JOEBXJ1VCMJTIJOHPSQPSBUJPOF4DJFOUJmD8PSMEPVSOBM7PMVNFrSUJDMFrQBHFTeScienticWorldJournalbioactivemoleculesfromvariousspeciesofdierentplantfamiliesweoerthiscompilationofthetraditionaluseschemicalconstit ID: 862143
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1 ReviewArticleTraditionalUses,ChemicalCon
ReviewArticleTraditionalUses,ChemicalConstituents,andBiologicalActivitiesofBixaorellanaL.:AReviewDanieladeAraújoVilar,MarinaSuêniadeAraujoVilar,TúlioFlávioAcciolydeLimaeMoura,FernandaNervoRaffin,MárciaRosadeOliveira,CamiloFlamariondeOliveiraFranco,PetrônioFilgueirasdeAthayde-Filho,MargarethdeFátimaFormigaMeloDiniz,andJoséMariaBarbosa-FilhoLaboratoryofPharmaceuticalTechnology,FederalUniversityofParaba,-JoaoPessoa,PB,BrazilDepartmentofPharmacy,FederalUniversityofRioGrandedoNorte,-Natal,RN,BrazilDepartmentofMolecularBiology,FederalUniversityofParaba,-JoaoPessoa,PB,BrazilStateCompanyofAgriculturalResearchofParaba,RuaEurpedesTavares,Tambia,-JoaoPessoa,PB,BrazilDepartmentofChemistry,FederalUniversityofParaba,-JoaoPessoa,PB,BrazilCorrespondenceshouldbeaddressedtoJoseMariaBarbosa-Filho;jbarbosa@ltf.ufpb.brReceivedFebruary;RevisedMay;AcceptedMay;PublishedJuneAcademicEditor:TsutomuHatanoCopyright©DanieladeAraujoVilaretal.isisanopenaccessarticledistributedundertheCreativeCommonsAttributionLicense,whichpermitsunrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalworkisproperlycited.BixaorellanaL.,popularlyknownasurucum,hasbeenusedbyindigenouscommunitiesinBrazilandothertropicalcountriesforseveralbiologicalapplications,whichindicatesitspotentialuseasanactiveingredientinpharmaceuticalproducts.eaimofthisworkwastoreportthemainevidencefoundintheliterature,concerningtheethnopharmacology,thebiologicalactivity,andthephytochemistrystudiesrelatedtoBixaorellanaL.erefore,thisworkcomprisesasystematicreviewabouttheuseofBixaorellanaintheAmericancontinentandanalysisofthedatacollected.isstudyshowsthewell-characterizedpharmacologicalactionsthatmaybeconsideredrelevantforthefuturedevelopmentofaninnovativetherapeuticagent.1.Introductioneuseofnaturalcompoundsofmineral,animal,orplantorigininfoodproducts,cosmetics,anddrugsbeganlongago.erearewrittenrecordsofancientEgyptianandChinesecivilizationsthathavemadeuseoftheseproducts.Nowadays,therehasbeenareturntothesearchforproductscallednatural,whichinfactneverceasedtoexist.eanalysisofthecompositionofmanydrugsshowsthatalmost %ofthoseinclinicalusearederivedfromnaturalcompounds.Furthermore,notonlyplantsbutalsoplantbyproductsarewidelyusedaspreservativesand avoringandcoloringagentsinvariousfoodandcosmeticpreparations[BixaorellanaisaplantnativetoBrazilbutgrowsinotherregionsofSouthandCentralAmerica.ItisgrownintropicalcountriessuchasPeru,Mexico,Ecuador,Indonesia,India,Kenya,andEastAfrica[eseedsofthisplantproduceoneofthedyesmostfrequentlyusedworldwide,notonlyinfoodproductsbutalsointhetextile,paint,andcosmeticindustries.Itsusehasbeenstimulatedduetothebanontheuseofsyntheticdyesinfoodandcosmetics,whereitisoneofthefewacceptedbytheWorldHealthOrganization(WHO),since,inadditiontobeingnontoxic,itdoesnotseemtochangethefoodvaluee].Anotherinterestingfactisthat%ofallnaturalcoloringagentsconsumedworldwidearederivedfromannatto[Annatto rstspreadintheformoffoodcoloring,alsoknownaspaprika,acondimentwidelyusedincookingtoenhancethecoloroffood.Today,however,itsusehasspreadintomanysegmentsofindustrialproduction.us,itisnowappliedontheskinintheformofmakeupandsunscreenandthereisresearchprovingthatitsusebringshealthbene ts,whichmakesproducersthankfulforcultivatingitt , ].erefore,inthecontinuationofourresearchon ) J O E B X J 1 V C M J
