MohamedSaleemT.Setal.|Int.J.Res.Pharm.Sci.

Vol1,Issue1,15,2010

www.ijrps.pharmascope.org

ISSN:09757538 ReviewArticle

HepatoprotectiveHerbsAReview

T.S.MohamedSaleem*,C.MadhusudhanaChetty,S.Ramkanth,V.S.T.Rajan, K.MaheshKumar,GauthamanK# DepartmentofPharmacology,AnnamacharyaCollegeofPharmacy,Rajampet516126 # DepartmentofPharmacognosy,HimalayanPharmacyInstitute,Majhitar,Sikkim ABSTRACT Liverisavitalorganplayamajorroleinmetabolismandexcretionofxenobioticsfromthebody.Liverinjuryor liverdysfunctionisamajorhealthproblemthatchallengesnotonlyhealthcareprofessionalsbutalsothephar maceuticalindustryanddrugregulatoryagencies.Livercellinjurycausedbyvarioustoxicchemicals(certainanti biotic, chemotherapeutic agents, carbon tetrachloride (CCL4), thioacetamide (TAA) etc.), excessive alcohol con sumptionandmicrobesiswellstudied.Theavailablesyntheticdrugstotreatliverdisordersinthisconditionalso causefurtherdamagetotheliver.Hence,Herbaldrugshavebecomeincreasinglypopularandtheiruseiswide spread.Herbalmedicineshavebeenusedinthetreatmentofliverdiseasesforalongtime.Anumberofherbal preparationsareavailableinthemarket.Thepresentreviewisaimedatcompilingdataonpromisingphytochemi calsfrommedicinalplantsthathavebeentestedinhepatotoxicitymodelsusingmodernscientificsystem. Keywords:Herbaldrugs,LiverInjury,Carbontetrachloride(CCL4),Hepatotoxicity,Serumtransaminases. INTRODUCTION Liver is considered to be one of the most vital organs that functions as a centre of metabolism of nutrients such as carbohydrates, proteins and lipids and excre tion of waste metabolites. Additionally, it is also han dlingthemetabolismandexcretionofdrugsandother xenobiotics from the body thereby providing protec tion against foreign substances by detoxifying and eli minating them. The bile secreted by the liver has, among other things, plays an important role in diges tion. Liver cell injury caused by various toxicants such ascertainchemotherapeuticagents,carbontetrachlo ride, thioacetamide etc., chronic alcohol consumption andmicrobesiswellstudied.Enhancedlipidperoxida tionduringmetabolismofethanolmayresultindevel opment of hepatitis leading to cirrhosis. Since time immemorial, mankind has made the use of plants in the treatment of various ailments. The Indian Tradi tional Medicine like Ayurveda, Siddha and Unani are predominantly based on the use of plant materials. Herbaldrugshavegainedimportanceandpopularityin recent years because of their safety, efficacy and cost effectiveness. The association of medical plants with otherplantsintheirhabitatalsoinfluencestheirmedi cinal values in some cases. One of the important and
*CorrespondingAuthor Email:saleemcology@gmail.com Contact:+919701978543 Receivedon:17.11.2009 Revisedon:04.12.2009 Acceptedon:09.12.2009
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welldocumentedusesofplantproductsistheiruseas hepatoprotective agents. Hence, there is an ever in creasing need for safe hepatoprotective agent (Agar wal,2001). Hepatoprotectiveherbs Herbalbasedtherapeuticsforliverdisordershasbeen inuseinIndiaforalongtimeandhasbeenpopularized world over by leading pharmaceuticals. Despite the significant popularity of several herbal medicines in general, and for liver diseases in particular, they are still unacceptable treatment modalities for liver dis eases.Thelimitingfactorsthatcontributetothiseven tuality are (i) lack of standardization of the herbal drugs; (ii) lack of identification of active ingre dient(s)/principles(s);(iii)lackofrandomizedcontrolled clinicaltrials(RCTs),and(iv)lackoftoxicologicalevalu