Dedication
Tomymother,MariaIrma,forherlove,care,andsacrificethathasenabledmereachthis academiclevel
Contributorsxxiii
Prefacexxxi
Acknowledgmentsxxxv
1.Mitochondrialphysiology:Anoverview1 VittoriaInfantino,SimonaTodisco,andPaoloConvertini
1.Introduction1
2.TCAcycleandoxidativephosphorylationsystem activity2
3.Mitochondrialdynamics:Fusionandfission6
4.Mitochondrialbiogenesisandmitophagy8
5.Mitochondria-relatedcelldeath12
6.Mitochondrialredoxbiology15
7.Concludingremarks20 References20
2.Molecularmarkersofmitochondrialintoxication29
DanielleGabrielSeloto,JoyceSantanaRizzi, ThaniaRiosRossiLima,andLı´lianCristinaPereira
1.Mechanismsofinteractionleadingtomitochondrial injury29
2.Markersofmitochondrialdamage32
3.Chemical-inducedmitochondrialdamage:Caseexamples38
4.Conclusions41 References41
3.Drug-inducedmitochondrialimpairment: Mechanismsandtestingsystems49
RezaHeidari,MohammadMehdiOmmati, andHosseinNiknahad
1.Introduction49
2.Mechanismsofdrug-inducedmitochondrial impairment53
3.Testingsystemsforevaluatingdrug-induced mitochondrialimpairment59
4.Biomarkersofdrug-inducedmitochondrialinjuryin clinicalsettings62
5.Protectivestrategiesagainstdrug-inducedmitochondrial dysfunction64
6.Outlook67 Conflictsofinterest68 References68
4.Clinicalconsequencesofdrug-inducedmitochondrial dysfunction77
RebeccaL.Jensen,RobynT.Kiy,FatenF.BinDayel, andAmyE.Chadwick
1.Introduction78
2.Clinicalmanifestationsofdrug-inducedmitochondrial dysfunction80
3.Interindividualvariation92
4.Concludingremarks93 References94
5.Challengesinmitochondrialprofilingduring pre-clinicalstudies101
Gonc ¸aloJ.M.Afonso,RuiF.Simo ˜ es,SoniaL.C.Pinho, PauloJ.Oliveira,andTeresaCunha-Oliveira
1.Introduction102
2.Experimentalmodelsandconditions107
3.Mitochondrialmicroscopy,concernsandpitfalls114
4.Studyingmitochondrialbiologyusingmachinelearning methodologies119
5.Conclusion123 Acknowledgments124 References124
6.Mitochondrialdysfunctionandunderlyingmolecular mechanismsinacrylamide-inducedtoxicity133
YiChen,JiawenLu,andChunchaoNie
1.Introduction133
2.AAinducesthedestructionanddysfunctionof mitochondria134
3.AAinducesDNAdamageandinfluencescellcycle andgrowth135
4.AAinducesextensiveoxidativestressinmitochondria136
5.Signalingpathwaysinvolvedinmitochondrial dysfunctioninducedbyAA138
6.Conclusion142 References142
7.Theeffectsofairpollutiontoxicantsonthemitochondria147 CamilaKochi,ShamaAhmad,andSaminaSalim
1.Introduction147
2.Mitochondriastructureandfunction148
3.Mitochondrialdynamics149
4.Oxidativestressandthemitochondria150
5.Majortypesofhazardousairpollutants150
6.Majororgansaffectedbyairpollutantsanddisease exacerbations152
7.AirpollutantsasasourceofROSinthemitochondria154
8.Conclusion159
9.Futuredirection159 Acknowledgments159 References159
8.MitochondrialtoxicityofaflatoxinB1167 OluwakemiA.Rotimi,IsaacsonB.Adelani, OpeyemiC.DeCampos,TolulopeD.Olawole, andSolomonO.Rotimi
1.Introduction167
2.BiotransformationofAFB1167
3.AFB1toxicityofthemitochondria169 4.Conclusion176 References176
9.Theeffectsofalcoholabuseagainstthemitochondria: Functionalconsequencesforliver,muscle,andthebrain181 MargretheA.OlesenandRodrigoA.Quintanilla
1.Introduction181
2.Alcoholtoxicity182
3.Alcoholconsumptionaffectsmitochondrialfunction184