2 T I J O H $ P S Q P S B U J P O F
T I J O H $ P S Q P S B U J P O F 4 D J F O U J m D 8 P S M E + P V S O B M 7 P M V N F \r " S U J D M F * % \r Q B H F T eScienti cWorldJournalbioactivemoleculesfromvariousspeciesofdi erentplantfamilies[],weo erthiscompilationofthetraditionaluses,chemicalconstituents,andbiologicalactivitiesofBixaorellanaeaimofthisreviewistohighlightthebiologicalandphytochemicalstudiesthathavebeenpublishedaboutBixaorellanainSouthandCentralAmericaandtrytocorrelatethesestudieswiththepopularusesofthisplantinthoseregions,aswellastoevaluatewhetheritschemicalcompositioncansupportthereportedbiomedicalpropertiesrelatedtoBixaorellana2.MaterialsandMethodsInthiswork,thebiologicalactivitiesandcompoundsisolatedfromBixaorellanaweresearchedusingthedatabaseoftheWebofScience,Scielo,andtheUniversityofIllinoisinChicagoNAPRALERT(acronymforNAturalPRoductsALERT).edatawereupdatedinApril,usingBixaorellana,chemical,andbixinaskeywordsforthisreview.ereferencesfoundinthesurveywerelaterconsultedfordetailsaboutthemodelsormechanismsofbioassaysusedtotesttheextractsofBixaorellana3.BotanicaleannattotreebelongstothefamilyBixaceaeandthegenusBixa.Despitetheexistenceofseveralspecies,themostcommoninourcountryisBixaorellanaL.,namedaerFranciscoOrellana,whowasthe rstEuropeantonavigatetheAmazon[AccordingtoRevilla[B.orellanaisasmalltreeorshrubmeasuringfromto metersinheight,sometimesreachingaheightofmeters.etrunkisshort,measuring cmindiameter,withdarkgraybarkwithlenticelsinverticalrows.eleavesarealternate,tocmlongand tocmwide,sharp,greenonbothsides,andwithextendedpetioles.AccordingtoOliveiraetal.[],seedsmeasure. . cminlengthand.-.cmindiameter,andtheirshapevariesfrompyramidaltoalmostconical.enumberofseedspercapsulevariesaccordingtotheauthor:Alonso[]foundthateachbivalvarcapsulemaycontainfromto seeds,onaverage.eseedsareconsideredtheplantpartofcommercialimportance,sincethepericarp(layerthatsurroundstheseeds)containsthepigmentsthathavewideindustrialappli-cation.About%ofthispigmentisthecarotenoidknownasbixin,whichhasthedyepropertyandcanbeextractedwithvegetableoilsorchemicalbases.Dependingonthecultivarandclimaticconditionsoftheregion,thebixincontentcanvaryfromto %intheseedaril.eremainderiscomposedofotherdyesandinertsubstancesofminorimportance[4.UseinTraditionalMedicineAnnattoisanativeplantfromSouthAmerica,morespecif-icallyoftheAmazonregion.epopularnameurucumcomesfromtheTupiwordru-ku,whichmeansred.InBrazil,thisplantiscommonlyknownasurucum,urucu,¸afrao,ac¸afroa,andac¸afroeira-da-terra.Itisknownbyotherpopularnamesinothercountries:atole,achiote,andbija(PeruandCuba);axiote(Mexico);achiote,achote,anatto,bija,andsanto-domingo(PuertoRico);bixa(Guyana);analto(Honduras);guajachote(ElSalvador);onottoandonotillo(Venezuela);achioteandurucu(Bolivia);urucu(Argentina);roucou(Trinidad);roucouandkoessewee(Suriname);andannatto(UnitedStates).ewidedisseminationofitsuseinthoseregionsisrelatedtothegrowingdemandfornaturaldyesbymanypharmaceutical,cosmetic,textile,andespeciallyfoodindustries[AccordingtoCorrea[],seedsurucumsuppliesseedsthathavebeenusedasacondimentaswellaslaxative,cardiotonic,hypotensive,expectorant,andantibiotic.Inaddition,ithasanti-in ammatoryactivityforbruisesandwoundsandhasbeenusedforthetreatmentofbronchitisandforwoundhealingpurposes.Oilisalsoobtainedfromthisplant.einfusionoftheleaveshasbeenshowntob