ation(Radhaetal.,2005).Theuseofnaturalremedies for the treatment of liver diseases has a long history, starting with the Ayurvedic treatment, and extending to the Chinese, European and other systems of tradi tionalmedicines.The21stcenturyhasseenaparadigm shifttowardstherapeuticevaluationofherbalproducts in liver disease models by carefully synergizing the strengths of the traditional systems of medicine with that of the modern concept of evidencebased medi cinal evaluation, standardization and randomized pla cebocontrolledclinicaltrialstosupportclinicalefficacy (Thyagarajanetal.,2002). A large number of plants and formulations have been claimed to have hepatoprotective activity. Nearly 160 phytoconstituents from 101 plants have been claimed

MohamedSaleemT.Setal.|Int.J.Res.Pharm.Sci.Vol1,Issue1,15,2010

topossessliverprotectingactivity.InIndia,morethan 87plantsareusedin33patentedandproprietarymul tiingredient plant formulations (Handa et al., 1986). Inspite of the tremendous advances made, no signifi cant and safe hepatoprotective agents is available in modern therapeutics. Therefore, due importance has been given globally to develop plantbased hepato protectivedrugseffectiveagainstavarietyofliverdis orders.Thepresentreviewisaimedatcompilingdata basedonreportedworksonpromisingphytochemicals frommedicinalplantsthathavebeentestedinhepato toxicitymodels. Flacourtiaindica The extracts of the aerial parts of Flacourtia indica (Burm.f.)Merr.,wereevaluatedforhepatoprotective properties.Inparacetamolinducedhepaticnecrosisin rat models, all extracts were found to reduce serum aspartatetransaminase(AST),serumalaninetransami nase (ALT) and serum alkaline phosphatase(ALP). The most significant reduction of the serum level of AST and ALT were exhibited bypetroleum etherand ethyl acetate extracts at a single oral of dose of 1.5g/kg of body weight with a reduction of 29.0% AST & 24.0% ALTlevelbypetroleumetherextract,and10.57%AST &6.7%ALTlevelbyethylacetateextractcomparedto paracetamol (3 g/kg of body weight) treated animals. Histopathological examination also showed good re covery of paracetamolinduced necrosis by petroleum ether and ethyl acetate extracts. On the other hand, the methanol extract did not show any remarkable effect on paracetamolinduced hepatic necrosis. The hepatoprotectiveeffectsexhibitedbypetroleumether and ethyl acetate extract might be mediated through the inhibition of microsomal drug metabolizing en zymes (Nazneen et al., 2008). But, in this study the dosetheyhaveusedistohighanditisnotsuccessful orrationaleforhumandose. Annonasquamosa The extracts of Annona squamosa (300 & 350 mg/kg bw)wereusedtostudythehepatoprotectiveeffectin isoniazid + rifampicininduced hepatotoxic model in albinoWistarrats.Therewasasignificantdecreasein total bilirubin accompanied by significant increase in the level of totalprotein and also significantdecrease in ALP, AST, and ALT in treatmentgroup as compared to the hepatotoxic group. In the histopathological study, the hepatotoxic group showed hepatocytic ne crosis and inflammation in the centrilobular region with portal triaditis. The treatment group showed mi nimalinflammation withmoderate portaltriaditis and their lobular architecture was normal (Saleem et al., 2008).Inanotherstudy,theprotectiveeffectwaseva luated in diethylnitrosamine induced hepatotoxicity. This study revealed that the extracts of Annona squa mosa exerted hepatoprotective effect and the plant extract could be an effective remedial for chemical inducedhepaticdamage(Rajetal.,2009).
