芥子气暴露后动物体内生物标志物——DNA加合物的检测和代谢研究.pdf(3)

，employedgood retrospective(NT-HETEG)，NT-(2-hydroxyethylthioethyl)．2’一guaninewhichisformedwitheachN7byreactingbis(2．ethyl-N7-guanine)thioether(Bis—GXinDNAof twodouble-stranded(dsDNA)，positionguanines酽一HETEA)，andN3．(2-hydroxyethylthioethyl)-2’．adenineNT-HETEG,is onewithwhichtheguaninereactingabundance,therepossesseshighestofofSMinnobondschloromethanethe霄position。withhydrogengroupforwitheachWatson．CrickB／s—G，tworeactingdestroyed，whileguaninestypeofSMintheSOastoaffectthe structureofchloromethanespacegroupsN亨positionformedwithDNAs．AndforSM，thehydrogenOr-HETEG,onceduringalkylationzhikuquan20150721arethusbrokendown+anddouble-strandDNAsthebasesarecleavedbondsbetweenittheminimumisstillacceptedTherefore，althoughoccupiespercentage,扩一HETEGonthethemainfortheDNA bySM．BasedasproductresponsibledamagesofSM—DNAadductscouldtheanalysiscompletelysurveybase．pairingprinciple，theafterSMDNA and conditionofthe damagerepairexposure，alkylation，obtaindegreeoftreatmentwhichcouldevidencesfortheevaluation regime．effectivelyprovidesensitivethreeofnovelandThisworkincludestheall，theitems，firstfollowingmethodofliquidultrahighperformanceisotope．dilutionforthesimultaneousmassdevelopedspectrometry(UPLC—MS／MS)WasadductsintissuesandurinedeterminationoffourSM，DNAsamples．Then，isthemain ibrSMthattheadsorption pathexposure，theconsideringpercutaneousanimalmodelswithdermal toSMwerethetissuesandurineexposure developed，and．囊。

万方数据inscheduleandthemethodsmentionedabove·werecollectedanalyzedbysamplesfourlearntheandtimeofthesecancontent，distribution，doserelationshipLastly,weandkindsofSM．DNAadductsinvivotounderstandtheofSMdistributionregularitymetabolisminfromtowhole．organismpartThesixthisthesis．composefollowingchaptersThefirstistheintroductionoftheSM，whichchapterdisplayedphysicochemicaloftheandstatedindetailofthewas introducehistory．Therepropertyusingbrieflymetabolic invivoandthemechanismsofwhichthetoxicitySM，inpathwaypossibleandmethodsofbiomarkerswereinthisDNA lesionanalysishighlightedalkylatedandinnovationswerespecificstudyobjectivespointsproposed．chapter．Finally,theInthesecondsensitivemethodofID--UPLC··MS／MSwasforchapter,adevelopedfourSM．DNAadductsintissues．Fortheadductsthesimultaneousdeterminationofzhikuquan20150721wereboundmetabolitesinDNAwasforthemolecule，itinevitablycomplicatepretreatment．Afteraseriesofinmethodwasdecidedasoptimizationprocesspretreatment，theaofextractionandDNAprocessproteinenzymolysis，DNAbyphenol—chloroformwithalcoholtoextractDNAfollowedbasicsedimentationmolecule，andbygroupfromDNA formicacid．TheSM—DNAadductsuncombinedwerehydrolysis usingdeterminedUPLC—MS／MS．TheofthemethodWaS83—11LODbyrecovery8％，withwasandofO．02-0．1 and ofO．05-0．2methodng／mL LOQng／mL．Thishigh-efficientstabletomaketheresultsreceivableinthe ofinthethirdanalysispracticalsampleschapter．InthethirdanimalmodelofSDratsdermaltoSMinchapter,theexposedmaindifferentwastissuesofdosagedeveloped．The．．9．。