3 ee ectiveagainstbronchitis,sorethroat,an
ee ectiveagainstbronchitis,sorethroat,andeyein ammation.epulp,whichincludestheseed,isusedforsodrinksandfebrifuge.Moreover,itcanprovidevaluabledyeingmaterialssuchasyellow(orellin)andred(bixin)substances,withthelatterconstitutingacrystallizedactiveingredient.Inthefoodindustry,itisusedtocolorbutter,margarine,mayonnaise,sauces,mustard,sausage,soup,juice,icecream,bakeryproducts,macaroni,andcheese,whereitiscommonlycalleddoreino(ofthekingdom),comingfromHolland.Itisalsowidelyusedintheprintingindustryanddyemanufacturing.ManyAboriginesuseannattofordyeing,wherethedyeisnaturallyobtainedasamixtureandusedtocolorceramicsandothervasesfordomesticuse.Inaddition,mostendogenouspeopleusethisdyeontheirskintobeautifythemselvesduringreligiousritualsandmainlytoprotectthemselvesfromultravioletradiationandfrommosquitoesthatinfestforests[].ebastprovides bersforroughcordage,andthepowderresultingfromgrindingtheseedshasbeenusedasanaphrodisiac.Finally,theinfusionofcoldbudsservestowashin amedeyes,whereasthedecoctionoftheleaveshasbeenusedforantiemetictherapyduringpregnancy[](Tableus,despitethedi erentcultureandtraditionsamongthecountriesinSouthandCentralAmerica,severalofthepopularusesofBixaorellanaarethesame,forexam-ple,antipyretic,aphrodisiac,antidiarrheal,antidiabetic,andinsectrepellent.5.ChemicalCompoundsBixin,ared-coloredcarotenoid,isthepigmentpresentinhighconcentrationintheannattoseedaril.Itisthemainsubstanceresponsibleforthedyeingcharacteristicsofseeds,whereitsconcentrationcanbeashighas .%.However,di erentseedsmayhavelevelslessthan.%,andbecausetheircommercialvalueisbasedonthebixinpercentage,levelshigherthan. %areusuallyrequiredforexport[ eScienti cWorldJournalT:TraditionalusesofannattoinAmericancountries. Country/usePlantpartReferences ArgentinaAntipyretic/cardiotonic/antidiarrhealSeeds[Antidiarrheal/dyes/condimentSeeds[BrazilBodypaintSeeds[InsectrepellentSeeds[Condiment/foodcoloringSeeds[AntipyreticSeeds[Antipyretic/laxatives/burnsSeeds[MalariaSeeds[ColombiaSnakebiteLeaves[AphrodisiacSeeds[CubaAphrodisiacSeeds[GuatemalaGonorrhea/dysenteryLeaves[HepatitisLeaves[DysenteryLeaves[BlooddiseasesLeaves[GonorrheaRoots[DiabetesRoots[HondurasAromatic/foodcoloringSeeds[Pain/digestive/dysenteryLeaves[JamaicaDiabetesSeeds[NicaraguaRespiratoryandpulmonarydisorders/diarrhea/diuretic/burnsLeaves+seeds[LaborpainsSeeds[Cough/cold/diuretic/diarrhea/burns/laborpainsSeeds[ParaguayInsecticide/repellentSeeds[DiabetesSeeds[PeruAphrodisiac/aphrodisiac/diuretic/antidisenteria/astringentFruits[Antipyretic/skinproblemsLeaves[Alcoholichepatitis/wormsRoots[Antipyretic/aphrodisiac/dysentery/astringent/stomachSeeds[TrinidadandTobagoDiureticLeaves[DiabetesRoots[DiabetesRoots[ Bixinwasisolatedforthe rsttimefromtheseedsofBixaorellanain andin itscompletechemicalstructureandstereochemistryweredeterminedbyHandC-NMR.Bixinbelongstothesmallclassofnaturalapocarotenoids,whoseformationoccursbytheoxidativedegradationofCcarotenoids(TableBixinconsistsofachainof carbonsandhasthemolec-ularformulaC(MW=. ).Ithasacarboxylicacidandmethylestergroupattheendsofthechain.Bixinoccursinnatureas -),butduringtheextractionprocessitisomerizesresultinginthe -form(trans),whichiscalledisobixin(Figure eScienti cWorldJournalT:emaincarotenoidsfromtheseedsofBixaorellana CarotenoidCountryofisolationPhysicalaspectReferences Apo--carotene,-olBrazilOil[BetacaroteneBrazil]Surinam