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Silybummarianum The protectiveeffects of polyphenolic extracts of Sily bum marianum and Cichorium intybus on thioaceta mide induced hepatotoxicity in rat was investigated (Madanietal.,2008).Theextractswereinjectedtothe 1 rats,atadoseof25mgkg bodyweighttogetherwith thioacetamideatadoseof50mgkgbodyweight.Sig nificant decrease in the activity of aminotransferases, alkalinephosphataseandbilirubinwasobservedinthe groups treated with extracts and thioacetamide com paredwiththegroupthatwastreatedonlywiththioa + + cetamide.ThelevelofNa ,K andliverweightbetween differentgroupswasnotsignificantlyaltered.Thisfind ingssuggestedthehepatoprotectiveeffectofSilybum marianumandCichoriumintybusextractsonlivercells duetothepresenceofflavonoidsandtheirantioxidant effects(Madanietal.,2008). Chamomilecapitula The effect of ethanolic extract of Chamomile recutita capitula (400 mg kg1, P.O.) on blood and liver gluta thione, Na+ K+ ATPase activity, serum marker en zymes, serum bilirubin, glycogen and thiobarbutiric acid reactive substances against paracetamolinduced liverdamageinratshavebeenstudiedtofindoutthe possible mechanism of hepatoprotection. It was ob servedthatextractofChamomilerecutitahasreversal effects on the levels of abovementioned parameters inparacetamolhepatotoxicity(GuptaandMisra,2006) suggesting its hepatoprotective and/or hepato stimulantactivity. Cocciniagrandis Alcoholic extract of the fruits of Coccinia grandis Linn (Curcubitaceae)wasevaluatedinCCl4inducedhepato toxicity in rats and levels of AST, ALT, ALP, total pro teins, total and direct bilirubin were evaluated. At a dose level of 250 mg/kg, the alcoholic extract signifi cantly (p<0.05) decreased the activities of serum en zymes (AST, ALT and ALP) and bilirubin which were comparable to that of silymarin (Vadivu et al., 2008) revealingitshepatoprotectiveeffect. Wedeliacalendulacea The hepatoprotective activity of ethanolic extract of Wedelia calendulacea L. (Family: Asteraceae) was stu died against CCl4induced acute hepatotoxicity inrats. ThetreatmentwithethanolicextractofWedeliacalen dulacea showed a dosedependent reduction in CCl4 inducedelevatedserumenzymeactivitieswithparallel increase in total proteins and bilirubin, indicating the extract could enhance the return of noram functional status of the liver comparable to normal rats. The weight of the organs suchas liver, heart, lung, spleen and kidney in CCl4induced hepatic damaged animals that received ethanolic extract of Wedelia calendula cea showed an increase over CCl4treated control group(Murugaianetal.,2008).
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Prostecheamichuacana Methanol, hexane and chloroform extracts of Proste chea michuacana (PM) were studied against CCl4 induced hepatic injury in albino rats. Pretreatment with methanolic extract reduced biochemical markers of hepatic injurylevels demonstrated dosedependant reduction in the in vivo peroxidation induced by CCl4. Likewise,pretreatmentwithextractsofPMonparace tamolinduced hepatotoxicity and the possible me chanism involved in this protection were also investi gatedinratsafteradministeringtheextractsofPMat 200,400and600mg/kg.Thedegreeofprotectionwas measured by monitoring the blood biochemical pro files.Themethanolicextractoforchidproducedsignifi canthepatoprotectiveeffectasreflectedbyreduction intheincreasedactivityofserumenzymes,andbiliru bin.Theseresultssuggestedthatmethanolicextractof PM could protect paracetamolinduced lipid peroxida tiontherebyeliminatingthedeleteriouseffectsoftoxic metabolites of paracetamol. This hepatoprotective activity was comparable with sylmarin. Hexane and chloroformextractsdidnotshowanyapparenteffect. The findings indicated that the methanolic extract of PMcanbeapotentialsourceofnaturalhepatoprotec tiveagent(RosaandRosario,2009). Aeglemarmelos Aegle marmelos leaves (Bael, family of Rutaceae) which is also called as Bilva in ancient Sanskrit, was usedasherbaldrugintheIndianSystemofmedicine. The hepatoprotective effect of Aegle marmelos in al coholinducedliverinjurywasevaluatedratsusinges sential marker biochemical parameters. The results indicated that, the Bael leaves have excellent hepato protective effect. Similar findings were also reported byotherworkers(Singananetal.,2007). Cassiaroxburghii Seeds of Cassia roxburghii DC had been used in eth nomedicine for various liver disorders for its hepato protective