Theoreticalbasis
Mainlyapplythetheoriesandtechniquesofbasicdisciplinessuchasphysiology,pharmacology,biology,biochemistryandpathology;throughanimalexperiments,clinicalobservationsandepidemiologicalinvestigationmethods,Tostudytheabsorption,distribution,metabolismandexcretionofforeignsubstances,toxiceffectsandtheirmechanisms,andpoisoningtreatment,notonlytoprotecthumansandotherorganismsfromtheharmfuleffectsofchemicalsubstances,toprotectthehealthofthepeople,butalsotodirectlydevelopgoodSelectthepoisonsthatactbycomparingtoxicityandselectivepoisoningmethodstodevelopmoreselectivedrugsandpesticides,andconductsafetyevaluationorriskevaluationofchemicalsubstances,formulatesanitarystandards,andprovidescientificbasis.Toxicologyiscloselyrelatedtopharmacology,andhasnowdevelopedintoanindependentsubjectwithcertainbasictheoriesandexperimentalmethods,andgraduallyformedsomenewbranchesoftoxicology.
Role
Thecurrentlyaccepteddefinitionoftoxicologyisthescienceofstudyingtheharmofexogenouschemicalsubstancestoorganisms.Sincetheresearchpurposeoftoxicologyistoprotectthehealthorsafetyoforganisms,toxicologybelongstopreventivemedicineintermsofthenatureofthediscipline,anditrunsthroughtheideaofpreventionasthemainstay.Sincetoxicologyhasawiderangeofresearchobjects,includingchemicalfactors,physicalfactors,andbiologicalfactors,andorganismsincludehumans,animals,andplants,toxicologyisrelatedtopharmacology,physiology,pathology,chemistry,biochemistry,andbiology;Ithasconnectionswithindustry,agriculture,andeconomy;ithasconnectionswithforensicmedicine,clinicalmedicine,ecologyandenvironmentalprotection;itcanbesaidthatithasconnectionswiththeentirefutureoflifeonearth.Therefore,toxicologyhasawiderangeofapplicationsinthefieldsofclinicalmedicine,pharmacy,environmentalprotection,zoology,eugenics,occupationallaborprotection,andfoodhygiene.Therefore,theclassificationoftoxicologyisverycomplicatedandcanbeclassifiedfromdifferentangles,whichisnotcompletelyconsistent.
Classification
Fromtheresearchcontent,itcanbedividedintothreeparts:descriptivetoxicology,mechanismtoxicologyandmanagementtoxicology(alsocalledregulatorytoxicology).
Accordingtostandarddisciplines,itcanbedividedinto:forensictoxicology,clinicaltoxicology,managementtoxicologyorregulatorytoxicology,researchtoxicology,etc.
Fromappliedtoxicologycanbedividedinto:foodtoxicology,industrialtoxicology,pesticidetoxicology,militarytoxicology,radiationtoxicology,environmentaltoxicology,ecotoxicologyandotherbranches.
Theresearchobjectscanbedividedinto:insecttoxicology,veterinarytoxicology,humantoxicologyandphytotoxicology.
Fromtheresearchfield,itcanbedividedinto:pharmaceuticaltoxicology,environmentaltoxicology,foodtoxicology,industrialtoxicology,clinicaltoxicology,forensictoxicology,analyticaltoxicology,militarytoxicology,managementtoxicology,etc..
Fromtheresearchtargetorgansorsystems,itcanbedividedinto:organtoxicology,livertoxicology,kidneytoxicology,eyetoxicology,ototoxicology,neurotoxicology,reproductivetoxicology,immunotoxicology,etc..
1.Concept
1.Toxicologyisthescienceofstudyingthedamagingeffectsofchemicalsubstancesonbiologicalorganismsandthemechanismofactionfromamedicalpointofview.However,inrecentyears,theresearchscopeoftoxicologyhasexpandedtovariousharmfulfactors,suchasnuclide,microwaveandotherphysicalfactorsandbiologicalfactors,etc.,notlimitedtochemicalsubstances;butthemainresearchcontentofclassicaltoxicologyisstilltheeffectofchemicalsubstancesonthebody.Thebiologicalroleandmechanismof
IIHygieneToxicologyisadisciplinethatstudiesthedamageeffectandmechanismofforeigncompoundsthathumansmaybeexposedtointheprocessofproductionandlifefromtheperspectiveofpreventivemedicine.Itisanimportantbranchoftoxicologyandabasicdisciplineofpreventivemedicine.Itprovidestoxicologicaltheoriesandresearchmethodsforlaborhygiene,environmentalhygieneandfoodhygiene,andisanimportantpartofpreventivemedicine.
3Foreigncompoundsaresomechemicalsubstancesthatexistinhumanlifeandtheexternalenvironment,andmaycomeintocontactwiththebodyandenterthebody.Foreigncompoundsarenotcomponentsofthehumanbody,nornutrientsrequiredbythehumanbody,noraretheynecessarytomaintainthebody’snormalphysiologicalfunctionsandlife,buttheycancontactthebodythroughcertainlinksandpathwaysfromtheexternalenvironmentandenterthebody.Itexhibitscertainbiologicaleffectsinthebody.Commonforeigncompoundsincludeagriculturalchemicals,industrialchemicals,drugs,foodadditives,dailychemicals,variousenvironmentalpollutants,andmycotoxins.
2.HygieneToxicologyResearchTasks
Inthefieldofpreventivemedicine,therearethreemainresearchtasksinHygieneToxicology.Thefirstistostudytheinteractionbetweenthebodyandforeigncompounds,thatis,themechanismofpoisoning.;Thesecondistoevaluatethesafetyofforeigncompounds;thethirdistoprovideascientificbasisfortheformulationofrelevanthealthstandardsandmanagementprograms.
3.Hygienictoxicologyresearchmethods
Oneanimalexperiment
1.Invivoexperimentmethod
Usuallyperformedinwholeanimals,Theexperimentalanimalisexposedtoacertaindoseofthetestedforeigncompoundaccordingtotheactualcontactmethodofthehumanbodyforacertainperiodoftime,andthenthepossiblemorphologicalorfunctionalchangesoftheanimalareobserved.Experimentsmostlyusemammals,suchasrats,mice,guineapigs,rabbits,hamsters,dogs,andmonkeys.Thegeneraltoxicityofforeigncompoundsisusuallytested,suchasacutetoxicitytest,sub-chronictoxicitytestandchronictoxicitytest.
2.Invitroexperimentalmethods
Mostusefreeorgans,primaryculturedcells,celllinesandorganelles.Theorganperfusiontechnologycanbeusedtoperfusetheliver,kidneys,lungs,andbrains,sothattheisolatedorganscanmaintainalivingconditionforacertainperiodoftime,contactwiththetestedforeigncompounds,andobservethemorphologicalandfunctionalchangesoftheorgans.Atthesametime,itcanalsoobservethemetabolismofthetestsubstanceintheorgans;freecellsandorganellesaremostlyusedforpreliminaryscreeningofthevariousdamageeffectsofforeigncompoundsonthebody,themechanismofactionandthein-depthstudyofthemetabolictransformationprocess,whichhavemanyadvantages.
Theabove-mentionedstudiesattheoverall,organ,cellularandsubcellularlevelseachhavecertaincharacteristicsandlimitations.Inactualwork,themostappropriatemethodshouldbeusedmainlyaccordingtothepurposeandrequirementsofexperimentalresearch.Andmutualauthentication.
