vedic period). The first written reports dateback to 600 B.C. with the Caraka Samhita of Indiaand the early notes of the Eastern Zhou dynasty of

China that became systematized around 400 B.C.Milk thistle extracts were used as early as the 4thcentury B.C., became a favored medicine forhepatobiliary diseases in the 16th century, andexperienced a revival in central Europe in the late1960s (17, 18). Scientific data demonstrated thatIn 1971 Silymarin was f irst reported for theirhepatoprotective action against ethanol inducedhepatotoxicity in experimental rats and further provedasantidote for Amanita phalloides intoxication in therat in 1975 (19-21).

Herbal induce hepatoprotection/Herbal induced hepatotoxicity:HIHP/HIHT

Herbal induce hepatoprotection: HIHP

Minimizing side effects of medicines and increasingtherapeutic efficacy of medicines is the basic needof today. Alternative system of medicine proven forminimizing side effects by using various safe systemslike Ayurveda, Unani etc. Traditional, complementaryand alternative medical (TCAM) systems which areused by 80% of people in the so-called developingworld, by 360 million people in China and by around150 million citizens and 300,000 registered healthcareprofessionals in Europe (10). The therapy based ontraditional Chinese medicine (TCM) uses variousherbs. The time tested contribution of the herbs inthe traditional systems of medicine.

The herbal drugs are traditionally used in thetreatment of liver diseases caused by viral hepatitis,alcohol, toxic drugs and plant toxins. Silymarin fromSi lybum mar ianum, andrographo l ide f romAndrographis paniculata, curcumin from Curcumalonga, picroside and kutkoside form Picrorrhizakurroa, phyl lanthin and hypophyl lanthin f romPhyllanthus niruri, glycyrrhizin from Glycyrrhiza glabraare traditionally used in the treatment of l iverd iseases and represent the phy tochemica lconstituents and have been studied for their chemicaland biological profile and clinical efficacy. Theseshow hepatoprotection due to antioxidant effect, butother effects like immunomodulatory, antiviral, anti-inflammatory, anti-fibrotic, membrane stabilizing andantiprotozoal activities are also documented (22). Aliterature survey was carried out to find out the currentscenario of hepatoprotective herbal plants from thevarious sources and which compiled in Table III.


TABLE III : List of hepatoprotective herbal plants.

S. Biological Family Active Extract Part used Causative agent Mechanism ReferencesNo. sources component for hepatotoxicity of action

1. Acalypha Euphorbiaceae Flavonoids Methanol Leaves CCL4 Antioxidant, Free (23)racemosa radical scvanging

2. Actinidias Actinidiaceae Flavonoids Ethanol Roots Alcohol Antioxidant (24)deliciosa

3. Aegle Rutaceae γ-sitosterol, Ethanol Leaves Alcohol Antioxidant (25)Marmelos aegelin, lupeol,

rutin, marmesinin,β-sitosterol,marmeline

4. Annona Annonaceae Aporphine Ethanol Leaves Alcohol Antioxidant (26)squamosal alkaloid

5. Anoectochilus Orchidoideae Kinsenoside Methanol Leaves CCL4 Antioxidant, Free (27)formosanus radical scvanging

6. Achillea Asteraceae Caffeic acid Methanol Whole plant D-galactosamine Antioxidant (28)millefolium

7. Andrographis Acanthaceae Andrographolide Ethanol Aerial parts PCM Antioxidant (29)paniculata

8. Aspalathus Theaceae Catechin Aqueous Leaves CCL4 Antioxidant, Free (30)linearis Flavonoids radical scvanging

9. Bacopa Plantaginaceae Bacoside A Isolated Whole plant Nitrosodiethyla- Free radical (27)monniera compound mine scvanging

(ROS inhibition)