activity. The methanolic extract of Cassia roxburghii reversed the toxicity produced by ethanol CCl4 combination in dose dependent manner in rats. Theextractatthedosesof250mg/kgand500mg/kg are comparable to the effect produced by Liv52, a well established plantsbased hepatoprotective for mulation against hepatotoxins (Arulkumaran et al., 2009). Orthosiphonstamineus The hepatoprotective activity of the methanol extract of Orthosiphon stamineus was assessed in paraceta molinduced hepatotoxicity rat model. Change in the levelsofbiochemicalmarkerssuchasAST,ALT,ALP andlipidperoxideswereassayedinbothparacetamol treated and control (untreated) groups. Treatment with the methanolic extract of O. stamineus leaves (200 mg/kg) has accelerated the returnof the altered levelsofbiochemicalmarkerstothenearnormalpro
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file in the dosedependent manner (Maheswari et al., 2008). Ficuscarica The methanolic extract of the leaves of Ficus carica Linn. (Moraceae) was evaluated for hepatoprotective activityinCCl4inducedliverdamagedrats.Theextract at an oral dose of 500 mg/kg exhibited a significant protectiveeffectreflectedbyloweringtheserumlevels of AST, ALT, total serum bilirubin, and malondialde hyde equivalent, an index of lipid peroxidation of the liver(Krishnaetal.,2007). Lepidiumsativum The role hepatoprotective of methanolic extract of Lepidiumsativumatadoseof200and400mg/kgwas investigated in CCl4induced liver damage in rats. Sig nificant reduction in all biochemical parameters were found in groups treated with Lepidium sativum. The severefattychangesintheliversofratscausedbyCCl4 were insignificant in the Lepidium sativum treated groups(Afafetal.,2008). Sargassumpolycystum The protective effect of ethanol extract of Sargassum polycystumwasevaluatedinDgalactosamineinduced hepatitisinrats.PriororaladministrationofS.polycys tum extract [125mg/kg bodyweight/day for 15 days] significantly attenuated (P<0.05) the Dgalactosamine induced increases in the levels of diagnostic marker enzymes (AST, ALT and ALP) in plasma of rats. It has also demonstrated antioxidant activity against D galactosamineinduced hepatitis byinhibiting the acti vation of lipid peroxidation and by preserving the he patic enzymatic and nonenzymatic antioxidant de fense system at near normal. The antihepatotoxic po tential of S. polycystum might possibly due toits anti oxidant property and membrane stabilizing action (Meenaetal.,2008). Solanumnigrum The effects of Solanumnigrumextract (SNE) was eva luatedonthioacetamide(TAA)inducedliverfibrosisin mice.MiceinthethreeTAAgroupsweretreateddaily with distilled water and SNE (0.2 or 1.0 g/kg) via ga strogavage throughout the experimental period. SNE reduced the hepatic hydroxyproline and smooth muscle actin protein levels in TAAtreated mice. SNE inhibited TAAinduced collagen (1)(I), transforming growthfactor1(TGF1)andmRNAlevelsintheliver. Histological examination also confirmed that SNE re ducedthedegreeoffibrosiscausedbyTAAtreatment. Oral administration of SNE significantly reduces TAA inducedhepaticfibrosisinmice,probablythroughthe reductionofTGF1secretion(Hsiehetal.,2008). In other study, the protective effects of aqueous ex tractofSN(ASNE)againstliverdamagewereevaluated in CCl4 induced chronic hepatotoxicity in rats. The resultsshowedthatthetreatmentofASNEsignificantly
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lowered the CCl4induced serum levels of hepatic en zyme markers, superoxide and hydroxyl radicals.Liver histopathology showed that ASNE reduced the inci dence of liver lesions including hepatic cells cloudy swelling,lymphocytesinfiltration,hepaticnecrosis,and fibrous connective tissue proliferation induced by CCl4 inrats.Therefore,theresultsofthisstudysuggestthat ASNEcouldprotectliveragainsttheCCl4inducedoxid ative damage in rats, and this hepatoprotectiveeffect might be contributed to its modulation on detoxifica tion enzymes and its antioxidant and free radical sca vengereffects(Linetal.,2008).Thepresenceofplant extracts of Solanum nigrum and Cichorium intybus in the reaction mixture containing calf thymus DNA and free radical generating system protect DNA against oxidativedamagetoitsdeoxyribosesugarmoiety.The effect was dependent on the concentration of plant extracts.However,theeffectofCichoriumintybuswas much pronounced as compared to the effect of Sola num nigrum. These studies suggested that