4 ee]BixinBrazil ]Peruu ]Domin![ee]BixinBrazil
]Peruu ]Domin](862143/ee-bixinbrazil-peruu-dominicanrep-surina.jpg "ee]BixinBrazil
]Peruu ]Domin")
ee]BixinBrazil ]Peruu ]DominicanRep.. ]Surinamee]USA[ ]Z-CaroteneBrazilOil[CryptoxanthinSuriname]Dimethyl-(-diapocarotene- , -dioateBrazilOil[Dimethyl-(-diapocarotene- , -dioateBrazilOil[PhytoeneBrazilOil[Phyto ueneBrazilOil[GeranylgeraniolBrazilOil[LuteinSuriname ]Methyl-()--oxo- ,-diapocarotene- -oateBrazilOil[Methyl-(-oxo- , -diapocarotene- -oateBrazilOil[Methyl-(-oxo- ,-diapocarotene- -oateBrazilOil[Methyl-(apo-lycopenoateBrazilOil[Methyl-(apo-lycopenoateBrazilOil[Methyl-(apo-lycopenoateBrazilOil[Methyl-(all-apo-lycopenoateBrazilOil[NeurosporeneBrazilOil[NorbixinBrazil ]Trans-bixinJamaica ]ZeaxanthinSuriname Source:[Manyothercarotenoids(C,andCoccurinBixaorellanabutconstituteaminorpercentageofthepigments.emajoroilyconstituentofannattoseedsisgeranylgeraniol,representing%ofdryseeds.Norbixin(Figure)isademethylatedderivativeofbixinandalthoughitisanaturallyoccurringcompound,itisalmostalwaysreferredtoasasaponi cationproductofbixin.isistheformusedforcommercialpurposes[Currently,morethantwodozensubstanceshavebeenisolatedfromtheseedsofBixaorellana.Besidesbixinandnorbixin,othercompoundssuchasisobixin,beta-carotene,cryptoxanthin,lutein,zeaxanthin,orellin,bixein,bixol,cro-cetin,ishwarane,ellagicacid,salicylicacid,threonine,tomen-tosicacid,tryptophan,andphenylalaninehavebeenfoundintheseedsofannatto.Inaddition,thefollowingcompounds,intheirrespectiveconcentrations,arefoundintheseseeds:to %cellulose,. to . %sugars,.to.%essentialoils,% xedoils,.to. %pigments,andto %proteinsandandbeta-carotene,aswellastanninsandsaponinsins , ].Mercadanteetal.[]isolatedeightapocarotenoidsfromannattoseeds:methyl(Z,Z,Z)-apo- -lycopenoate,methyl(Z)-apo--lycopenoate,methyl(all-E)-apo-lycopenoate,methyl(all-E)--apo-beta-carotene--oate,methyl(all-E)-apo- -lycopenoate, -geranylgeranyl-methyl- ,diapocaroten- -dioate, -geranylgeranyl--methyl-(Z)- , -diapocaroten- - -dioate,and -geranylgeranyl- -methyl- - -diapocaroten- - -dioate.Morethanvolatilecompoundshavebeendetectedinaqueousandorganicextracts,where ofthesehavealreadybeenidenti ed(e.g.,bornylacetate,-caryophyllene,copaene,-cubebene,(+)-cyclosativene,geranylphenylac-etate,-heptanetiol,-methylpyridine,-methylpyridineelemene,-humulene,isoledene,-pinene,seline- -en--ol,-selinene,()-spathulenol,and(+)-ylangene)[Becauseannattoisarichsourceofcarotenoidsitisofgreatcommercialimportance.Infact,thetherapeuticpropertiesofannatto(e.g.,antioxidantandhypoglycemic)havebeenattributedtoitshighlevelsofcarotenoids[Tablelistssomeofthesecompounds.epigmentsinannattoseedscanbeextractedbymechanicalprocessesthroughgrindingtheseedsandbyphysical-chemicalmethodsusingsolventsorenzymes[esolventextractioncanbeperformedusingthreebasicmethods:alkalineextraction(NaOHorKOHsolutions),whichresultsintheconversionofbixintonorbixin;extractionwithoil(soybean,corn);andextractionusingorganicsolvents(hexane,chloroform,ethanol,acetone,or eScienti cWorldJournal Bixin (-bixin or -bixin)COOHCOOMe 16 MeOOC Isobixin (-bixin or trans-bixin)COOH COOHHOOC Norbixin (c) Geranylgeraniol F:Chemicalstructureofsomepigmentsofannatto.propyleneglycol),whichresultsinthepurestformofpig-ments.Barbosa-Filhoetal.[]studiedtheseedsoffourtypesofannattocultivatedinParabaState,Brazil,namely,cas-caverde(greenpeel),cascavermelha(redbark),bicodecalango(lizardbeak),andgraop