10. Bauhinia Leguminosae Kaempferol Ethanol Stem bark CCL4 Free radical (31)variegate scvanging

(ROS inhibition),Antioxidant

11. Berberis Berberidaceae Flavonoids Methanol Leaves PCM Antioxidant (32)tinctoria

12. Boswellia Burseraceae Boswellic n- Hexane Oleo gum resin CCL4 Antioxidant (33)

serrate acid, quercetin

13. Butea superb Papilionaceae Flavonoids Ethanol Stem bark CCL4 Antioxidant (34)

14. Curcuma Zingiberaceae Curcumin Ethanol Rhizomes Thioacetamide Antioxidant, Free (35)longa radical scvanging

15. Cassia Fabaceae Anthraquinones, n-heptane Leaves PCM Antioxidant (36)fistula flavonoids

16. Cajanus Fabaceae Methulcajanone, Protein Leaves PCM Significantly reduce (37)indicus cajaminose, fraction the liver enzyme

lupeol level, Antioxidant,Antioxidant, Freeradical scvanging

17. Capparis Capparidaceae Cappariloside Ethanol Roots CCL4 Antioxidant (38)spinosa A, Stachydrin

18. Cassia Leguminosae Achrosin, Aqueous Roots CCL4 Antioxidant (39)occidentalis aloeemodin,

emodin

19. Careya Myrtaceae Flavonoids Methanol Stem bark CCL4 Significantly reduce (40)arborea the liver enzyme

level, Antioxidant

20. Carmellia Theaceae Caffeine Aqueous Leaves CCL4 Antioxidant (41)sinensis

21. Cichorium Asteraceae Flavonoids Ethanol Leaves CCL4 Antioxidant (42)intybus

22. Commiphora Burseraceae Lupeone Ethanol Aerial parts CCL4 Antioxidant (43)opobalsamum

23. Croton Euphorbiaceae Flavonoids Essential oil Leaves PCM Significantly reduce (44)zehntneri the liver enzyme

level, Antioxidant


24. Curculigo Amaryllidaceae Flavonoids Methanol Rhizomes CCL4 Antioxidant, Free (45)orchioides radical scvanging

25. Diospyros Ebenaceae β-sitosterol, Methanol Bark CCL4 Antioxidant (46)malabarica Gallic acid,

betulin

26. Enicostema Gentianaceae Apigenin, Ethanol Leaves and CCL4 Antioxidant, Free (47)axillare Flavonoids roots radical scvanging

27. Epaltes Compositae Flavonoids Aqueous Whole plant CCL4 Antioxidant, Free (48)divaricate radical scvanging

28. Ervatamia Apocynaceae Coronaridine, Methanol Leaves CCL4 Antioxidant, Free (49)coronaria heyneanine, radical scvanging

voacristine,voacamine

29. Equisetum Equisetaceae Onitine, Ethanol Leaves PCM Antioxidant (28)arvense kaempferol-3o-

glucoside

30. Eclipta Asteraceae Coumestans, Ethanol Aerial part CCL4 Significantly reduce (50)alba wedelolactone, the liver enzyme