Twopopulationsurveys
Inordertoverifytheresultsofanimalexperimentsonhumans,populationsurveysaresometimesrequired.Accordingtotheresultsofanimalexperimentsandthenatureoftheforeigncompounds,appropriateobservationindicatorsareselectedandthepopulationsurveyisconductedbyepidemiologicalmethods.Thecharacteristicofpopulationsurveyisthatitcanobtainthedatadirectlyobservedinthehumanbody,butitissusceptibletotheinfluenceandinterferenceofmanyotherconfoundingfactors;theresultsandevaluationmustberemovedfromthefalseandthetruth,fromtheoutsidetotheinside,andcomprehensivelyconsideredandanalyzedwiththeresultsofanimalexperiments.Amorerealisticconclusion.
1.Toxicity
Toxicityistheabilityofasubstancetocausedamagetothebody.Highlytoxicsubstances,aslongasrelativelysmallamounts,cancausecertaindamagetothebody;whilelesstoxicsubstancesrequirealargeramounttobecometoxic.Thelevelofsubstancetoxicityisonlyofrelativesignificance.Inacertainsense,aslongasitreachesacertainamount,anysubstanceistoxictothebody;ingeneral,ifitislessthanacertainamount,nosubstanceistoxic;thekeyistheamountofsuchsubstanceincontactwiththebody.Inadditiontothenumberofsubstancesincontactwiththebody,itisalsorelatedtothephysicalandchemicalpropertiesofthesubstanceitselfandthewayinwhichitcomesintocontactwiththebody.
2.Dose
Doseisanimportantfactorindeterminingthedamageeffectofforeigncompoundsonthebody.Theconceptofdoseisrelativelybroad,anditcanrefertotheamountgiventothebody,ortheamountofforeigncompoundsincontactwiththebody,theamountofforeigncompoundsabsorbedintothebody,andtheconcentrationorcontentofforeigncompoundsinthetargetorgan'ssiteofactionorbodyfluids.Sincetheinternaldoseisnoteasytodetermine,thegeneralconceptofdosereferstotheamountofforeigncompoundgiventothebodyortheamountofbodycontact.Theunitofdosageisexpressedastheamountofforeigncompoundexposedperunitbodyweight,forexample,mg/kgbodyweight.
1.Lethaldose
Thelethaldoseisthedosethatcancausethebodytodie.However,inagroup,thenumberofdeadindividualsvariestoalargeextent,andtherequireddosesarealsoinconsistent.Therefore,lethaldosehasthefollowingdifferentconcepts.
⑴.Theabsolutelethaldose(LD100)referstothelowestdosethatcancausealldeathsinagroup.
⑵.Themedianlethaldose(LD50)referstothedoserequiredtocause50%ofthedeathofagroupofindividuals,alsocalledthelethalmediumdose.TheunitofLD50ismg/kgbodyweight.ThesmallertheLD50value,thestrongerthetoxicityoftheforeigncompound;conversely,thelargertheLD50value,thelowerthetoxicity.
2.Themaximumno-effectlevel(maximalno-effectlevel)
Themaximumno-effectlevelmeansthataforeigncompoundcomesintocontactwiththebodyinacertainwayorroutewithinacertainperiodoftime.Accordingtothecurrentlevelofknowledge,usingthemostsensitivetestmethodsandobservationindicators,ithasnotbeenpossibletoobservethehighestdoseofanydamagingeffectonthebody.
Thedeterminationofthemaximumnon-effectdoseisbasedontheresultsofsubchronictoxicityorchronictoxicitytests,andisthemainbasisforassessingthedamageeffectofforeigncompoundsonthebody.Basedonthis,theacceptabledailyimtarie(intake,ADI)andthemaximumallowableconcentration(MAC)ofaforeigncompoundcanbeformulated.ADIreferstothedailyintakeoftheforeigncompoundforthelifeofhumanswithoutcausinganydamagingeffects.MACreferstotheconcentrationatwhichaforeigncompoundcanexistintheenvironmentwithoutcausinganydamagetothehumanbody.
3.Theminimumeffectivedose(minmaleffectlevel)
Theminimumeffectivedosemeansthatwithinacertainperiodoftime,aforeigncompoundcomesintocontactwiththebodyinacertainwayorway,whichcanmakeTheminimumdoserequiredforanobservationindextobegintochangeabnormallyortocausethebodytobegintohaveadamagingeffect,canalsobecalledthepoisoningthresholddose,orthepoisoningthreshold.Theoretically,thedifferencebetweenthemaximumnon-effectdoseandtheminimumeffectdoseshouldbeverysmall,becauseanysmalloreveninfinitelysmallincreaseinthedosethatdamagesthebodyshouldtheoreticallyincreaseaccordingly.However,sincetheobservationindexofthedamageeffectislimitedbythesensitivityoftheobservationmethodofthisindex,subtlechangesmaynotbedetected.Onlywhenthedifferencebetweenthetwodosesreachesacertaindegree,thedifferenceinthedegreeofdamagecanbeclearlyobserved.Therefore,thereisstillacertaingapbetweenthemaximumnon-effectdoseandtheminimumeffectivedose.
Whenthetime,modeorrouteofthecontactoftheforeigncompoundwiththebodyandtheobservationindicatorschange,themaximumnon-effectdoseandtheminimumeffectivedosewillalsochange.Therefore,whenexpressingthemaximumnon-effectivedoseandminimumeffectivedoseofaforeigncompound,thespeciesstrain,contactmodeorroute,contactdurationandobservationindicatorsofthetestanimalmustbestated.Forexample,afteracertainorganophosphoruscompoundisadministeredtorats(wistarstrain)for3months,themaximumnon-effectdosethatreducestheactivityofwholebloodcholinesteraseby50%is10mg/kgbodyweight.
Three.Effectandresponse
Oneeffectreferstothebiologicalchangesthatcanbecausedbyacertaindoseofforeigncompoundsincontactwiththebody.Thedegreeofthischangeisexpressedinunitsofmeasurement,suchasseveral,milligrams,units,etc.
Thesecondresponseisthatafteracertaindoseofaforeigncompoundcomesintocontactwiththebody,itexhibitsacertaineffectandreachesacertaindegreeofratio,ortheratioofthenumberofindividualsthatproduceaneffectinacertaingroup,generallyin%Orratiorepresentation.
Four.Dose-responserelationshipanddose-responserelationship
Dose-effectrelationshipordose-responserelationshipisanimportantconceptintoxicology.Ifacertaindamagingeffectinthebodyisdefinitelycausedbyaforeigncompound,theremustbeacleardoseeffectordoseresponserelationship,otherwiseitisnotcertain.
Dose-effectanddose-responserelationshipcanbeexpressedbyacurve,thatis,themeasurementunitrepresentingtheintensityoftheeffectorthepercentageorratiooftheresponseistheordinate,andthedoseistheabscissa,andthescatterdiagramcanbedrawn.Drawacurve.Differentforeigncompoundscausedifferenttypesofeffectsorreactionsunderdifferentspecificconditions.Themainreasonisthatthecorrelationbetweentheeffectorreactionandthedoseisinconsistent,whichcanpresentdifferenttypesofcurves.Ingeneral,thedose-effectordose-responsecurvehasthefollowingbasictypes:
1.Thelineareffectortheintensityoftheresponsehasalinearrelationshipwiththedose;asthedoseincreases,theintensityoftheeffectorresponsealsoincreases.Increase,andisproportionaltotherelationship.Butinbiologicalorganisms,thislinearrelationshiprarelyoccurs,andonlyinsomeinvitroexperiments,withinacertaindoserange.