4.Strategiestoreducemitochondrialinjuryinducedbyalcohol188
5.Conclusions192
Acknowledgments195 References195 Furtherreading204
10.Theeffectofaluminumonmitochondrialdysfunctions205 MarianaMachado-Neves,FernandaCarolinaRibeiroDias, GrazielaDominguesdeAlmeidaLima, andIaraMagalha ˜ esRibeiro
1.Introduction205
2.Aluminumandhumanexposure206
3.Aluminumtoxicokinetic207
4.Basicmechanismofactionofaluminum208
5.MitochondrionasatargetorganelleforAltoxicity210
6.Aluminumtoxicityandtheconsequencestohigh energy-requiringtissues216
7.Conclusion227 Acknowledgments227 References228
11.Discoveryofamiodaronemitochondrialtoxicity inliverandbeyond235 BernardFromenty
1.Introduction235
2.Amiodarone-inducedhepatotoxicity235
3.Drug-inducedmicrovesicularsteatosisand mitochondrialdysfunction236
4.Firstevidencethatamiodaronecouldinhibitmitochondrial FAO236
5.Amiodarone-inducedinhibitionofthemitochondrial respiratorychain237
6.Amiodarone-induceduncouplingofoxidative phosphorylation238
7.Amiodaroneaccumulateswithinthemitochondria239
8.Amiodarone-inducedmitochondrialdysfunction: Aschematicoverview240
9.Subsequentconfirmationthatamiodaronecan impairmitochondrialfunctions241
10.Frommitochondrialdysfunctiontohepatic steatosisandsteatohepatitis242
11.Amiodarone-inducedmitochondrialdysfunction inothertissues243
12.Concludingremarks243 Acknowledgment244
Conflictofinterest245 References245
12.Ammonia249
RezaHeidari,MohammadMehdiOmmati, andHosseinNiknahad
1.Introduction:Ammoniametabolism,hyperammonemia,and hepaticencephalopathy249
2.Mitochondria:Themainsubcellulartargetof ammoniatoxicity251
3.EffectsofammoniaonorgansotherthanCNS258
4.Therapeuticapproachesandfutureperspectives262 Conflictsofinterest264 References264
13.Mitochondrialdisruptionasacontributingfactor fortheneurotoxicityofamphetamines271
DanielJoseBarbosa,FelixCarvalho,andHelenaCarmo
1.Introduction271
2.Thetricarboxylicacidcycleasatargetofamphetamines272
3.Effectsofamphetaminesonthemitochondrialelectron transportchain273
4.Amphetaminesandtheoutermitochondrialmembrane enzymesmonoamineoxidase281
5.Effectsofamphetaminesonthemitochondrial biogenesis284
6.Effectsofamphetaminesonmitochondrialsurvival mechanisms286
7.Amphetaminesimpairthemitochondrialfusion/fission equilibrium286
8.Effectsofamphetaminesonthedistributionand transportdynamicsofmitochondria287
9.Concludingremarks289 References289
14.Mitochondrialintoxicationbyanthracyclines299 AlessandraMurabito,MicheleRusso,and AlessandraGhigo 1.Introduction299
15.Antidepressants,mood-stabilizingdrugs,andmitochondrial functions:Forbetterorforworse323
GraemePreston,DanaElSoufiElSabbagh,TimL.Emmerzaal, EvaMorava,AnaCristinaAndreazza,ShamimaRahman, andTamasKozicz
1.Introduction323
2.Mitochondrialenergymetabolismandpsychopathology324
3.Howmitochondrialfunctionsareassessed?327
4.Theeffectsofantidepressantsandpsychiatricdrugson mitochondrialfunctions330
5.Discussion338
6.Knowledgegaps338
7.Conclusions341 References342
16.TheeffectsofHIVandtheantiretroviralsonthe mitochondria351
SergioBarrosoandGlo ` riaGarrabou
1.Humanimmunodeficiencyvirus351
2.Mitochondrialdamagemeasurements359
3.Antiretroviraltherapy359
4.Discussion371 References372
17.Theeffectofarsenicalcompoundsonmitochondrial metabolism379