Flavonoids level, Antioxidant

31. Euphorbia Euphorbiaceae Flavonoids Aqueous Aerial parts CCL4 Antioxidant (51)antiquorum

32. Foeniculum Apiaceae Essential oils Ethanol Fruit CCL4 Reduction in (50)vulgare ROS level

33. Ginkgo Ginkgoaceae Flavonoids Dry Leaves CCL4 Antioxidant (52)biloba

34. Garcinia Clusiaceae Garcinone E Ethanol Whole plant CCL4 Reduction in (50)mangostana ROS level

35. Glycyrrza Leguminosae Glycyrrhzin Ethanol Roots CCL4 Antioxidant (53)glabra

36. Hygrophila Acathaceae Mystic, palmatic, Aqueous Roots CCL4 Antioxidant, Free (54)spinosa radical scvanging

37. Ichnocarpus Apocynaceae Flavonoids CHCl3 Whole plant PCM Antioxidant, Free (55)frutescens radical scvanging

38. Indigofera Fabaceae Flavonoids Ethanol Whole plant CCL4 Antioxidant, Free (56)

trita radical scvanging

39. Launaea Asteraceae Glutenol, Ethanol Leaves and roots CCL4 Antioxidant (47)pinnatifida Hopenol-b

40. Leucophyllum Scrophulari- diayangambin, Methanol Aerial parts CCL4 Antioxidant (57)frutescens aceae epiyangambin,

diasesartemin,andepiashantin

41. Mamordica Cucurbit- B-sitosterol, Ethanol Roots CCL4 Antioxidant, Free (58)dioica aceae saponins, radical scvanging

glycosides,triterpenes ofursolic acid,hederagenin,

oleanolic acid,aspiranosterol,stearic acid,gypsogenin

42. Nelumbo Nymphae- nuciferine, Ethanol Flowers CCL4 Antioxidant (59)nucifera aceae roemerine,

anonaine

43. Nigella Ranuncul- Lophenol, Ethanol Seeds CCL4 Antioxidant (60)sativa aceae gramisterol,

obtusifoliol

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44. Ocimum Lamiaceae Aesculectin, Ethanol Leaves Rifampicin Significantly (61)sanctum Aesculin, reduce the liver

Apgenin, Caffiec enzyme level,acid, Chlorgenic Antioxidantacid, Apigenin,

Apigenin-oglucuronide,Triacontanol

ferulate,Vicenin-2,Circineol,

Gallic acid,Galuteolin,Isorientin,Isovitexin,Circineol,Luteolin,

Molludistin,Orientin,

Urosolic acid,Vallinin, Viceni

45. Parkinsonia Fabaceae glycosides, Ethanol Leaves CCL4 Antioxidant (62)aculeate flavonoids

46. Pergularia Asclepiad- quercetin-3- Ethanol Aerial parts CCL4 (63)daemia aceae glucoside

47. Phoenix Palmae Carotenoids, Aqueous Pits and flesh CCL4 Significantly reduce (64)dactylifera anthocyanins, the liver enzyme

procyanidins, level, Antioxidant,flavonoids decrease the

level of ROS

48. Phyllanthus Euphorbiaceae Coumarins, Methanol Leaves CCL4 Antioxidant (65)polyphyllus flavonoids

49. Pterocarpus Fabaceae Santalin, Aqueous Stem bark CCL4 Antioxidant (66)santalinus flavonoids

50. Punica Punicaceae Flavonoids Powdered Peel CCL4 Antioxidant (67)granatum drug

51. Phyllanthus Euphorbiacea Phyllanthus Alcoholic Whole plant PCM Significantly reduce (68)niruri protein the liver enzyme

level, Antioxidant

52. Raphanus Cruciferae Flavonoids Aqueous Seeds CCL4 Antioxidant (69)sativus

53. Rhododendron Ericaceae Taraxerol, Ethanol Leaves CCL4 Antioxidant (70)arboretum Hyperoside,

Quercetin,Betulinic Acid

54. Rubia Rubiaceae Ruberythric Methanol Whole plant CCL4 Antioxidant (71)cordifolia acid,

Anthraquinone

55. Sarcostemma Asclepiad- Bergenin, Ethyl acetate Aerial parts CCL4 Antioxidant (72)brevistigma aceae brevine,

brevinine,sarcogenin,

sarcobiose andflavonoids

56. Saponaria Caryophyll- Saponins, Powdered drug Flower buds CCL4 Antioxidant (67)officinalis aceae sapindoside

A and B,kaempferol,quercetin,

B-sitosterol,palmitic,stearic,oleic,

linoleicand

57. Smilax Liliaceae Flavonoids Ethyl acetate Fruits CCL4 Reduction in (73)chinensis ROS level

58. Solanum Solanaceae Flavonoids Ethanolic Seeds CCL4 Antioxidant, Free (74)

nigrum radical scvanging


59. Solanum Solanaceae Carbohydrates, Ethanol Roots CCL4 Antioxidant, Free (75)trilobatum saponins, radical scvanging

phytosterols,tannins,

flavonoidsand cardiacglycosides,Sobatum,

β-solamarine,solasodine,

solaine

60. Swertia Gentianaceae loganic acid, Ethanol Roots PCM Antioxidant, Free (76)longifolia gentiopicroside, radical scvanging