万方数据蒋lj学位论文AbstmctadductsweredeterminedinthoseandbrainwerecollectedandtheSM—DNApancreasinlearnthetissueswiththemethodmentioned two，tocontent，chapter systematicallyfourkindsofSM-DNAandtimeoftheseadducts，distribution，doserelationshipthe influenceonthedifferentfunctionandwhichcouldSMorganscompletelydisplaydifferenttoxicanttheirunderdosage．repairprocesstimethefoundthedoseand dependentresults，we significantAccordingthefirstoffouradductsoftheseSM-DNAadducts．Fortime，thesequenceresponsesaswasachi州edthattheDNASMwas06．HETEG(《o．1％)，whichproofeddamageby alkylationthatliver benotthewasalsomayunderestimatedpresumedseriously．Meanwhile，itthe wasmoreasSMofseverelySM，whilelung injuredtargetingorganmainlySMcouldreach theBlood-BrainitWasbelievedthatthroughincreases，anddosageSMandstoreitmorethereare contentof toabsorbeasily，Barrie，sincehighlipidzhikuquan20150721oftheofSM．becauselipotropismaftertheofbonemarrowInthefourthdamageexposureinvestigatedchapter,weimmuneandimmunecellswithanessentialcentraltoSM。

whi汰isorganproducesbaseontheirbonemarrowcellsthisthedifferentfeature。Inseparatedpart，weobservedthedifferentbetweenthecellsafter受a缒滗s，andresponsesseparatedtheeffectonimmuneoftocouldbetounderstandsystemSM，which helpfulexposedlevels．SMincellularthattheofthehadanItwasfoundmonocyte，especiallylymphocytequantitycellswere撞euteincreaseandfollowedthemultinuclearbydecreasingrapidly,whilewas relevanttrendofimmunecellsvariationhighlythesametime，theunchanged。AtadductsinofdeterminedtheSM-DNA￡otheelinicalmanifestationanimals。

Then，we．10． 万方数据DNAandvariationofmarrowthecorrelationwith ofthebonecells，todamagestudythatthecontentofBis-Gwas50％offourimmune wasfoundhigh，aboutsystem．ItSM．DNAthecritical ofDNAinbonemarrow．Therewasadducts，promptingdamageinandmultinuclearcontentofSM—DNAadductscells，whichasimilarmonocyteattackSMbetween andmultinucleardeclaredthetrendofbymonocleequivalentofSM—DNAadductinincreasedcells．ItwasshowedthatthecontentmonocletoitsaddeddemonstratedtheofSMowingamount芥子毒气 中毒时间，whichprinciple alkylationprocess．Inthefifthurinewerechosentobeurineischapter,thesamplesdetected，sincethecarrierofthefinal ofwastounderstandthewholemetabolism，itprocesspossiblefrom ofDNA toterminationofDNA intheentireprocessincept damagerepairbodyholisticofSM—DNAinurine．byapproachFirstofnovelandsensitivemethodofall，a zhikuquan20150721 isotope-dilutionultrahighmassperformanceliquidchromatography—tandemwithsolidextractionwasforthesimultaneouscombining phasedevelopeddeterminationoffourSM．DNAadducts．Alowerlimitofdetectionof2—5ng-L～，andalowerlimitofof5．10thequantitationng·L～were11weinrecoveriesfrom87％to6％．ThenthismethodtherangedappliedfourSM．DNAadductsinurineofSDratsandrabbitsafterdermaldeterminationofinthreedoseastotherelatedmetabolicexposurebySMlevels，SOinvestigatebehaviorinvivo．Forthefirst SM SDratandrabbitresultstime，inexposedurine，ourrevealedasimilarrelativeaccumulationabundanceoffourSM—DNAadducts，whichwassimilartrendwiththeresultinmetabolicofDNAtissue．Meanwhile，theprocessSMwasinjuriesbysurveyedmacroscopically． 万方数据簿：|：学位论文AbstractInthesixthwasintroduced。