2.Theparabolicdosehasanon-linearrelationshipwiththeeffectorresponse,thatis,asthedoseincreases,theintensityoftheeffectorresponsealsoincreases,buttheincreaseisrapidatfirst,andthenbecomesslow,sothatthecurveissteepatfirst,Andthengently,intoaparabolicshape.Ifyouchangethedosetoalogarithmicvalue,itbecomesastraightline.Therelationshipbetweendoseandeffectorresponse,replacedbyastraightline,canfacilitatemutualcalculationsbetweenlowdoseandhighdose,orlowresponseintensityandhighresponseintensity.
3,S-shapedcurveThecharacteristicofthiscurveisthatinthelowdoserange,asthedoseincreases,theresponseoreffectintensityincreasesmoreslowly,andwhenthedoseishigher,theresponseoreffectintensityalsoincreases.Therapidincrease,butwhenthedosecontinuestoincrease,theresponseoreffectintensityincreasesandtendstobeslow.Thecurvestartstobeflat,thenhasasteepridge,andthenflattensoutintoanirregularS-shape.Themiddlepartofthecurve,thatis,theresponserateisabout50%,theslopeisthelargest,andthedosechangesslightly,andtheresponsehasalargeincreaseordecrease.Itismorecommoninthedose-responserelationship,andpartofthedose-effectrelationshipalsoappears.S-shapedcurvesaredividedintotwotypes:symmetricalandasymmetrical.ThetwoendsoftheasymmetricS-shapedcurveareasymmetric,oneendislongerandtheotherendisshorter.Iftheabscissa(dose)oftheasymmetricS-shapedcurveisexpressedinlogarithm,itbecomesasymmetricalS-shapedcurve;ifthereactionrateisreplacedwithaprobabilityunit,itbecomesastraightline.
Five.Damageandnon-damagingeffects
Onenon-damagingeffectsaregenerallyconsideredthatnon-damagingeffectsdonotcausechangesinthebody'sfunctionmorphology,growthanddevelopmentandlifespan;donotcausecertainfunctionsofthebodyThedecreaseincapacitydoesnotcausedamagetothebody'sabilitytocompensatefortheadditionalstressstate.Allbiologicalchangesinthebodyshouldbewithinthebody’scompensatorycapacity.Whenthebodyceasestobeexposedtotheexotoxiccompound,thebody’sabilitytomaintainhomeostasisshouldnotbereduced.Sensibilityshouldnotincreaseeither.Steadystateisatendencyorabilityofthebodytokeepitsinternalenvironmentstableandunchanging.
TwodamagingeffectsThedamagingeffectsareoppositetothenon-damagingeffects,andshouldhavethefollowingcharacteristics:
1.Thenormalshapeofthebodyandthegrowthanddevelopmentprocessareseverelyaffected,andthelifespanwillalsobeshortened.
2.Thefunctionalcapacityofthebodyorthecompensatoryabilityoftheextrastressstateisreduced.
3.Thebody'sabilitytomaintainstabilitydecreases.
4.Thebodyismoresusceptibletotheadverseeffectsofcertainotherfactors.
Itshouldbepointedoutthatbothdamagingandnon-damagingeffectsbelongtothebiologicaleffectsofforeigncompoundsinthebody.Inbiologicaleffects,changesinquantityoftencausequalitativechanges,sodamagingandnon-damagingeffectsThedamageeffectonlyhasacertainrelativesignificance.Inaddition,theobservableindicatorsfordeterminingdamagingandnon-damagingeffectshavealsobeencontinuouslydeveloped.
Six.NormalvaluesThedeterminationofdamagingandnon-damagingeffectsofteninvolvesthenormalrangeofmanyindicatorsofthebody,andsometimesitisnecessarytodeterminethenormalvalue.First,itmustbeclearthat"normalvalue"onlyhasarelativemeaning.Inactualwork,accordingtothecurrentlevelofknowledge,individualswhoareconsidered"healthy"or"normal"willbemeasuredforanobservationindex,andtheaveragevalue±2standarddeviationswillbeusedasthenormalvaluerange.Statisticalmethodscanbeusedtodeterminewhetherthechangeofthisindicatordeviatesfromthenormalvaluerange.Whenacertainobservationindicatormeetsoneofthefollowingconditions,itcanbeconsideredashavingdeviatedfromthenormalvaluerangeandbelongstoadamagingeffectoranon-damagingeffect.
⒈Comparedwiththecontrolgroup,thereisastatisticallysignificantdifference(P<0.05),anditsvalueisnotwithinthenormalrange.
⒉Comparedwiththecontrolgroup,thereisastatisticallysignificantdifference(P<0.05),butitsvalueiswithinthegenerallyrecognized"normalvalue"range;butifthecontactisstopped,suchadifferenceIfitcontinuesforaperiodoftime,itisadamagingeffect.
⒊Comparedwiththecontrolgroup,thereisastatisticallysignificantdifference(P<0.05),butitsvalueiswithinthegenerallyrecognized"normalvalue"range;butifthebodyisinafunctionalorbiochemicalresponseInanexcitedstate,thisdifferenceismoreobvious,whichisadamagingeffect.
1.Theconceptofbiologicaltransport
Theabsorption,distributionandmetabolismofforeigncompoundsinthebodyarecollectivelyreferredtoasbiologicaltransport.
Second,themechanismofbiologicaltransport
Thebiologicaltransportofforeigncompoundsinthebodyismainlythroughthefollowingmechanisms:
OnesimplediffusionThediffusionofforeigncompoundsinthebodyisbasedonitTheconcentrationgradientdifferencedeterminesthediffusiondirectionofthesubstance,thatis,themolecularconcentrationofthebiofilmdiffusesfromthesidewiththehigherconcentrationtothesidewiththelowerconcentration.Whenthetwosidesreachadynamicequilibrium,thediffusionstops.Thesimplediffusionprocessdoesnotneedtoconsumeenergy,theforeigncompoundsdonotreactchemicallywiththemembrane,andthebiomembraneisnotactiveandisonlyequivalenttoaphysicalprocess,soitiscalledsimplediffusion.Simplediffusionisthemainmechanismforthebiologicaltransportofforeigncompoundsinthebody.Ingeneral,mostforeigncompoundsarebiotransportedbysimplediffusion.Inadditiontothedifferenceintheconcentrationgradientofthetwobiofilmsthatcanaffectthesimplediffusion,thereareotherfactorsthatcanalsoaffectthesimplediffusionprocess.
1.Thesolubilityofforeigncompoundsinlipidscanbeexpressedbythelipid-waterpartitioncoefficient,thatis,theratiooftheconcentrationofforeigncompoundsinthelipidphasetotheconcentrationinthewaterphase(theconcentrationinthelipidphase/Concentrationinthewaterphase).Thegreaterthefat-waterpartitioncoefficient,theeasieritistodiffusethroughthebiofilm.However,intheprocessofbiotransportation,foreigncompoundsmustpassthroughthewaterphaseinadditiontothelipidphase.Becausethestructureofthebiomembraneincludesthelipidphaseandthewaterphase,thesolubilityofaforeigncompoundinwateristoolow,evenifthelipid-waterpartitioncoefficientistoolow.Itisverylarge,anditisnoteasytodiffusethroughbiofilms.Onlyforeigncompoundsthatareeasilysolubleinfatandwatercandiffusemosteasilythroughbiofilms.
2.Theionizationordissociationstateoftheforeigncompound.Foreigncompoundsinanionicstatecannoteasilypassthroughbiologicalmembranes;conversely,foreigncompoundsinanon-dissociatedstatecaneasilypassthrough.Thedegreeofdissociationofforeigncompoundsisdeterminedbyitsdissociationconstant(pK)andthepHofthemedium.Inadditiontotheabovetwomainfactors,therearemanyotherfactorsthatcanalsoaffectsimplediffusion.