gentiolactone

61. Syzygium Myrtaceae β-caryophyllene, Ethanol Roots CCL4 Antioxidant, Free (77)aromaticum Eugenol radical scvanging

62. Silybum Asteraceae Silymarin Ethanol Whole plant CCL4 Antioxidant (78)marianum

63. Terminalia Combretaceae Flavonoids Aqueous Ethanol Whole plant CCL4 Antioxidant (79)belerica

64. Thespesia Malvaceae Alkaloid, Methanol Aerial parts CCL4 Antioxidant (80)lampas Flavonoids

65. Trigonella Disogenin, Ethanol Seed Ethanol Antioxidant, (81)foenum gitogenin, Help in inhibitinggraecum neogitogenin, the metaboloism

homorientin of ethanol tosaponaretin, Acetaaldehydeneogigogenin or decrease

the formationof acetatae

66. Urtica Urticaceae Flavonoids, Ethanol Leaves CCL4 Antioxidant (82)parviflora alkaloids,

sterols,tannins

67. Vetiveria Poaceae Valencene Methanol Roots Ethanol Antioxidant (83)zizanioides

68. Vicia Fabaceae Quercetin, Ethanol Aerial parts CCL4 Significantly reduce (84)calcarata kaempferol the liver enzyme

level, Antioxidant

69. Xylopia Annonaceae Flavonoids Crude Stem bark Alcohol Antioxidant, Free (85)phloiodora essential oil & leaves radical scvanging

Pharmacological potential of Hepatoprotective herbalplants:

There are numerous plants and traditional formulationsavailable for the treatment of liver diseases. About600 commercial herbal formulations with claimedhepatoprotective activity are being sold all over theworld. Around 170 phytoconstituents isolated from110 plants belonging to 55 families have been reportedto possess hepatoprotective activity. In India, morethan 93 medicinal plants are used in differentcombinations in the preparations of 40 patentedherbal formulations (86). However, only a smallproportion of hepatoprotective plants as well asformulat ions used in tradi t ional medicine arepharmacologically evaluated for their safety andefficacy. Early of 90s century, researchers are

working on exploring the potential of herbal extractsto treatliver disorders. The list of trade names andmanufacture of multiple herbal preparations forhepatoprotection is shown in Table IV (86).

Herbal induced hepatotoxicity: HIHT

As there are always two sides of the coin, beneficialand harmful effects of the medicines as well.The hepatotox ic i ty of herbs was extensivelyacknowledged. Herbal remedies have been knownas hepatotoxins causing numerous liver damages.The adverse effects of herbal products must becompletely reported to health care providers in orderto reduce unwanted side effects of alternativemedicines. In this context, considering overall positiveeffects and pleiotropic effects of herbal drugs, there


TABLE IV : Trade name and manufacture of multiple herbal preparations for hepatoprotection.

S.No. Name of the formulation Plants used in the formulation

1. BONLIV M/S Pharm Products, Thanjavur Eclipta alba, Wedelia calendulacea, Phyllanthus niruri, Tribulusterrestris, Glycyrrhiza glabra.

2. LIVOZON M/S Hind Chemicals, Kanpur Phyllanthus niruri, Tinospora cordifolia, Triphala (Terminalia chebula,Terminalia bellarica, Emblica offficinalis).

3. BILGERIN M/S Standard Pharma-Remedies, Calcutta Andrographis paniculata, Apium graveolens, Asteracantha longifolia,Operaculina turpethum, Swertia chirata, Trachyspermum ammi,Trigonella foenumgraecum.

4. VIMLIV M/S Solumiks Bombay Boerhaavia diffusa, Cichorium intybus, Eclipta alba, Phyllanthussimplex, Picrorhiza kurroa.

5. TEFROLI M/S TTK Pharm Madras Andrographis paniculata, Eclipta alba, Ocimum sanctum, Tephrosiapurpurea, Terminalia chebula.

6. LIVOTRIT M/S Zandu Pharmaceuticals Bombay Andrographis paniculata, Boerhaavia diffusa, Eclipta alba, Operaculinaturpethum, Picrorhiza kurroa, Plumbago zeylanica, Rhamnus wightii,Tinospora cordifolia.