MarianaMachado-NevesandAnaCla ´ udiaFerreiraSouza
1.Introduction379
2.Physicochemicalpropertiesofarsenicandarsenical compounds380
3.Arsenicpoisoningandtheriskforhumanhealth381
4.Intracellularmetabolismofpentavalentandtrivalent arsenicals382
5.Toxicmechanismofarsenicalcompounds385
6.Mitochondriaastargetorganellestoarsenictoxicity387
7.Ameliorationofarsenic-inducedmitochondrialoxidative stressanddysfunction398
8.Conclusion399 Acknowledgments400 References400
18.MechanismsofbisphenolAtoxicityinmitochondria409 MohammadAminDehghani,AliSabahi,AtefehRaesiVanani, NasrinAmirrajab,AmirChakeriAnsari,AmirhosseinBazmi,and KhashayarAlikarami
1.BisphenolAtoxicity409
2.MitochondrialdiseaseandBPAtoxicity410
3.MitochondrialmetabolisminBPAtoxicity411
4.MitochondrialoxidativestressinBPAtoxicity412
5.Nrf2/Keap1pathwayandBPAtoxicity413
6.MitochondrialrespirationandtheROS-mediated mitochondrialpathwayinBPAtoxicity414
7.MitochondrialmembranepotentialandBPAtoxicity416
8.Mitochondria-mediatedapoptosispathwayandBPAtoxicity417
9.MitochondrialbiogenesisinBPAtoxicity418
10.MitophagypathwayinBPAtoxicity419
11.MitochondrialdysfunctioninBPAtoxicity:Miscellaneous419
12.Conclusion/futuredirections420 References421
19.Chemotherapeuticdrugs425
AdaPopolo
1.Roleofmitochondriaincancer425
2.Targetingmitochondriaforanticancertherapy427
3.Mitochondriaasthetargetforchemiotherapeuticsside effects428
4.Conclusions433 References433
20.Effectsofcuprizoneonmitochondria439
JenniferMcDonoughandSarahSternbach
1.Introductiontocuprizone439
2.Cuprizoneandmitochondrialdysfunction440
3.Advancesinamelioratingmitochondrialdamagefrom cuprizone444
4.Finalremarksandconclusion446 References446
Furtherreading450
21.Effectsof Δ9-tetrahydrocannabinolonmitochondria451
TinaPodinicandSandeepRaha
1.Endocannabinoidsystem451
2.Roleofmitochondriainendocannabinoidsignaling456
3.Mitochondrialfunctionsandcellularhealth461
4.Conclusion465 References466
22.Effectsoffoodadditivesonthemitochondriaintegrity andfunctioning475
RevathiBoyina,SujathaDodoala,andSumalathaGindi
1.Introduction475
2.Effectoffoodadditivesonmitochondriastudiedbyinvitro experimentation478
3.Isolatedmitochondriaexperimentation(exvivo)479
4.Foodadditivesthatalterthemitochondria-dependent apoptosis481
5.FoodadditivesaffectingROSproductioninmitochondria483
6.Foodadditivesaffectingtheelectrontransportchainand metabolisminmitochondria484
7.Effectoffoodadditivesonmitochondriainvivo experimentation485
8.Conclusion488 References488
23.Mitochondriaasatoxicologicaltargetforfungicides493 Mo ´ nicaG.Silva,DanielaMendes,M.ManuelOliveira, PaulaB.Andrade,RomeuA.Videira,andFranciscoPeixoto
1.Theuseandrelevanceoffungicides—Abriefoverview493
2.Amitochondria-drivenjourneythroughtheeukaryotic kingdoms499
3.Mitochondrialtoxicityoffungicides—Anorgan-targeted analysis503 References515
24.Theeffectsofmethylglyoxalonthemitochondria527 Miklo ´ sPeterKalaposandLidiadeBari
1.Introduction527
2.Briefoverviewofmethylglyoxalmetabolismfrom mitochondrialstandpoint528
3.Thedirecteffectofmethylglyoxalonrespiration530
4.Indirectmitochondrialeffectsofmethylglyoxaladded invivo ortocellcultures533
5.Conclusionsandperspectives537 References540