5 reto(blackgrain),withrespecttotheiroi
reto(blackgrain),withrespecttotheiroil(materialextractedwithhexane)andsolid(materialextractedwithchloroform)contents,andalsopurebixin,whichwasobtainedbysuccessiverecrystallizationfromthechloroformfraction.Purebixinappearsasred-purplecrystalswithameltingpointof C.edi erentconcentrationsfoundfortheoilfraction,chloroformextract,andbixinareasfollows:redbark .%,lizardbeak .%,greenpeel.%,andblackgrain. %.Redbarkshowsthehighestyieldforbothsolventfractions,andthebixinamountisaround%.isspecieshasbeenreportedasthemostusedinfolkmedicine.Ontheotherhand,blackgrainshowsnegligibleamountsofbixin.6.BiologicalActivityTableshowsdatafoundinstudiesperformedwithannattoin di erentcountriesintheAmericancountries.Toobtaintheextractsandfractionstested,severalplantpartswereused,suchasleaf,root,seed,shoot,andeventhewholeplant.edatasurveyedwereclassi edaccordingtothepharmacologicalactivitytested.Amongthetwenty-oneactivitiestested,thosewiththelargestnumberofstudiesperformedwereantifungalactivity(),antibacterialactivity(),antimalarialactivity( ),andmutagenicactivity().Cytotoxicactivityandtoxicityhavebeenlittlestudied,withthreeandtwostudies,respectively.Pharmacologicalactivitieshavebeenevaluatedinanimalmodels(preclinicalstudies),humanmodels(clinicalstudy),cellcultures(studies),andinvitrotests(studies).AntifungalactivityhasbeeninvestigatedinonecountryinCentralAmerica(Guatemala)andintwocountriesinSouthAmerica(EcuadorandArgentina)usingelevendi er-entfungalstrains[Freixaetal.[]conductedastudyinEcuadortoassesstheantifungalactivityofextractsfromthedriedleavesoftheannattotreeinresponsetofungispecies,obtainingsatisfactoryantifungalactivityagainstTrichophytonmenta-grophytestrains.InGuatemala,threedi erentstrainswereusedtoevaluateantifungalactivity,withnosatisfactoryactivitybeingobserved[eextractsofannattoleaveshavebeenevaluatedforantibacterialactivityagainstdi erentbacterialstrainsBacillussubtilis,Escherichiacoli,Micrococcusluteus,Pseu-domonasaeruginosa,Staphylococcusaureus,Salmonellatyphi,Shigelladysenteriae,andStaphylococcusepidermidis),show-ingnoactivity.AntimalarialactivityhasbeendeterminedagainstPlas-modiumgallinaceumPlasmodiumlophurae,andPlasmodium.AlthoughthestudiesconductedpreviouslyintheUnitedStatesdidnotshowsigni cantresults[],Valdesetal.()reportedamoderateactivityoftheseedextractsofBixaorellanaagainstPlasmodiumbergheiandfalciparum7.MutagenicandCytotoxicActivitiesNosigni cante ectwasobservedwhenextractsofannattoseedsweretestedformutagenicactivityinstudiesperformedintheUnitedStatesandBrazil[Extractsobtainedfromannattoseedsandleaveshavebeentestedincellculturesandthebrineshrimpassay,respectively,andhavebeenfoundtolackcytotoxicityineithermodelused.eseexperimentswerecarriedoutinGuatemalaandtheDominicanRepublic[Ontheotherhand,astudyperformedinCubawithmedicinalplantsthatwereactiveininhibitinghumanlungcarcinomacellgrowthshowedthattheethanolicextractofBixaorellanapresentedcytotoxicityatconcentrationsbelowg/mL[8.ToxicologicalActivitiesCurrently,concernsaboutthee ectofsyntheticdyesonhumanhealthareincontestable,makingpeopleincreasinglychoosethoseofnaturalorigin,believingthattheyaredevoidoftoxice ects.isisnotentirelytrue,becauseevenamedicationfromanaturalsourcecanbeapoison,depending eScienti cWorldJournalT:BiologicalactivitiesofextractsofannattoinAmericancountries. CountrybiologicalactivityPartusedTypeofextractOrganis
