Review Article Herbal Induced Hepatoprotection and Hepatotoxicity : A Critical Review Onkar Bedi 1 , Krishna Reddy V. Bijjem 1 , Puneet Kumar 1 and Vinod Gauttam 2 * Departments of 1 Pharmacology & 2 Pharmacogonosy, 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 homecoming to nature. In the present situation, the dietary changes lead to liver disorders like non-alcoholic and alcoholic fatty liver disorders. India is one of the world’s twelve leading biodiversity centers with the presence of over 45,000 diverse plant species, out of this about 15,000-20,000 plants have good medicinal and therapeutic properties of which only about 7,000-7,500 are being used by traditional practitioners. Hepatic injury accounts for 3.5%-9.5% of all adverse drug reaction reports and up to 14.7% of fatal adverse reaction. Hepatic disorders/toxicity can occur by several mechanisms like Cytochrome P450 activation, lipid peroxidation, Induction of nitric acid synthase, mitochondrial dysfunction, activation of pro-inflammatory mediators and Bile acid-induced liver cell death. There are a number of drugs or therapies available for the treatment of hepatic disorders, but still there is a need for the novel drug discovery which can target multiple disease pathways. Traditional medicines have exhaustive ancient and scientific literature for curing a lot of life threatening disorders with less or no side effects. There are number of scientifically proved hepatoprotective herbal drugs like Andrographis paniculata, Ocimum sanctum, Solanum nigrum, Silybum marianum, Phyllanthus niruri etc. which are widely used for the treatment of liver disorders. However, there are various herbal plants and 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 crucial aspects of phytoconstituents with reference to their hepatoprotective as well as hepatotoxic effects linked to 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 of Pharmacy, Moga (Punjab) India; E-mail [email protected], Mobile number: 09876499479, Phone number: 01636-324200, 324201, Fax number: 01636-239515 (Received on April 12, 2015)
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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 :
8 Bedi, Bijjem, Kumar and Gauttam Indian J Physiol Pharmacol 2016; 60(1)
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.
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
Indian J Physiol Pharmacol 2016; 60(1) Herbal Induced Hepatoprotection And Hepatotoxicity 9
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)
10 Bedi, Bijjem, Kumar and Gauttam Indian J Physiol Pharmacol 2016; 60(1)
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).
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.
Indian J Physiol Pharmacol 2016; 60(1) Herbal Induced Hepatoprotection And Hepatotoxicity 11
TABLE III : List of hepatoprotective herbal plants.
S. Biological Family Active Extract Part used Causative agent Mechanism ReferencesNo. sources component for hepatotoxicity of action
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
Indian J Physiol Pharmacol 2016; 60(1) Herbal Induced Hepatoprotection And Hepatotoxicity 15
TABLE IV : Trade name and manufacture of multiple herbal preparations for hepatoprotection.
S.No. Name of the formulation Plants used in the formulation
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
Indian J Physiol Pharmacol 2016; 60(1) Herbal Induced Hepatoprotection And Hepatotoxicity 17
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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