Secondfiltration
Filtrationistheprocessbywhichforeigncompoundspenetratethehydrophilicporesofbiologicalmembranes.Alargeamountofwatercanentercellsthroughtheporeswiththehelpofosmoticpressuregradientandhydrostaticpressure.Foreigncompoundscanbetransportedpassivelywithwaterasacarrier.
ThreeActiveTransport
Theprocessinwhichforeigncompoundsmovefromlowconcentrationtohighconcentrationthroughbiofilm.Itsmainfeaturesare:①Reversibleconcentrationgradienttransport,soitconsumesacertainamountofmetabolicenergy;②Thetransportprocessrequirestheparticipationofcarriers.Thecarrierisoftenaproteinonthebiomembrane,whichcanformacomplexwiththeforeigncompoundtobetransportedtotheothersideofthemembrane,andthenreleasetheforeigncompound,thecarrierreturnstotheoriginalplace,andcontinuesforthesecondtransport;③ThecarrierSinceitisacomponentofthebiofilm,ithasacertaincapacity;whenthecompoundconcentrationreachesacertainlevel,thecarriercanbesaturated,andthetransportreachesthelimit;④Theactivetransporthasacertainselectivity.Thatis,thecompoundmusthaveacertainbasicstructurebeforeitcanbetransported;aslightchangeinthestructurecanaffecttheprogressofthetransport;⑤Ifthebasicstructureofthetwocompoundsissimilar,thesametransportsystemisrequiredinthebiologicaltransportprocess,andthetwocompoundscanappearCompetition,andproducecompetitiveinhibition.
Fourcarrierdiffusion
Forforeigncompoundsthatarenoteasilysolubleinlipids,theprocessinwhichthecarriermovesfromahighconcentrationtoalowconcentrationisused.Sincetheconcentrationgradientcannotbereversedfromlowconcentrationtohighconcentration,metabolicenergyisnotconsumed.Duetotheuseofthecarrier,thebiofilmhasacertaindegreeofinitiativeorselectivity,butitcannotreversetheconcentrationgradient,soitbelongstothenatureofdiffusion,andcanalsobecalledfacilitatingdiffusionorpromotingdiffusion.Water-solubleglucoseentersthebloodfromthegastrointestinaltract,enterstheredbloodcellsfromtheplasma,andentersthenervetissuefromtheblood,allofwhicharediffusedthroughthecarrier.
Wuppingandphagocytosis
Liquidorsolidforeigncompoundsaresurroundedbytheprotrudingbiofilm,andthenthesurroundeddropletsorlargerparticlesareincorporatedintothecelltoachievetransportThepurposeoftheformeriscalledpinocytosisandthelatteriscalledphagocytosis.Eliminationofforeignbodiesinthebody,suchasthephagocytosisofmicroorganismsbywhitebloodcells,andtheeliminationoftoxicforeignbodiesbyhepaticreticuloendothelialcellsareallrelatedtothis.
3.Theconceptofabsorptionandthewayofabsorption
Theconceptofabsorption
Absorptionisthewaythatforeigncompoundsenterthebloodthroughthebody’sbiologicalmembranesprocess.
SecondPathofAbsorption
1.Absorptionthroughthegastrointestinaltract
Thegastrointestinaltractisthemainabsorptionpathwayofforeigncompounds.Manyforeigncompoundscanenterthedigestivetractalongwithfoodordrinkingwaterandbeabsorbedinthegastrointestinaltract.Generally,theabsorptionprocessofforeigncompoundsinthegastrointestinaltractismainlythroughsimplediffusion,andonlyafewkindsofforeigncompoundsareabsorbedthroughadedicatedactivetransportsystemthatabsorbsnutrientsandendogenouscompounds.
Theabsorptionofforeigncompoundsinthegastrointestinaltractcanbecarriedoutinanypart,butmainlyinthesmallintestine.Theabsorptionofforeigncompoundsinthestomachismainlythroughasimplediffusionprocess.Duetotheextremelyhighacidityofgastricjuice(pH1.0),weakorganicacidsmostlyexistinundissociatedforms,sotheyareeasilyabsorbed;butweakorganicalkalishaveahighdegreeofdissociationinthestomachandaregenerallynoteasytoabsorb.
Theabsorptioninthesmallintestineismainlythroughsimplediffusion.ThepHinthesmallintestineisrelativelyneutral(pH6.6),andthedissociationofthecompoundisdifferentfromthatinthestomach.Forexample,weakorganicbasesaremainlyinanon-dissociatedstateinthesmallintestine,sotheyareeasilyabsorbed.Weakorganicacidsaretheoppositeofthismechanism.Forexample,benzoicacidisnoteasilyabsorbedinthesmallintestine.Butinfact,becausethesmallintestinehasalargesurfacearea,villiandmicrovillicanincreasethesurfaceareabyabout600times,sothesmallintestinecanalsoabsorbaconsiderableamountofbenzoicacid.Inaddition,thesmallintestinalmucosacanalsoabsorbsmallmoleculeswithamolecularweightof100to200orlessthroughafiltrationprocess,andgastrointestinalepithelialcellscanalsoabsorbsomeparticulatematterthroughpinocytosisorphagocytosis.
2.Absorbedthroughtherespiratorytract
Thelungisthemainabsorptionorganintherespiratorytract.Thealveolarepithelialcelllayerisextremelythinandthebloodvesselsareabundant.Therefore,gas,volatileliquidvaporandsmallgasThesolisabsorbedquicklyandcompletelyinthelungs.Thefastestabsorptionisgas,smallparticleaerosolsandsubstanceswithahigherpartitioncoefficientoffatandwater.Foreigncompoundsabsorbedthroughthelungsaredifferentfromthoseabsorbedthroughthegastrointestinaltract.Theformerdoesnotentertheliverwiththeportalveinbloodflow,andwithoutthebiotransformationprocessintheliver,itdirectlyentersthesystemiccirculationandisdistributedthroughoutthebody.Theabsorptionofgases,volatileliquidsandaerosolsintherespiratorytractismainlythroughsimplediffusion,andisaffectedbymanyfactors,mainlytheconcentrationdifferencebetweenalveolargasandplasma.Theconcentrationofagasinthealveolargascanbeexpressedbyitspartialpressureinthealveoli.Thepartialpressureofagasisthepercentageofthetotalpressureofthealveolargas.Thehigherthepartialpressure,thegreatertheamountofbodycontact,andtheeasieritistoabsorb.Astheabsorptionprocessproceeds,thepartialpressureofthegasinthebloodwillgraduallyincrease,andthepartialpressuredifferencewilldecreaseaccordingly.Thepartialpressureofthegasinthebloodwillgraduallyapproachthepartialpressureofthealveolargas,andfinallyreachequilibriumandassumeasaturatedstate.Inthesaturatedstate,theratiooftheconcentrationofgasintheblood(mg/L)totheconcentrationinthealveolargas(mg/L)iscalledtheblood/gaspartitioncoefficient,thatis,theconcentrationofgasintheblood/theratioofgasinthealveoliConcentrationratio.Thelargertheblood/gasdistributioncoefficient,thehigherthesolubility,andtheeasierthegasisabsorbed.
Theabsorptionrateofgasintherespiratorytractisalsorelatedtoitssolubilityandmolecularweight.Ingeneral,theabsorptionrateisdirectlyproportionaltothesolubility.Whennon-fat-solublesubstancesareabsorbed,theypassthroughthehydrophilicpores,andtheirabsorptionspeedismainlyaffectedbythesizeofthemolecularweight;substanceswithlargemolecularweightsarerelativelyslowtoabsorb,andviceversa.Forsubstancessolubleinbiofilmlipids,theabsorptionratehaslittletodowithmolecularweight,butismainlydeterminedbyitsfat/waterpartitioncoefficient.Theabsorptionrateisrelativelyhighwhenthelipid/waterpartitioncoefficientislarge.