6 mtestedModeltestedDoseusedActivityRefere
mtestedModeltestedDoseusedActivityReferences ArgentinaAntibacterialLEEtOHBacillussubtilisInvitro mg/mLInactive[EscherichiacoliInvitro mg/mLInactive[MicrococcusluteusInvitro mg/mLInactive[PseudomonasaeruginosaInvitro mg/mLInactive[StaphylococcusaureusInvitro mg/mLInactive[AntifungalLEEtOHAspergillusnigerInvitro mg/mLInactive[CandidaalbicansInvitro mg/mLInactive[AntiviralSEEtOHVirusHerpessimplexCellculture.mg/mLInactive[InsecticidalAPMeOHInsectSitophilusoryzae %Inactive[BrazilAntimalarialSECHClMousePlasmodiumbergheimg/kgInactive[AntioxidantSEEtOHInvitroDPPHassay.gLActive[InsectrepellentSEPetr.ethHamsterLutzomyialongipalpisg/LActive[SEEtOHMosquitoAedesaegypti.mg/mLActive[MolluscicidalSEEtOHConchBiomphalariaglabrata,ppmInactive[MutagenicPowderMouseBonemarrowcells, ppmInactive[ToxicitySEPowderRatInvivo mg/kgInactive[AntileishmanialLE/ROEtOHLeishmaniaamazonensisInvitro, , mg/mLActive[AntileishmanialSEOELeishmaniaamazonensisInvitro/ // /g/mLActive[HyperlipidemiaSEHOMouseInvitroandmg/kgActive[ColombiaSnakebiteLEEtOHMouseBothropsatroxLD g/animalActive[CostaRicaAnti-in ammatoryROEtOHRatPawedema/carrageenanmg/kgInactive[CubaPositiveinotropice ectAPHOGuineapigIsolatedatriumLInactive[AntimalarialPlasmodiumgallinaceum/falciparumInvivo/invitro mg/kgActive[CytotoxicSEEtOHTumorcellsInvitro, mg/mLActive[EcuadorAntifungalLEMeOHAspergillusnigerInvitromg/diskInactive[CandidaalbicansInvitromg/diskInactive[CryptococcusneoformansInvitromg/diskInactive[FusariumoxysporumInvitromg/diskInactive[NeurosporacrassaInvitromg/diskInactive[PenicilliumpurpurogenumInvitromg/diskInactive[TrichophytonmentagrophytesInvitromg/diskActive[ eScienti cWorldJournalT:Continued. CountrybiologicalactivityPartusedTypeofextractOrganismtestedModeltestedDoseusedActivityReferences GuatemalaAntibacterialLEVariousEscherichiacoliInvitroL/diskInactive[PseudomonasaeruginosaInvitroMICmg/mLInactive[SalmonellatyphiInvitroMICmg/mLInactive[ShigelladysenteriaeInvitroLInactive[StaphylococcusaureusInvitroMICmg/mLInactive[AntifungalLEHAspergillus avusInvitroMICmg/mLInactive[CandidaalbicansInvitroMICmg/mLInactive[MicrosporumgypseumInvitroMICmg/mLInactive[AntigonorrhealLEEtOHNeisseriagonorrheaInvitroL/diskActive[AntitrypanosomalLEEtOHTrypanosomacruziInvitroMICmg/mLInactive[CytotoxicLEHOCrustaceanArtemiasalinaLC ,ppmInactive[Inhib.ofplateletaggregationSE/InvitrorombinaggregationIC . mg/mLInactive[HawaiiContraceptiveRO/Mouse/.mL/animalInactive[JamaicaHypoglycemicSECHClDoggActive[ODogmL/animalActive[AntioxidantSEEtOHInvitroInvitro. and. g/mLActive[MexicoAllergenicSEOilHuman L/personActive[ParaguayInsecticidalSEPetr.etherInsectRhodniusneglectusgInactive[PuertoRicoMolluscicidalTPHOConchLymnaeacubensisLDMppmInactive[DominicanRepublicCytotoxicSEEtOHCellcultureMoltcellsg/mLInactive[TrinidadandTobagoAntibacterialSEEtOAcEscherichiacoliInvitro,g/mLInactive[PseudomonasaeruginosaInvitro,g/mLInactive[AnticonvulsantRAEtOHMouseSeizures/electroshockmg/kgInactive[RatSeizures/pentylenetetrazolemg/kgInactive[AntimalarialSECHClChickenPlasmodiumgallinaceummg/kgInactive[MutagenicSEMeOHSalmonellatyphimuriummg/plaqueInactive[InvitroPlacentaltrophoblastsmg/plaqueInactive[HypotensiveRAEtOHRat mg/kgActive[ToxicityRAHOMouseLD mg/kgInactive[ LE:leaf;AP:aerialpart;TP:totalpla