7. LIVOTONE M/S Herbals (ABS) Pvt. Ltd. Andrograhis paniculata, Apium graveolens, Asteracantha longifolia,M/S East India Pharm. Works., Calcutta Holarrhaenaantidysentrica, Rhamnus purshiana, Trigonella

foenumgraecum.8. LIVOSPIN M/S Herbals (ABS) Pvt. Ltd. Ammora rohituka, Andrographis paniculata, Embelia ribes, Tephrosia

purpurea, Ipomoea turpethum, Moringa oleifera, Oldenlandiacorymbosa, Salvia plebia, Swertia angustifolia.

9. LIVOSIN M/S Jupiter Pharm, Calcutta Avena sativa, Carica papaya, Ferula asafoetida, Mentha longifolia,Strychnosnuxvomica, Panicum miliaceum, Podophyllum hexandrum,Cassia angustifolia, Zingiber officinale.

10. LIVOPEP M/S Anakam Lab, Calcutta Andrographis paniculata, Apium graveolens, Asteracantha longifolia,Oldenlandiacorymbosa, Trachyspermum ammi, Trigonellafornumgraecum.

11. LIVOMYN M/S Charak Pharmaceuticals (India) Ltd. Andrographis paniculata,Aphanamixis polystachya, Boerhaavia

Samalkha diffusa, Caesalpinia bonduc, Casearia esculenta, Cassia sophera,Eclipta alba, Embeliaribes, Fumaria officinalis, Holarrhaenaantidysentrica, Hordeum vulgare, Lagenaria siceraria, Lawsonia(Haryana) inermis, Ocimum sanctum, Operculinaturpethum, Oryzasativa, Piper longum, Plumbago zeylanica, Rosa hinensis, Swertiachirata, Tephrosia purpurea, Tinospora cordifolia, Zingiber officinale.

12. LIVOKIN M/S Herbo-Med, Calcutta, Aristata Andrographis paniculata, Apium graveolens, Carum copticum, Berberisaristata, Cichorium intybus, Cyperus rotundus, Eclipta erecta, Ipomoeaturpethum, Oldenlandia corymbosa, Picrorhiza kurroa, Plumbagozeylanica, Solanum nigrum, Tephrosia purpurea, Terminalia chebula,Trigonella foenumgraecum.

13. LIVODIN M/S Madona Pharm. Res., Calcutta Aloe indica, Aphanamixis polystachya, Andrographis paniculata,Boerhaaviadiffusa, Carum copticum, Cassia angustifolia, Eclipta alba,Embeliaribes, Holarrhaena antidysentrica, Hygrophila spinosa,Oldenlandia corymbosa, Piper nigrum, Solanum xanthocarpum,Tinospora cordifolia.

14. LIVIN M/S Arya Audhadhi Pharm., WorksIndore Acorus calamus, Andrographis paniculata, Aphanamixis olystachya,Baliospermummontana, Boerhaavia diffusa, Cassia sophera, Citruluscolocynthis, Eclipta alba, Embelia Ribes, Ficus religiosa, Jateorhizapalmata, Ocimum sanctum, Lawsoniainermis, Operculina turpethum,Piper Chaba, Plumbago zeylanica, Salvadorapersica, Tephrosiapurpurea, Terminalia chebula, Tinospora cordifolia, Zingiberofficinale,Trachyspermum ammi.

15. LIVER M/S Bhatiya Aushadh Normanshala, Gujarat Achillea millifolium, Aconitum heterophyllum, Cassia occidentalis,Embelia ribes, Piper longum, Solanum nigrum, Tamarix gallias,Swertia chirata.

16. LIVERTONE M/S Gamber Laboratories, Bombay Emblica officinalis, Picrorhiza kurroa, Rheum palmatum, Terminaliabellirica, Terminalia chebula.

17. LIVER RIN M/S Herbs ERA Pharmaceuticals, Andrographis paniculata, Melia azerdarach, Oldenlandia corymbosa,Udayrajpur (WB) Picrorhizakurroa, Rubia cordifolia, Cassia angustifolia.