Factorsthataffecttheabsorptionofchemicalsthroughtherespiratorytractincludealveolarventilationandbloodflow.Theratioofalveolarventilationtobloodflowiscalledtheventilation/bloodflowratio,especiallywithalveolarventilationandbloodflow.Theratioofthetwoisrelated.
3.Absorptionthroughtheskin
Theabsorptionofforeigncompoundsthroughtheskincangenerallybedividedintotwostages.Thefirststageistheprocessofforeigncompoundspassingthroughtheepidermisoftheskin,thatis,thestratumcorneum.Forthepenetrationstage.Thesecondstageistheabsorptionstagefromthestratumcorneumintothenipplelayeranddermis,andisabsorbedintotheblood.
Themainmechanismofabsorptionthroughtheskinissimplediffusion,andthediffusionrateisrelatedtomanyfactors.Themainrelevantfactorsinthepenetrationstagearethemolecularweightoftheforeigncompound,thethicknessofthestratumcorneum,andthefatsolubilityoftheforeigncompound.Thespeedoffat-solublenon-polarcompoundspassingthroughtheepidermisisdirectlyproportionaltotheleveloffat-soluble,thatis,thesizeofthefat/waterpartitioncoefficient.Thehighfat-solubleonepenetratesfaster,butitisinverselyproportionaltothemolecularweight.
Intheabsorptionstage,foreigncompoundsmusthaveacertainwatersolubilitytobeeasilyabsorbed,becauseplasmawaterisanaqueoussolution.Atpresent,itisbelievedthatthefat/waterpartitioncoefficientiscloseto1,thatis,compoundswithcertainfat-solubleandwater-solublepropertiesareeasilyabsorbedintotheblood.
Inaddition,temperature,humidityandskindamagecanalsoaffectskinabsorption.
Four.Theconceptofdistributionandthemainfactorsaffectingthedistribution
Theconceptofdistribution
Distributionistheabsorptionofforeigncompoundsintothebloodorotherbodyfluids.Theprocessofdispersingtheflowofbloodorlymphtothecellsofvarioustissuesthroughoutthebody.
Twomainfactorsaffectingthedistribution
1.Foreigncompoundsbindtoplasmaproteins.Afterenteringtheblood,foreigncompoundsoftenbindtoplasmaproteins,especiallyplasmaalbumin.Thiscombinationisreversible,anditcanberegardedasaprocessinwhichforeigncompoundsaredistributedandtransportedinthebody.Foreigncompoundsboundtoplasmaalbuminandunboundfreechemicalsubstancesareindynamicbalance,andbecausethespecificityofplasmaalbuminandchemicalsubstancesisnotstrong,whenthereisanotherforeigncompoundordrugorphysiologicalmetaboliteAttimes,competitioncanoccur.Forexample,DDE(DDTmetabolite)cancompetitivelyreplacethebilirubinthathasbeenboundtoalbuminandfreeitintheblood.
2.Foreigncompoundscanbecombinedwithothertissuecomponents.Foreigncompoundscanalsobecombinedwithothertissuecomponents,suchasavarietyofproteins,mucopolysaccharides,nucleoproteins,andphospholipids.Thesecombinationshavedistributionalsignificance,andsomealsohavetoxicologicalsignificance.Forexample,carbonmonoxideandhemoglobinhaveahighaffinity,leadingtohypoxiaandpoisoning.Anotherexampleistheherbicideparaquat,nomatterhowitisexposed,itcanbeconcentratedanddistributedinthelungstocausedamage.
3.StorageanddepositionofforeigncompoundsinadiposetissueandbonesFat-solubleforeigncompoundscanbestoredinadiposetissueanddonotexhibitbiologicalactivity.Onlywhenfatispassivelyusedandforeigncompoundsbecomefreeagain,thebiologicaleffectsappear.ThisishowDDTisstoredinadiposetissue.
Bonecanalsobeusedasastorageanddepositionplaceformanyforeigncompounds.Forexample,leadcanreplacecalciuminbones,and40%oftheleadabsorbedbythebodycanbedepositedinbones,whichisrelativelylessharmfultothebody.Butundercertainconditions,itcanbereleasedfreelyandenterthesystemiccirculation,causingdamagetothebody.
4.TheinfluenceofvariousbarriersinthebodyThereareseveralmembranebarriersinthebody,whichareofgreatsignificanceforprotectingsomeorgans.Ithasimportanttoxicologicalsignificancetostudywhetherthedistributionofforeigncompoundsinthebodycanpenetratethesebarriers.
⑴Blood-brainbarrier
Aspecialfunctionalstructurecomposedofcapillaryendothelialcellsandpiamaterthatgathersastrocytessurroundingcapillaries¾¾;blood-brainbarrier.Theimportanceoftheblood-brainbarrieristoensuretheexchangeofnormalmetabolitesbetweenbloodandbraintissue,preventtheentryofunneededsubstances,andmaintainthenormalfunctionofthebrain.Generally,foreigncompoundscanpenetrateonlywhentheyhavelowmolecularweightandhighfatsolubility.However,ionized,ionic,andwater-solublechemicalsaredifficulttopassthroughtheblood-brainbarrier.Forexample,inorganicmercuryisnoteasytoenterthebraintissue,whilemethylmercuryeasilypenetratestheblood-brainbarrier,causingdamagetothecentralnervoussystem.
⑵Placentalbarrier
Inadditiontotheexchangeofnutrients,oxygen,carbondioxideandmetabolitesbetweenthemotherandthefetus,theplacentaalsopreventssomeforeigncompoundsfromenteringthroughtheplacentafromthemotherThefunctionoftheembryotoensurethenormalgrowthanddevelopmentofthefetus.Theanatomicalbasisoftheplacentalbarrieriscomposedofseverallayersofcellslocatedbetweenthematernalbloodcirculationsystemandtheembryo.Differentspeciesofanimalsandthesamespecieshavedifferentlevelsofplacentalcellsatdifferentstagesofpregnancy.Forexample,pigsandhorseshave6layers,ratsandguineapigshaveonlyonelayer;rabbitshave6layersatthebeginningofpregnancyandonlyhaveonelayerattheendofpregnancy.Thinnerplacenta,thatis,thosewithfewercelllayers,arerelativelyeasytopenetrateforeigncompounds.Forexample,ratplacentaisthinnerthanhumans,andforeigncompoundsareeasilypenetrated.Therefore,itmaybemorecomplicatedtoperformteratogenictestswithpregnantrats.
Themechanismofmostforeigncompoundspassingthroughtheplacentaissimplediffusion,andnutrientsnecessaryforembryonicdevelopmententertheembryothroughactivetransport.
V.Excretionconceptandmainpathways
OneexcretionconceptExcretionistheprocessbywhichforeigncompoundsandtheirmetabolitesaretransportedoutsidethebody,andisthelastpartoftheentireprocessofbodymaterialmetabolismLink.
Twomainwaysofexcretion
1.Thekidneysexcreteforeigncompoundsthroughthekidneysalongwithurine.Itisalsothemostimportantexcretionorgan.Therearethreemainexcretionmechanisms:namelyGlomerularfiltration,simpleglomerulardiffusionandactivetubulartransport,amongwhichsimplediffusionandactivetransportaremoreimportant.