7 nt;RO:root;SE:seed;/:notgiven;LD : %le
nt;RO:root;SE:seed;/:notgiven;LD : %lethaldose;IC :concentrationthatinhibits %ofthee ect;MIC:minimuminhibitoryconcentration. eScienti cWorldJournalonthedosethatisadministered.efailuretorequirein-depthdatarelatedtotoxicologicalandchemicalanalysesfortheregistrationoffoodadditivesderivedfromnaturalsources[]certainlymakestheinformationaboutpossibleunwantede ectsand/orpharmacologicalactivitiesresultingfromtheiruse,muchrarerthanexpectedinviewoftheimportanceofthetopic.InBrazil,theuseofannattoissowidespreadthatitssafetyisnotevenquestioned.Paumgarttenetal.[]evaluatedthetoxicityofannattoextractsinrats.Dosesupto mg/kgbodyweight/daywereintroduceddirectlyintothestomachofpregnantratstoevaluatethee ectonthemotherandfetus,andnoadversee ectswerefoundforeither.eannattoextractdidnotinduceanincreaseintheincidenceofvisibleexternal,visceral,orskeletalanomaliesinthefetuses.erefore,thestudysuggestedthattheannattoextractwasnottoxictoratsnorwasitembryotoxic.StudiesperformedinBrazilbyAlvesdeLimaetal.[],whereextractsofannattoweremixedwiththefoodofmalerats,showedthattheconcentrationstestedhadnomutagenicorantimutagenicactivityintheirbonemarrowcells.AparalleltoxicitystudyconductedbyHagiwaraetal.[]showedthat.%annattoextractadministeredforthirteenweeksinthefeedofmaleandfemaleratsdidnotshowanyadversee ects.However,whenhigherdoseswereadministered(.and.%),theauthorsnoticedanincreaseinliverweightaswellaschangesinbloodchemistries,includingincreaseinalkalinephosphatase,phospholipids,andtotalprotein,aswellasalbuminandalbumin/globulinratio.Hagiwaraetal.[]alsoevaluatedextractsofannattoforlivercarcinogenicityinratsandfoundnoevidenceoflivertumors,evenwhengiventoanimalsatahighdoseofmg/kgbodyweight/day,comparedtoanacceptabledoseof.to. mg/kg/day,thusindicatingthatthedangerofahepatocarcinogenice ectinhumansmaybeabsentornegligible.Atoxicitytestwasperformedwithextractsobtainedfrombothplantseedsandshoots,andnosigni cante ectwasobserved.eexperimentswereperformedintheUnitedStatesusingmiceastheanimalmodelanditwasfoundthattheLD wasgreaterthanmg/kg[9.CorrelationbetweentheBiologicalActivities,Phytochemistry,andtheTraditionalUsesofBixaorellanaTableshowsthatmanyofthetraditionalusesofBixaorellanaarethesameinseveralcountriesofSouthandCentralAmerica,whichsuggestsitse ectivenessasather-apeuticagent.ExtractsofBixaorellanashowedbiologicalactivitiessuchasantioxidant,hypotensive,molluscicide,andantimalarialagainstA cellsforcarcinomaofthelung,allergy,hypoglycemic,antifungal,antioxidant,insectrepellent,antigonococcal,andantivenomserumandsomeofthemareinaccordancewiththetraditionaluse;forexample,inBrazilitisusedtoextracttheseedswithpurposerepellentinsecticideandantimalariaandscienti cstudiesinthesamecountrywiththeLutzomyialongipalpisinsectrepellentactionandproveastudyinCubaprovedthepharmacologicalactionforantimalarialactivitywhentestedagainstPlasmodium.Someofthemareinaccordancewiththetraditionaluse;forexample,seedextractshavebeenusedinBrazilandCubaasinsectrepellentandantimalarial.Antioxidantandinsectrepellentactivitiescanbeattributedtothecarotenoidsandtheessentialand xedoils,respectively.Despitethepreviousreportsaboutthepresenceofcom-ponentswithanti-in ammatoryproperties,suchassalicylicacid,lutein,polyphenols,andtannins,thisactivityhasnotyetbeenprovenforBixaorellanaextracts.Similarly,theplantsessentialand xedoilshaveshownantibacterialproperties,althoughthisactivit