18. LIVERGEN M/S Standard Pharmaceuticals, Calcutta Andrographis paniculata, Apium graveolens, Asteracanthalongifolia, Cassia angustifolia, Trachyspermum ammi, Trigonellafoenumgraecum.

19. LIVATONA M/S Scientific Research Industries Andrographis paniculata, Asteracantha longifolia, Glycyrrhiza glabra,Pvt. Ltd., Lucknow Odenlandia corymbosa, Senna angustifolia, Trachysparmum ammi,

Trigonella foenumgraecum


20. LIVARIN M/S Patiala Ayurvedic Pharmacy, Sirhind Andrographis paniculata, Aloe barbadensis, Boerhaavia diffusa,Cassia fistula,Picrorhiza kurroa, Solanum nigrum, Tecoma undulata.

21. LIVA-16 M/S Maduna Pharmaceuticals Research, Calcutta Alstonia scholaris, Andrographis paniculata, Boerhaavia diffusa,Cassiaangustifolia, Eclipta alba, Hygrophila spinosa, Oldenlandiacorymbosa, Piperlongum, Solanum xanthocarpum, Tinosporacordifolia, Vernonia anthelmintica

22. LIVA M/S Hebid (India), Pvt. Ltd., Calcutta Andrographis paniculata, Apium graveolens, Berberis aristata,Boerhaavia diffusa, Carica papaya, Asteracantha longifolia, Cassiaangustifolia, Plumbago zeylanica, Solanum nigrum, Tephrosia hirta,Terminalia arjuna, Trachyspermum ammi.

23. LIV-77 M/S Globe Pharmaceuticals, Jullundar City Boerhaavia diffusa, Cichorium intybus, Berberis aristata, Ecliptaalba, Heliotropum strigosum, Paunella domestica,Tinospora cordifolia,Trigonellafoenumgraecum.

24. KAMALAHAR M/S Khatore Ayurvedic Orissa Tecoma undulata, Phyllanthus urinaria, Embelia ribes, TaraxacumPharmaceutials, Barbil officinale, Nyctanthes arbortristis, Terminalia arjuna.

25. STIMULIV M/S Francho-Indian Pharmaceuticals Andrographis paniculata, Eclipta alba, Fumaria officinalis, CynaraLtd., Bombay scolymus.

26. HEPATOCARD M/S Surajmani EnterprisesA-1, Picrorhiza kurroa, Andrographis paniculata, Phyllanthus amarus,Daman, Somnath Road, Dabhei Daman Boerhaaviadiffusa, Azadirachta indica, Triphala (Terminalia chebula,

Terminalia bellirica,Emblica officinalis), Eclipta alba, Zingiberisofficinalis, Piper longum.

27. Liv 52 (Himalaya Drug Co, Bangalore) Achillea millefolium, Capparis spinosa, Cassia occidentalis, Cichoriumintybus, Solanum nigrum, Tamarix gallica, Terminalia arjuna

28. Livergen (Standard Pharmaceuticals, Andrographis paniculata, Apium graveolens, Asteracantha longifolia,Serampore, West Bengal) Cassia angustifolia, Trachyspermum ammi, Trigonella foenumgraecum

29. Livokin (Herbo-med, Kolkata) Andrographis paniculata, Apium graveolens, Berberis lycium, Carumcopticum, Cichorium intybus, Cyperus rotundus, Eclipta alba, Ipomoeaturpethum, Oldenlandia corymbosa, Picrrorhiza kurroa, Hygrophilaspinosa, Plumbago zeylanica, Solanum nigrum, Tephrosia purpurea,Terminalia arjuna, Terminalia chebula, Trigonella foenumgraecum

30. Octogen (Plethico Pharmaceuticals Ltd., Indore) Arogyavardhini rasa, Phyllanthus niruri

31. Stimuliv (Franco-Indian Pharmaceuticals Andrographis paniculata, Eclipta alba, Phyllanthus niruri, JusticiaPvt. Ltd., Mumbai) procumbens

32. Tefroliv (TTK Pharma Pvt. Ltd., Chennai) Andrographis paniculata, Eclipta alba, Ocimum sanctum, Phyllanthusniruri, Picrrorhiza kurroa, Piper longum, Solanum nigrum, Tephrosiapurpurea, Terminalia chebula

TABLE V : List of hepatotoxic herbal plants.