Glomerularfiltrationisakindofpassivetransport.Theglomerularcapillaryhasporeswithadiameterofabout40°Aandamolecularweightoflessthan70,000substancesthatcanbefiltered.Therefore,mostoftheforeigncompoundsortheirmetabolitescanbefilteredout,andonlythechemicalsubstancesboundtoplasmaproteinsaredifficulttopassthroughtheporesduetotheirexcessivemolecularweight.However,itshouldbepointedoutthatallchemicalsubstancesortheirmetaboliteswithalargelipid/waterpartitioncoefficientcanbereabsorbedintothebloodbyrenaltubularepithelialcellsinasimplemanner.Onlywater-solublesubstancesorionicsubstancesentertheurine.
Theactivetransportofrenaltubulesisactuallytheactivesecretionofrenaltubules.Thistypeofactivetransportcanbedividedintotwosystems,oneisforthetransportoforganicanionchemicals;theotherisforthetransportoforganiccationchemicals.Bothsystemsarelocatedintheproximalconvolutedtubulesoftherenaltubules.Bothofthesetwotransportsystemscantransportsubstancesthatareboundtoproteins,andthereisacompetitionbetweentwochemicalsubstanceswhentheypassthroughthesametransportsystem.
2.Excretionwithbilethroughtheliver
Excretionfromthebodywithbilethroughtheliverisanotherexcretionpathwayfortheeliminationofforeigncompoundsinthebodyafterthekidneys.Thebloodfromthegastrointestinaltractcarriestheabsorbedforeigncompoundsintotheliverfirstthroughtheportalvein,thenflowsthroughtheliverandthenentersthesystemiccirculation.Foreigncompoundsundergobiotransformationintheliverfirst,andpartofthemetabolitesformedduringthebiotransformationprocesscanbedirectlyexcretedintobilebyhepatocytes,andthenmixedwithfecestobeexcreted.
Afterforeigncompoundsenterthesmallintestinealongwithbile,theremaybetwoways:①Partoftheeasilyabsorbedforeigncompoundsandtheirmetabolitescanbereabsorbedinthesmallintestine,andthenreturntotheliverthroughtheportalvenoussystem.Withtheexcretionofbile,enterohepaticcirculationiscarriedout.Enterohepaticcirculationhasimportantphysiologicalsignificance,allowingsomecompoundsneededbythebodytobereused.Forexample,95%ofvariousbileacidsarereabsorbedandreusedbythewallofthesmallintestineonaverage.Intermsoftoxicology,becausesomeforeigncompoundsarere-absorbed,theirresidencetimeinthebodyisprolonged,andthetoxiceffectwillalsobeenhanced.②Someforeigncompoundsformconjugatesduringthebiotransformationprocessandappearinthebileintheformofconjugates;theintestinalfloraandglucuronidaseintheintestinecanhydrolyzepartoftheconjugates,andtheforeigncompoundscanItisabsorbedagainandenterstheenterohepaticcirculation.
3.Excretedwithexhaledbreaththroughthelungs
Manygaseousforeigncompoundscanbeexcretedthroughtherespiratorytract.Suchascarbonmonoxide,certainalcoholsandvolatileorganiccompoundscanbeexcretedthroughthelungs.Themainmechanismofitsexcretionthroughthelungsissimplediffusion,andthespeedofexcretionismainlydeterminedbythesolubilityofthegasintheblood,thebreathingrateandthespeedofbloodflowingthroughthelungs.Gaseswithlowsolubilityintheblood,suchasnitrousoxide,areexcretedfaster;whilesubstanceswithhighsolubilityintheblood,suchasethanol,areexcretedslowlythroughthelungs,theeffectofbreathingspeedisslightlydifferentfordifferentcompounds.Forexample,etherhasahighsolubilityintheblood,anditisexcretedveryquicklythroughthelungsduringhyperventilation.Thedischargeofsomegasesthatarenoteasilysolubleinblood(suchassulfurhexafluoride)isalmostunaffectedbyhyperventilation.
Theforeigncompoundsdissolvedinthesecretionoftherespiratorytractandtheparticulatematteringestedbymacrophageswillbedischargedalongwiththesecretiononthesurfaceoftherespiratorytract.
4.Otherexcretionpathways
Foreigncompoundscanalsobeexcretedthroughotherpathways.Forexample,itisexcretedthroughthegastrointestinaltract,alongwithsweatandsaliva,andalongwithmilk.Althoughtheproportionofthisexcretionpathwayintheentireexcretionprocessisnotimportant,somehavespecialtoxicologicalsignificance.Forexample,excretionwithmilk.Manyforeigncompoundscanentermilkbysimplediffusion.Organochlorinepesticides,ether,polyhalogenatedbiphenyls,caffeineandcertainmetalscanbeexcretedwithmilk.Ifacertainsubstanceisinrepeatedcontactwiththemotherforalongperiodoftime,itislikelytobeconcentratedinthemilk.Theimportantsignificanceliesinthedamagetothebaby;becausecalculatedbytheunitweight,theforeigncompoundingestedbythebabythroughthemilkisoftenlargerthanthegeneralpopulation.
1.Theconceptofbiotransformation
Theprocessbywhichforeigncompoundsundergoaseriesofchemicalchangesinthebodyandformtheirderivativesanddecompositionproductsiscalledbiotransformation,ormetabolictransformation.Theresultingderivativesaremetabolites.Afterbiologicaltransformationofforeigncompounds,somecanachievedetoxificationandreducetoxicity.However,somecanincreaseitstoxicity,andevenproduceteratogenicandcarcinogeniceffects.Therefore,metabolictransformationshouldnotonlyberegardedasadetoxificationprocess,butthemetabolicprocesshasadualityinthetoxicityofforeigncompounds.
Second,thetypeofbiotransformationreaction
Oxidation
Oxidationcanbedividedintocatalyzedbymicrosomalmixedfunctionoxidaseandnon-microsomalmixedfunctionoxidase.Twooxidationreactionscatalyzed.
Microsomesarefragmentsformedduringthehomogenizationoftheendoplasmicreticulum,notindependentorganelles.Theendoplasmicreticulumcanbedividedintotwotypes:roughsurfaceandslipperysurface.Therefore,theformedmicrosomesalsohaveroughsurfaceandslipperysurface,buttheyallcontainmixed-functionoxidase,thelatterismoreactive.
⒈Micrososmalmixedfunctionoxidase(MFO),alsoknownasmixedfunctionoxidaseormicrosomalmonooxygenase,canbeabbreviatedasmonooxygenase.Inthisprocess,NADPHalsoneedstoprovideelectronstoreducecytochromeP-450andformacomplexwiththesubstratetocompletethisreactionprocess.
Mixed-functionoxidaseisanenzymesystemontheendoplasmicreticulummembranewithacomplexcomposition.ThemaincytochromeP-450oxidase,alsoknownascytochromeP-450dependent,isnowknown.Sexualmonooxygenase,aswellasreducedcoenzymeII-cytochromeP-450reductase.Inaddition,italsocontainsmicrosomalFDA-monooxygenase.ThisenzymeischaracterizedbynotcontainingcytochromeP-450,butcontainsflavinadeninedinucleotideinsteadofcytochromeP-450toparticipateinthemonooxygenasereaction.IntheoxidationofforeigncompoundscatalyzedbyFADmonooxygenase,NADPHandoxygenmoleculesarealsorequired.
Manyforeigncompoundscanbecatalyzedbymixed-functionoxidasesandoxygenatedtoformvarioushydroxylcompounds.Thehydroxylcompoundwillbefurtherdecomposedtoformvariousproducts,sotheoxidationreactionmayhavethefollowingtypes:
⑴Aliphatichydroxylation:alsoknownasaliphaticoxidation,itistheendofthesidechain(R)ofaliphaticcompoundsThepenultimateorsecondcarbonatomisoxidizedandformsahydroxylgroup.