25.Theeffectofmercuryonthemitochondria547 EnayatollahSeydiandJalalPourahmad
1.Mercury547
2.Mitochondria548
3.Hgandmitochondria548
4.Hgandsulfidryl(thiol/-SH)groups548
5.Hgandglutathione550
6.HgandmitochondrialETC550
7.Hgandmitochondrialmembranepotential551
8.Hgandapoptosis552 References552
26.Organohalides557 NancyD.DenslowandChristopherJ.Martyniuk
1.Introductiontoorganohalides558
2.Mitochondriaastargetstoenvironmentalcontaminants559
3.Organochlorinepesticides561
4.Perfluorinatedchemicals568
5.HighthroughputassessmentofOHsasmitochondrial toxicants574
6.Finalconclusions579 References579
27.Theeffectsoforganophosphatepesticideson mitochondria587 SaeedSamarghandian,TaherehFarkhondeh, MiladAshrafizadeh,MarjanTalebi,MichaelAschner,and MajidDarroudi
1.Background587
2.GeneralcharacteristicsofOPs588
3.MitochondrialdysfunctioninOPs-inducedneurotoxicity589
4.MitochondrialdysfunctioninOPs-inducedcardiotoxicity591
5.MitochondrialdysfunctioninOPs-inducedlivertoxicity591
6.MitochondrialdysfunctioninOPs-inducedkidneytoxicity593
7.MitochondrialdysfunctioninOPs-inducedimmunetoxicity593
8.MitochondrialdysfunctioninOPs-inducedtoxicity incancercell594
9.MitochondrialdysfunctioninOPs-inducedmuscular toxicity594
10.MitochondrialdysfunctioninOPs-inducedreproductive toxicity594
11.MitochondrialdysfunctioninOPs-inducedskintoxicity595 12.Conclusion595 References596 Furtherreading599
28.Mitochondrialoxygentoxicity601 RicardoAlva,MohammedAbbas,OliviaR.M.Bagshaw, ChrisMoffatt,GeorginaL.Gardner,andJeffreyA.Stuart
1.Introduction601
2.Mitochondriaassourcesandtargetsofoxygentoxicity602
3.TherapeutictargetingofmitochondrialROSagainstoxygen toxicity606
4.Conclusions608 References608
29.Polychlorinatedbiphenyls615 MelanieBlanc-Legendre
1.Polychlorinatedbiphenyls615
2.Structuralrequirements616
3.EffectsofPCBsonmitochondrialstructure:Cristae andmembraneintegrity618
4.EffectsofPCBsontheelectrontransportchainandoxidative phosphorylation645
5.EffectsofPCBsonmitochondria-relatedoxidativestressand mitochondrialuncoupling646
6.EffectsofPCBsoncalciumstorageandapoptosis648
7.Concludingremarks650 Acknowledgments651 References651
30.Theeffectsofpolycyclicaromatichydrocarbonson mitochondria663
KelliF.MalottandUlrikeLuderer
1.Polycyclicaromatichydrocarbonsandtheir bioactivation663
2.MitochondriaasrelevanttargetsofPAHexposure665
3.EffectsofPAHsonmitochondria671
4.Summary677 References678 Furtherreading681
31.Theeffectsofpyrethroidsonthemitochondria683
Patrı´ciadeBrumVieira,MauroEugenioMedinaNunes, DennisGuilhermedaCostaSilva,MelaniaSanter,and JefersonLuisFranco
1.Introduction683
2.Pyrethroidsmodeofactionandtoxicity685
3.Pyrethroidscaninducemitochondrialdysfunction687
4.Concludingremarks696 References700
32.Theeffectsofsodiumnitrateonmitochondria707 Perez-MoralesRebeca,Rı´os-Sa ´ nchezEfraı ´ n, Gonza ´ lez-DelgadoMarı´aFernanda,and Gonza ´ lez-ZamoraAlberto
1.Sourcesofexposuretonitrates707
2.Metabolismofnitratesanditscellulareffects711
3.Mitochondrialdysfunctionandmorphologicalchanges duringnitrateexposure715
4.Conclusions717 References718
33.Mitochondrialzinctoxicity723 OliviaR.M.Bagshaw,RicardoAlva,JeremyGoldman, JaroslawW.Drelich,andJeffreyA.Stuart
1.Introduction723
2.Zinctransport724
3.ConcentrationsofZn2+ inthecytosolandmitochondria726
