Oxidative mechanisms in the toxicity of metal ions

PergamonReviewArticleOXIDATIVEFreeRadicalBiology&Medicine,Vol.18,No.2,pp.321-336,1995Copyright©1995ElsevierScienceLtdPrintedintheUSA.Allrightsreserved0891-5849/95$29.00+.000891-5849(94)00159-6MECHANISMSINTHETOXICITYOFMETALIONSS.J.STOHSandD.BAGCHISchoolofPharmacyandAlliedHealthProfessions,CreightonUniversity,Omaha,NE,USA(Received2December1993;Revised29April1994;AcceptedI1July1994)AbstractTheroleofreactiveoxygenspecies,withthesubsequentoxidativedeteriorationofbiologicalmacromoleculesinthetoxicitiesassociatedwithtransitionmetalions,isreviewed.Recentstudieshaveshownthatmetals,includingiron,copper,chromium,andvanadiumundergoredoxcycling,whilecadmium,mercury,andnickel,aswellaslead,depleteglutathioneandprotein-boundsulfhydrylgroups,resultingintheproductionofreactiveoxygenspeciesassuperoxideion,hydrogenperoxide,andhydroxylradical.Asaconsequence,enhancedlipidperoxidation,DNAdamage,andalteredcalciumandsulfhydrylhomeosta-sisoccur.Fenton-likereactionsmaybecommonlyassociatedwithmostmembranousfractionsincludingmitochondria,micro-somes,andperoxisomes.Phagocyticcellsmaybeanotherimportantsourceofreactiveoxygenspeciesinresponsetometalions.Furthermore,variousstudieshavesuggestedthattheabilitytogeneratereactiveoxygenspeciesbyredoxcyclingquinonesandrelatedcompoundsmayrequiremetalions.Recentstudieshavesuggestedthatmetalionsmayenhancetheproductionoftumornecrosisfactoralpha(TNFc0andactivateproteinkinaseC,aswellasinducetheproductionofstressproteins,Thus,somemechanismsassociatedwiththetoxicitiesofmetalionsareverysimilartotheeffectsproducedbymanyorganicxenobiotics.Specificdifferencesinthetoxicitiesofmetalionsmayberelatedtodifferencesinsolubilities,absorbability,transport,chemicalreactivity,andthecomplexesthatareformedwithinthebody.Thisreviewsummarizescurrentstudiesthathavebeenconductedwithtransitionmetalionsaswellaslead,regardingtheproductionofreactiveoxygenspeciesandoxidativetissuedamage.Keywords---Iron,Copper,Cadmium,Chromium,Mercury,Nickel,Vanadium,Lead,Zinc,Freeradicals,Oxidativestress,Redoxcycling,Glutathionedepletion,Lipidperoxidation,DNAdamage,StressproteinsINTRODUCTIONAgrowingbodyofevidenceindicatesthattransitionmetalsactascatalystsintheoxidativedeteriorationofAddresscorrespondenceto:S.J.Stohs,Dean,SchoolofPhar-macyandAlliedHealthProfessions,CreightonUniversity,2500CaliforniaPlaza,Omaha,NE68178USA.DebasisBagchireceivedhisM.Sc.degreeinchemistrywithaspecializationinorganicchemistryfromJadavpurUniversity,Cal-cutta,India.HereceivedhisPh.D.inmedicinalchemistryfromtheIndianInstituteofChemicalBiology(anationallaboratoryofthegovernmentofIndia),Calcutta.HeconductedpostdoctoralresearchatBowlingGreenStateUniversity,OhioandtheUniversityofCon-necticut,Farmingtonfrom1985to1988.HeservedastheDivisionalManagerinresearchanddevelopmentofBergerIndiaLtd.,Calcutta,from1982to1985andagainfrom1988to1990.In1991,hejoinedtheCreightonUniversitySchoolofPharmacyandAlliedHealthProfessionsfaculty,andiscurrentlyanAssistantProfessorintheDepartmentofPharmaceuticalandAdministrativeSciences.Hisre-searchinterestsincludemechanismsoftoxicityofmetalsandvariouspesticides,andthedesignofnovelchemoprotectants.SidneyJ.StohsreceivedhisB.S.inpharmacyandanM.S.degreeinpharmacognosyfromtheUniversityofNebraska-Lincoln.HereceivedhisPh.D.inbiochemistryfromtheUniversityofWisconsin-Madison.HeservedonthefacultyattheUniversityofNebraska-Lincolnfrom1967to1975.HewasavisitingprofessoratKrolinskaInstitute,Stockholm,Swedenin1975to1976.From1976to1989,hewasattheUniversityofNebraskaMedicalCenter,chairingtheDepartmentofBiomedicinalChemistryfrom1976to1985Hebiologicalmacromolecules,andtherefore,thetoxici-tiesassociatedwiththesemetalsmaybedueatleastinparttooxidativetissuedamage.Recentstudieshaveshownthatmetalssuchasiron,copper,cadmium,chro-mium,lead,mercury,nickel,andvanadiumexhibittheabilitytoproducereactiveoxygenspecies,resultinginlipidperoxidation,DNAdamage,depletionofsulfhy-dryls,andalteredcalciumhomeostasis.Thetoxicitiesproducedbythetransitionmetalsgenerallyinvolveneurotoxicity,hepatotoxicity,andnephrotoxicity.Specificdifferencesinthetoxicitiesofmetalionsmayberelatedtodifferencesinsolubili-ties,absorbability,transport,chemicalreactivity,andthecomplexesthatareformedwithinthebody.InservedasAssistantDeanforResearchandDevelopmentintheCol-legeofPharmacyfrom1985to1987.Dr.StohswasavisitingscientistattheNationalInstituteofEnvironmentalHealthSciencesin1987to1988.HejoinedCreightonUniversityHealthSciencesCenterastheAssistantDeanforResearchin1989,withappoint-mentsintheDepartmentsofPharmaceuticalSciencesandPharma-cology.HewasappointedDeanoftheSchoolofPharmacyandAlliedHealthProfessionsin1990.Hisresearchinterestsincludemechanismsoftoxicityandthedevelopmentofchemoprotectiveagentsagainsttoxins.321322S.J.STOHSandD.BAGCHIspiteofthesefactors,thebasicmechanismsinvolvingproductionofreactiveoxygenspeciesarethesameforthesetransitionmetalions.Furthermore,thebasicmechanismofreactiveoxygenspeciesproductionandultimatetoxicityproducedbymetalionsmayinvolvemechanismsthatarecommontoredoxcyclingor-ganicxenobiotics,as,forex