⑵Aromatichydroxylation:Thehydrogenonthearomaticringisoxidized.Forexample,benzenecanformphenol,andanilinecanformp-aminophenoloro-aminophenol.Inthedeterminationoftheactivityofthemicrosomalmixedfunctionoxidase,thisreactioncanbeused,thatis,afterthehydroxylationofanilineasasubstratebyMFO,p-aminophenolisformed,anditscontentisdeterminedtoindicatetheactivityofanilinehydroxylase.Duringthehydroxylationprocess,o-aminophenolcanalsobeformed.
(3)Epoxidationreaction:Abridgestructureisformedbetweentwocarbonatomsofaforeigncompound,thatis,anepoxide.Generally,epoxidesareonlyintermediateproductsandwillcontinuetodecompose.However,afterpolycyclicaromatichydrocarboncompounds,suchasbenzo(a)pyrene,formepoxides,theycancovalentlybondwithcellbiologicalmacromolecules,inducingmutationsandcancerformation.
⑷N-dealkylationreaction:ThealkylgroupontheoxygenNoftheaminecompoundisoxidizedtoremoveanalkylgrouptoformaldehydesorketones.Carbamateinsecticides,suchascarbaryl,carcinogenazopigmentbutteryellowanddimethylnitrosaminecanallhavethisreaction.Dimethylnitrosaminecanalsoformafreemethylgroup[CH3+]afterN-dealkylation,whichcanmethylate(oralkylate)guanineonnucleicacidmoleculesinthenucleustoinducemutationorcarcinogenesis.
⑸O-dealkylationandS-dealkylationreaction:similartotheN-dealkylationreaction,butafteroxidation,thealkylgroupconnectedtotheoxygenatomorsulfuratomisremoved.
O-dealkylationcanoccurinp-nitroanisole.Thelatteriscatalyzedbymicrosomalmixedfunctionoxidase,andthecontentofp-nitrophenolformedisdetermined,whichcanrepresenttheactivityofmixedfunctionoxidase.
⑹N-hydroxylationreaction:hydroxylationiscarriedoutontheNatom,suchasanilineandcarcinogen2-acetamidofluorenecanoccur.AnilineundergoesN-hydroxylationtoformN-hydroxyaniline,whichcanoxidizehemoglobinintomethemoglobin.
⑺Alkylmetaldealkylationreaction:tetraethylleadcanbecatalyzedbymixedfunctionoxidasetoremoveanalkylgrouptoformtriethyllead.Asaresult,tetraethylleadcanexhibittoxiceffectsinthebody.
⑻Desulfurizationreaction:Desulfurizationreactionoftenoccursinmanyorganophosphoruscompounds.Inthisreaction,sulfuratomsareoxidizedtosulfateradicalsandfalloff.Forexample,parathionoxidativedesulfurizationbecomesparaoxon,anditstoxicityisenhanced.
⒉Theoxidationreactioncatalyzedbynon-microsomalmixed-functionoxidasesInlivertissuecytosol,plasmaandmitochondria,therearesomelessspecificenzymesthatcancatalyzetheoxidationandreductionofcertainforeigncompounds,Suchasalcoholdehydrogenase,aldehydedehydrogenase,catalase,xanthineoxidaseandsoon.
Thecytosoloflivercellscontainsmonoamineoxidaseanddiamineoxidase,whichcancatalyzetheoxidationofaminestoformaldehydesandammonia.Theoxidationreactioncatalyzedbydiamineoxidasemainlyinvolvestheformationofbiogenicaminesinthebody.Metabolicconversionofforeigncompoundsislessrelated.
⒊Co-oxidationintheprocessofprostaglandinbiosynthesisIntheoxidationreactionofforeigncompounds,inadditiontotheoxidationreactioncatalyzedbytheaforementionedmicrosomalmixed-functionoxidaseandnon-microsomalmixed-functionoxidase,ithasbeenobservedinrecentyearsToanoxidationreaction,someforeigncompoundscanbeoxidizedatthesametimeduringthebiosynthesisofprostaglandin,whichiscalledco-oxidationreaction.
Tworeductionreactions
Externalcompoundscontainingnitro,azoandcarbonylgroups,aswellasdisulfidesandsulfoxidecompounds,canbereducedinthebody,suchasnitrobenzeneandNitrobenzenecanbereducedtoformaniline.CarbontetrachloridecanbecatalyzedandreducedbyNADPH-cytochromeP-450reductaseinthebodytoformtrichloromethanefreeradicals(CCl3+),whichcandamagethelipidstructureoflivercellmembranesandcauseliversteatosisandnecrosis.Arsenicinpentavalentarseniccompoundscanalsobereducedtotrivalentarsenic.Trivalentarseniccompoundshavehighersolubilityinwater,sotheyaremoretoxicthanpentavalentarseniccompounds.
ThreeHydrolysis
Manyforeigncompounds,suchasesters,amidesandphosphatesubstitutionscontainingesterbondsareeasilyhydrolyzed.Therearemanyhydrolyticenzymesinplasma,liver,kidney,intestinalmucosa,muscleandnervetissue,aswellasinmicrosomes.Esteraseisaubiquitoushydrolase.Esteraseandamidasecanhydrolyzeestersandamines,respectively.
Thehydrolysisreactionisthemainmetabolicmodeofmanyorganophosphoruspesticidesinthebody,suchasdichlorvos,parathion,dimethoateandmalathionafterhydrolysis,thetoxicitydecreasesordisappears.Someinsectsareresistanttomalathion,thatis,duetothehighcarboxylesteraseactivityintheirbodies,itisveryeasytolosetheactivityofmalathion.Inaddition,pyrethroidinsecticidesarealsodetoxifiedbyhydrolyticenzymedegradation.
Fourbindingreaction
Thebindingreactionisabiosyntheticreactionbetweenforeigncompoundsenteringthebodyandsomeotherendogenouscompoundsorgroupsduringthemetabolicprocess.Inparticular,foreignorganiccompoundsandtheirmetabolitescontaininghydroxyl,amino,carbonylandepoxygroupsaremostlikelytooccur.Theproductsformedbythecombinationofforeigncompoundsandtheirmetaboliteswithcertainendogenouscompoundsorgroupsinthebodyarecalledconjugates.Coenzymesandtransferasesareneededintheconjugationreactionandconsumemetabolicenergy.Thesourceoftheso-calledendogenouscompoundorgroupistheproductofthenormalmetabolicprocessinthebody,anditmustbetheendogenouscompoundthatparticipatesinthebindingreaction.
Foreigncompoundscandirectlyundergoabindingreactionduringthemetabolicprocess,ortheycanundergothefirst-stagebiotransformationreaction(thefirstphasereaction)suchasoxidation,reductionorhydrolysisasdescribedabove,andthenthebindingreaction(thefirstphase)Two-phasereaction),undernormalcircumstances,throughthebindingreaction,ontheonehand,somefunctionalgroupsontheforeigncompoundmoleculecanbeinactivatedandlosetoxicity;ontheotherhand,mostforeigncompoundscanbepolarizedthroughthebindingreaction.Strengthen,reducefatsolubility,acceleratetheprocessofexcretionfromthebody.