8 yhasnotbeenproventoo.Ingeneral,thedataob
yhasnotbeenproventoo.Ingeneral,thedataobtainedinthisreviewdonotallowcorrelationsbetweenthebiologicactivitiestestedinvitrovivowiththecompoundsidenti edinthisspecies.However,takingintoaccounttherelatedactivitiessuchastheantipara-sitice ectandthelackofmutagenicandcytotoxicityactivity,itispossibletoconsiderBixaorellanaasapotentialsourceforthedevelopmentofphytopharmaceuticalproducts.Inconclusion,thestudiesdiscussedinthisreviewrepre-sentarichdatabasearoundtheBixaorellanaactivitiesanditspotentialuses,whichevokesthefeasibilityofphytophar-maceuticalstotreatsomediseaseswheneveranantioxidant,hypotensor,orhypoglycemiantactivityisnecessary.Althoughthecommercialexploitationofthisspeciesiswellestablished,thereareveryfewstudiesonitspharma-cologicale ects.Consideringtheneedfordevelopingasafeande ectiveproduct,morestudiesshouldbeperformedinordertocon rmotherbiologicalactivitiessupportedbythepopularusesofBixaorellana.ConflictofInterestseauthorsdeclarethattheyhavenocon ictofinterests.eauthorsaregratefultoCNPq/PRONEX/FAPESQandCAPESfor nancialsupportandtotheNAPRALERTDatabaseoftheUniversityofIllinois,USA,fortheliteratureBixaorellana.A.LeyvahelpedineditingtheEnglishlanguageofthepaper.[]M.B.Perecin,O.A.Bovi,andN.B.Maia,Pesquisacomplantasaromaticas,medicinaiscorantes:opapeldoInstitutoAgronomico,OAgronomico,vol. ,pp. ,.[]M.E.A.Elias,G.Schroth,J.L.V.Macedo,M.S.S.Mota,andS.A.DAngelo,Mineralnutrition,growthandyieldsofannattotrees(Bixaorellana)inagroforestryonanAmazonianFerralsol,ExperimentalAgriculture,vol.,no.,pp. ,.[]A.R.R.Bastos,J.G.Carvalho,R.P.Assis,andA.B.C.Filho,Marchadeabsorcaodenutrientesemurucum(Bixaorellana)tipocultivadopiavevermelhaemfasedeviveiro,Cerne,vol. ,pp. ,. eScienti cWorldJournal[]E.P.omas,M.Colvin,S.B.Rosen,C.Zuccarini,andS.Petzer,HIVprevalencestudyandcostinganalysisundertakenforthedevelopmentofanHIV/AIDSworkplacestrategyforbu alocitymunicipality,Tech.Rep.,MedicalResearchCouncil,Buf-falo,NY,USA, .[ ]C.F.Franco,OAgronegociodourucumnaregiaoNordeste,aoNacionaldaCadeiaProdutivadeUrucum,CD-Rom,.[ ]A.Giorgi,P.DeMarinis,G.Granelli,L.M.Chiesa,andS.Panseri,Secondarymetabolitepro le,antioxidantcapacity,andmosquitorepellentactivityofBixaorellanafromBrazilianAmazonregion,JournalofChemistry,vol.,ArticleID ,pages,.[]J.S.Silva,M.D.Moura,R.A.G.Oliveira,M.F.F.Diniz,andJ.M.Barbosa-Filho,Naturalproductinhibitorsofovarianneoplasia,Phytomedicine,vol.,no.-,pp. ,.[]F.C.F.Sousa,C.T.V.Melo,C.O.M.Citoetal.,Plantasmedicinaiseseusconstituintesbioativos:umarevisaodabioatividadeepotenciaisbenefciosnosdisturbiosdaansiedadeemmodelosanimais,RevistaBrasileiradeFarmacognosia,vol.,pp. ,.[]L.J.QuintansJr.,J.R.G.S.Almeida,J.T.Limaetal.,Plantswithanticonvulsantpropertiesareview,RevistaBrasileiradeFarmacognosia,vol.,pp. ,.[]H.D.S.Falcao,J.A.Leite,J.M.Barbosa-Filhoetal.,Gastricandduodenalantiulceractivityofalkaloids:areview,Molecules,vol.,no.,pp. ,.[]H.S.Falcao,I.R.Mariath,M.F.F.M.Diniz,L.M.Batista,andJ.M.Barbosa-Filho,PlantsoftheAmericancontinentwithantiulceractivity,Phytomedicine,vol. ,no.-,pp. ,[]I.R.Mariath,H.D.S.Falcao,J.M.Barbosa-Filhoetal.,PlantsoftheAmericancontinentwithantimalarialactivity,RevistaBrasileiradeFarmacognosia,vol.,no.,pp. ,.[]J.E.R.Hon,P.M.Soares,C.L.Meloetal.,Atividadefarmacolog
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