the ob served hepatoprotective effect of these crude plant extracts may be due to their ability to suppress the oxidativedegradationofDNAinthetissuedebris(Sul tana et al., 1995). Since these herbs are commonly known as hepatoprotective agents and have shown theirefficacyinprotectingagainstCCl4inducedhepatic injury(Karandhikar,1963;Bardhanetal.,1985),itmay be proposed that their efficacy may be attributed to theirfreeradicalscavengingability. DISCUSSION Popularityofherbalremediesisincreasinggloballyand atleastonequarterofpatientswithliverdiseasesuse ethnobotanicals.More efforts need to bedirected to wards methodological scientific evaluation for their safety and efficacy by subjecting to vigorous pre clinicalstudiesfollowedbyclinicaltrialstounravelthe mysterieshiddenintheplants.Thisapproachwillhelp exploring the real therapeutic value of these natural pharmacotherapeutic agents and standardized the dosageregimenonevidencebasedfindingstobecome more than a fashionable trend (Stickel and Schuppan, 2007). Many herbals are on the market to support health,relievesymptomsandcurediseases.However, most of these products lack scientific pharmacological validation. In experimental hepatotoxicity models in laboratory or higher animals, several herbals exerted hepatoprotective/curative effects that warrants their clinicaltesting.Duetolackofscientificbasedpharma cologicaldata,mostoftheherbalformulationscannot be recommended for the treatment of liver diseases (StickelandSchuppan,2007). In spite of the availability of more than 300 prepara tions for the treatment of jaundice and chronic liver diseases in Indian Systems of Medicine (using more than 87 Indian medicinal plants,) only four terrestrial plants have been scientifically elucidated while adher ing to the internationally acceptable scientific proto cols. Indepth studies have proved Sylibum marianum
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tobeantioxidative,antilipidperoxidative,antifibrotic, antiinflammatory, immunomodulating and liver rege nerative.Glycyrrhizaglabrahasbeenshowntobehe patoprotectiveandcapableofinducinganendogenous interferon. Picrorhiza kurroa is proved to be anti inflammatory, hepatoprotective and immunomodula tory. Extensive studies on Phyllanthus amarus have confirmed this plant preparation possessed antiviral againsthepatitisBandCviruses,hepatoprotectiveand immunomodulating effects, besides antiinflammatory properties(Thyagarajanetal.,2002). CONCLUSION Chronichepaticdiseasesstandasoneoftheforemost healthtroublesworldwide,withlivercirrhosisanddrug induced liver injury accounting ninth leading cause of death in western and developing countries. Therapies developed along the principles of western medicine are often limited in efficacy, carry the risk of adverse effects,andareoftentoocostly,especiallyforthede veloping world. Therefore, treating liver diseases with plantderivedcompoundswhichareaccessibleanddo not require laborious pharmaceutical synthesis seems highlyattractive.Inthisreviewarticle,anattempthas been made to compile the reported hepatoprotective plantsfromIndiaandabroadandmaybeusefultothe health professionals, scientists and scholars working thefieldofpharmacologyandtherapeuticstodevelop evidencebased alternative medicine to cure different kindsofliverdiseasesinmanandanimals. REFERENCES AfafI,Abuelgasim,NuhaHS,MohammedAH.Hepato protective effect of Lepidium sativum against car bontetrachlorideinduced damage inrats. Res J Ani malVeterinarySci2008,3:2023. AgarwalSS.Developmentofhepatoprotectiveformula tionsfromplantsources.In:PharmacologyandThe rapeuticsintheNewMillennium.EditedbyGuptaSK, NarosaPublishingHouse,NewDelhi,2001,357358. Ajay KG, Neelam M. Hepatoprotective activity of aqueousandethanolicextractofChamomilecapitula in paracetamolintoxicated albino rats. American J PharmacolToxicol2006,1(1):1720. ArulkumaranKS,RajasekaranA,RamasamyA,Jegadee san M, Kavimani S, Somasundaram A. Cassia rox burghii seeds protect liver against toxic effects of ethanolandcarbontetrachlorideinrats.IntJPharm TechRes2009,1(2):273246 Bardhan P, Sharma SK, Garg NK. In vitro effect of an ayurvedicliverremedyonhepaticenzymesincarbon tetrachloride treated rats. Indian Journal ofMedical Research1985,82:359364. ChangChi H, HsunLang F, WenChuan L. Inhibitory effectofSolanumnigrumonthioacetamideinduced liver fibrosis in mice. J Ethnopharmacol 2008, 119: 117121.
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