Sr. Name of the plant which cause Hepatotoxicity ReferenceNo. hepatotoxicity

1. Lanata camra Linn.(verbenaceae) Inhibition of bile secretion (87-88)2. Senecio vulgaris L.(Compositae) Causes liver ribosomal aggregates (89)3. Cycas revolute(Cycadaceae) Produces toxic intermediate by enzymep450 (90,91)4. Amanita Phalloides(Amanitaceae) Inhibition of biliary secretion (92-94)5. Blighia sapida (Ackee)(Sapindaceae) Inhibits several enzymes involved in the breakdown of

acyl COA compounds (95,96)6. Piper methysticum (Kava)(Piperaceae) Block several subtypes of the enzymeCytochrome p450 (97-101)7. Comfrey(Symphytum) It produces hepatic veno-occlusion (102-105)8. Larrea tridentate(Zygophyllaceae) Inhibition of bile secretion and hepatotoxicity of liver cells (106)9. Aesculus hippocastanum (Sapindaceae) Causes jaundice (The cause of liver injury attributed to horse

chestnut extracts is unknown, but is likely to be idiosyncratic.) (107)10. Chelidonium majus(Papaveraceae) Acute Hepatitis (108)11. Actaea Racemosa(Ranunculaceae) Hepatic necrosis and bridging fibrosis. (109)12. Serenoa repens(Arecaceae) Glutathione depletion, cirrhosis, (110)13. Symphytum officinale L.(Boraginaceae) Hepatic veno occlusive disease (111)14. Teucrium chamaedrys L(Lamiaceae) Acute and chronic hepatitis, immunoallergic factor,hepatic failure (112)15. Piper methysticum(Piperaceae) Glutathione depletion,immunoallergic factor,hepatic failure (113)16. Cassiaangustifolia (Caesalpinaceae) Acute hepatitis (114-116)17. Azadirachta indica (Meliaceae) Rey’s syndrome (114)18. Atractylis gummifera(Asteraceae) Mitochondrial toxicity, Acute liver failure (117-119)19. Callilepis laureola (Asteraceae) Hepatic necrosis, Oxidative phosphorylation inhibition (120-121)20. Amantia phalloides (Amanitaceae) Liver toxicity (94)


is a need to explore the side effects and adversedrug reaction (ADR) of herbal drugs with referenceto the hepatotoxicity which is mentioned in Table V.

Conclusion

Herbal plants or Ayurvedic drugs are the traditionalmedication trends for the treatment of variousoverwhelming disorders. The liver disorders are oneof the serious condition which increases day by daydue to changing dietary habits and lifestyle. Livertoxicity is very common and which impairs variousnormal physiological functions like metabolism,synthesis, storage and detoxification of many endoand exogenous compounds. There are many pathwaysinvolve in the pathogenesis of liver toxicity, so thereis need to develop or find drugs which act by multiplepathways to treat these type of toxicity. Furtherprotective role of Ayurvedic drugs is not ignoredbecause, Ayurvedic drugs are also acts by multiplepathways and shown full protection in liver disorders

so there is a need to study different herbal drugsand their protective mechanism for liver disorders. Inthis review, we have demonstrated various herbaldrugs with reference to their hepatoprotective role,hepatotoxic action and their various advantageousover al lopathic medicines. Scienti f ic evidencereported that in Ayurveda, there numerous herbswhich produce ser ious adverse events o fhepatotoxicity. Our motive is not to discourage theuse of herbal drugs, but aware all researchers aboutsuch a serious matter of herbal drugs induced toxicityand to reconsidered such herbal drugs.

Acknowledgments

The authors acknowledge Sh. Parveen Garg ChairmanI.S.F College of Pharmacy for providing facilities

Disclosure Statement

No competing financial interest exists

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