4.Zincinhibitionofmitochondrialbioenergetics727
5.AroleforZn2+ inmitochondrialdynamics731
6.Zincconcentrationsincellculturemedia733
7.Conclusions736 References737
Index745
Contributors
MohammedAbbas DepartmentofBiologicalSciences,BrockUniversity,St.Catharines,ON, Canada
IsaacsonB.Adelani DepartmentofBiochemistry,CovenantUniversity,Ota,Nigeria
Gonc ¸ aloJ.M.Afonso CNC—CenterforNeuroscienceandCellBiology,CIBB—Centrefor InnovativeBiomedicineandBiotechnology;IIIUC—InstituteforInterdisciplinaryResearch;PhD ProgrammeinExperimentalBiologyandBiomedicine(PDBEB),InstituteforInterdisciplinary Research(IIIUC),UniversityofCoimbra,Coimbra,Portugal
ShamaAhmad DivisionofMolecularandTranslationalBiomedicine,Departmentof AnesthesiologyandPerioperativeMedicine,TheUniversityofAlabamaatBirmingham, Birmingham,AL,UnitedStates
Gonza ´ lez-ZamoraAlberto EvolutionaryBiologyLaboratory,FacultyofBiologicalSciences, Jua ´ rezUniversityoftheStateofDurango,GomezPalacio,Durango,Mexico
KhashayarAlikarami SchoolofMedicine,AhvazJundishapurUniversityofMedicalSciences, Ahvaz,Iran
RicardoAlva DepartmentofBiologicalSciences,BrockUniversity,St.Catharines,ON,Canada
NasrinAmirrajab DepartmentofLaboratorySciences,SchoolofParamedicine,Ahvaz JundishapurUniversityofMedicalSciences,Ahvaz,Iran
PaulaB.Andrade REQUIMTE/LAQV,LaboratoryofPharmacognosy,DepartmentofChemistry, FacultyofPharmacy,UniversityofPorto,Porto,Portugal
AnaCristinaAndreazza TemertyFacultyofMedicine,DepartmentofPharmacology& ToxicologyandPsychiatry,UniversityofToronto,Toronto,ON,Canada
AmirChakeriAnsari SchoolofMedicine,AhvazJundishapurUniversityofMedicalSciences, Ahvaz,Iran
MichaelAschner DepartmentofMolecularPharmacology,AlbertEinsteinCollegeofMedicine, Bronx,NY,UnitedStates
MiladAshrafizadeh FacultyofEngineeringandNaturalSciences,SabanciUniversity;Sabanci UniversityNanotechnologyResearchandApplicationCenter(SUNUM),Istanbul,Turkey
OliviaR.M.Bagshaw DepartmentofBiologicalSciences,BrockUniversity,St.Catharines,ON, Canada
DanielJoseBarbosa CellDivisionMechanismsGroup,InstituteforResearchandInnovationin Health(i3S),UniversityofPorto,Porto;TOXRUN–ToxicologyResearchUnit,UniversityInstitute ofHealthSciences(IUCS),AdvancedPolytechnicandUniversityCooperative(CESPU),CRL, Gandra,Portugal
SergioBarroso MuscleResearchandMitochondrialFunctionLaboratory,Cellex-IDIBAPS, FacultyofMedicineandHealthSciences,UniversityofBarcelona,Barcelona,Spain
AmirhosseinBazmi SchoolofDentistry,AhvazJundishapurUniversityofMedicalSciences, Ahvaz,Iran
FatenF.BinDayel DepartmentofPharmacologyandTherapeutics,UniversityofLiverpool, Liverpool,UnitedKingdom
MelanieBlanc-Legendre MARBEC,UnivMontpellier,CNRS,Ifremer,IRD,INRAE,Palavas, France
RevathiBoyina VikasInstituteofPharmaceuticalSciences,Rajahmundry,AP,India
HelenaCarmo AssociateLaboratoryi4HB–InstituteforHealthandBioeconomy;UCIBIO–AppliedMolecularBiosciencesUnit,REQUIMTE,LaboratoryofToxicology,Departmentof BiologicalSciences,FacultyofPharmacy,UniversityofPorto,Porto,Portugal
FelixCarvalho AssociateLaboratoryi4HB–InstituteforHealthandBioeconomy;UCIBIO–AppliedMolecularBiosciencesUnit,REQUIMTE,LaboratoryofToxicology,Departmentof BiologicalSciences,FacultyofPharmacy,UniversityofPorto,Porto,Portugal
AmyE.Chadwick DepartmentofPharmacologyandTherapeutics,UniversityofLiverpool, Liverpool,UnitedKingdom
YiChen StateKeyLaboratoryofFoodScienceandTechnology,NanchangUniversity,Nanchang, People’sRepublicofChina
PaoloConvertini DepartmentofScience,UniversityofBasilicata,Potenza,Italy
TeresaCunha-Oliveira CNC—CenterforNeuroscienceandCellBiology,CIBB—Centrefor InnovativeBiomedicineandBiotechnology;IIIUC—InstituteforInterdisciplinaryResearch, UniversityofCoimbra,Coimbra,Portugal
DennisGuilhermedaCostaSilva OxidativeStressandCellSignalingResearchGroup,Federal UniversityofPampa,CampusSaoGabriel,SaoGabriel,RS,Brazil
MajidDarroudi HealthyAgeingResearchCentre,NeyshaburUniversityofMedicalSciences; DepartmentofBasicMedicalSciences,NeyshaburUniversityofMedicalSciences,Neyshabur,Iran
LidiadeBari InstituteofBiomembranes,BioenergeticsandMolecularBiotechnologies(IBIOM), ItalianNationalResearchCouncil(CNR),Bari,Italy
Patrı´ciadeBrumVieira OxidativeStressandCellSignalingResearchGroup,FederalUniversity ofPampa,CampusSaoGabriel,SaoGabriel,RS,Brazil
OpeyemiC.DeCampos DepartmentofBiochemistry,CovenantUniversity,Ota,Nigeria
MohammadAminDehghani ToxicologyResearchCenter,MedicalBasicSciencesResearch Institute;DepartmentofToxicology,SchoolofPharmacy,AhvazJundishapurUniversityof MedicalSciences,Ahvaz,Iran
NancyD.Denslow DepartmentofPhysiologicalSciencesandCenterforEnvironmentaland HumanToxicology,CollegeofVeterinaryMedicine,UniversityofFlorida,Gainesville,FL, UnitedStates
FernandaCarolinaRibeiroDias DepartmentofStructuralBiology,FederalUniversityof Tri^ anguloMineiro,Uberaba,Brazil
SujathaDodoala SriPadmavathiMahilaViswavidyalayam,Tirupathi,AP,India
JaroslawW.Drelich MaterialsScienceandEngineeringDepartment,MichiganTechnological University,Houghton,MI,UnitedStates
Rı´os-Sa ´ nchezEfraı ´ n CellularandMolecularBiologyLaboratory,FacultyofChemicalSciences, Jua ´ rezUniversityoftheStateofDurango,GomezPalacio,Durango,Mexico
DanaElSoufiElSabbagh TemertyFacultyofMedicine,DepartmentofPharmacology& ToxicologyandPsychiatry,UniversityofToronto,Toronto,ON,Canada
TimL.Emmerzaal DepartmentofClinicalGenomics,MayoClinic,Rochester,MN,United States;DepartmentofAnatomy,RadboudUniversityMedicalCenter,DondersInstitutefor BrainCognitionandBehaviour,Nijmegen,TheNetherlands
TaherehFarkhondeh FacultyofPharmacy,BirjandUniversityofMedicalSciences,Birjand,Iran
Gonza ´ lez-DelgadoMarı´aFernanda CellularandMolecularBiologyLaboratory,Faculty ofChemicalSciences,Jua ´ rezUniversityoftheStateofDurango,GomezPalacio,Durango, Mexico
JefersonLuisFranco OxidativeStressandCellSignalingResearchGroup,FederalUniversityof Pampa,CampusSa ˜ oGabriel,Sa ˜ oGabriel,RS,Brazil
BernardFromenty INSERM,UnivRennes,INRAE,InstitutNUMECAN(NutritionMetabolisms andCancer)UMR_A1341,UMR_S1241,Rennes,France
GeorginaL.Gardner DepartmentofBiologicalSciences,BrockUniversity,St.Catharines,ON, Canada
Glo ` riaGarrabou MuscleResearchandMitochondrialFunctionLaboratory,Cellex-IDIBAPS, FacultyofMedicineandHealthSciences,UniversityofBarcelona,Barcelona,Spain
AlessandraGhigo DepartmentofMolecularBiotechnologyandHealthSciences,Molecular BiotechnologyCenter,UniversityofTorino,Torino,Italy
SumalathaGindi VikasInstituteofPharmaceuticalSciences,Rajahmundry,AP,India