Accordingtothemechanismofthebindingreaction,thebindingreactioncanbedividedintothefollowingtypes:
⒈Glucuronicacidbindingglucuronicacidbindingmaybethemostcommonbindingreaction,mainlyforeignThecompoundanditsmetabolitesbindtoglucuronicacid.Thesourceofglucuronicacidistheproductionofuridinediphosphateglucose(UDPG)intheprocessofcarbohydratemetabolism.UDPGisthenoxidizedtoformuridinediphosphateglucuronicacid;UCPGAisthedonorofglucuronicacid,whichisusedinglucoseUndertheactionofaldyltransferase,itcombineswiththehydroxyl,aminoandcarboxylgroupsofforeigncompoundsandtheirmetabolites,andthereactionproductisβ-glucuronide.Glucuronicacidmustbeanendogenousmetabolite,andthosedirectlyimportedfromoutsidecannotundergobindingreactions.
Thebindingeffectofglucuronicacidismainlycarriedoutinlivermicrosomes.Inaddition,itcanalsooccurinthekidney,intestinalmucosaandskin.Afterthebindingreactionintheliver,foreigncompoundsareexcretedwithbile.Butsometimesapartofitisinthelowerpartoftheintestinaltract,whichcanbehydrolyzedundertheactionofβ-glucuronidaseintheintestinalflora,andthisforeigncompoundcanbereabsorbedtocarryoutenterohepaticcirculation,sothatitstaysinthebodyforalongertime.
⒉SulfuricacidbindingforeigncompoundsandtheirmetabolitesAlcohols,phenolsoraminecompoundscanbecombinedwithsulfuricacidtoformsulfateesters.Thesourceofendogenoussulfuricacidisthemetaboliteofsulfur-containingaminoacids,butitmustfirstbeactivatedbyadenosinetriphosphatetobecome3'-adenosinephosphate-5'-phosphatesulfuricacid(PAPS),andtheninteractwithphenolsundertheactionofsulfotransferase.,Alcoholsoraminesarecombinedintosulfateesters.Thecombinationofphenolandsulfuricacidismorecommon.
Sulfuricacidbindingreactionsaremostlycarriedoutinliver,kidney,gastrointestinalandothertissues;duetothelimitedsourceofsulfuricacidinthebody,itcannotbeadequatelyprovided,soitislessthanglucuronicacidbindingreactions.
Undernormalcircumstances,theoriginaltoxicityofforeigncompoundscanbereducedandlostthroughthesulfuricacidbindingreaction.However,someforeigncompoundsaremoretoxicafterbeingcombinedwithsulfuricacid.Forexample,2-acetamidofluorene(FAAorAAF),acarcinogenbelongingtoaromaticamines,undergoesN-hydroxylationinthebodytoformN-hydroxy-2-acetamidofluorene,anditshydroxylgroupcanbecombinedwithsulfuricacidtoformSulfate.ThiskindofAAFsulfatehasstrongcarcinogenicity,whichisstrongerthanAAFitself.Thisreactionoccursinrats,miceanddogs.However,someanimalslacksulfotransferaseintheirliversandcannotformsulfates.
⒊GlutathionebindingToxicmetalsandepoxidesinthebodycancombinewithglutathionetobedetoxified.Theglutathionebindingreactioniscatalyzedbyglutathionetransferase.Glutathioneiscontainedintheliverandkidney,andthecytosoliccontentofhepatocytesisrelativelyhigh.Inrecentyears,ithasalsobeenfoundtobepresentonlivermicrosomes.Thedirectcontactofmicrosomalglutathionetransferasewithforeigncompoundsmaybemoreimportantinthesignificanceoftheglutathionebindingreaction.
Thebindingreactionbetweenglutathioneandepoxideisveryimportant.Manyforeigncompounds,suchasmanycarcinogensandliverpoisonscanformepoxidesinthebody,andmostoftheseepoxideshaveastrongdamagingeffectoncells.Forexample,bromobenzeneepoxideismetabolizedintoepoxide.Bromobenzeneepoxideisastrongliverpoisonthatcancauselivernecrosis;butwhencombinedwithglutathione,itwillbedetoxifiedandexcreted.Thereisacertainlimittotheproductionandstorageofglutathioneinthebody.Ifalargeamountofepoxideisformedinashortperiodoftime,glutathionedepletionmayoccur,anditmaystillcauseseriousdamage.
⒋GlycinebindingSomeforeigncompoundscontainingcarboxylgroups,suchasorganicacids,canbecombinedwithaminoacids.Theessenceofthiskindofbindingreactionisakindofpeptidebinding,andthemostcommonbindingwithglycine,infact,otheraminoacidscanalsocarryoutthiskindofbinding.Forexample,tolueneismetabolizedinthebodytoproducebenzoicacid,whichcanbecombinedwithglycinetoformhippuricacidandbeexcretedfromthebody.Hydrocyanicacidcanbecombinedwithcysteineandexcretedbysalivaandurine.
⒌Acetylbindstoaromaticaminesinforeigncompounds,forexample,anilinecanreactwithacetyl-CoAthroughitsaminogroup,andacetyltransferasecatalyzesaromaticaminestoformtheiracetylderivatives.Inaddition,aliphaticaminedrugshavesimilarreactions.ThesourceofacetylaseAisthemetabolitesofsugar,fatandprotein.
⒍MethylbindingThereactionofbiogenicamineswithmethylgroupsinthebody,alsoknownasmethylation.Themethylgroupcomesfrommethionine.ThemethylgroupofmethionineisactivatedbyATPtobecomeS-adenosylmethionine,whichiscatalyzedbymethyltransferasetocombinethebiogenicamineswiththemethylgroupfordetoxificationandexcretion.Inthedetoxificationofforeigncompounds,methylbindingdoesnotoccupyanimportantposition.
Two.Factorsaffectingbiotransformation
Onespeciesdifferencesandindividualdifferences
Therateofbiotransformationofthesameforeigncompoundcanvarygreatlyindifferentanimals,forexampleThebiologicalhalf-lifeofanilineis35minutesinmiceand167minutesindogs.Themetabolismofthesameforeigncompoundinanimalsofdifferentspeciescanbecompletelydifferent.Asmentionedabove,N-2-acetamidofluorenecanundergoN-hydroxylationinrats,miceanddogsandcombinewithsulfuricacidtoformsulfateesters,showingastrongcarcinogeniceffect.N-acetamidofluorenegenerallydoesnotoccuringuineapigs.Itishydroxylated,soitcannotbecombinedtoformasulfate,andithasnoorveryweakcarcinogeniceffect.
Theindividualdifferencesinthebiotransformationprocessofforeigncompoundsinvivoarealsomanifestedintheactivityofcertainmetabolicenzymesineachbody.Forexample,arylhydrocarbonhydroxylase(AHH)canhydroxylatearomatichydrocarboncompoundsandproducecarcinogenicactivity,anditsactivityvariessignificantlybetweenindividuals.Inthecaseofthesameamountofsmoking,peoplewithhigherAHHvitalityhavea36timeshigherriskoflungcancerthanthosewithlowvitality;peoplewithmoderateAHHvitalityintheirbodieshavea16timeshigherriskoflungcancerthanthosewithlowvitality.
Inhibitionandinductionoftwoforeigncompoundmetabolizingenzymes
⒈Inhibitionofthebiologicaltransformationofaforeigncompoundcanbeinhibitedbyanothercompound,whichinhibitsandcatalyzesthebiologicaltransformationoftheenzymeClassrelated.Enzymesystemsinvolvedinbiotransformationgenerallydonothavehighsubstratespecificity.Severaldifferentcompoundscanbeusedassubstratesofthesameenzymesystem,thatis,thebiotransformationprocessofseveralforeigncompoundsiscatalyzedbythesameenzymesystem..Therefore,whenaforeigncompoundappearsinthebodyoritsnumberincreases,itcanaffectthecatalyticeffectofacertainenzymeonanotherforeigncompound,thatis,thetwocompoundsarecompetitivelyinhibited.
⒉Inductionofsomeforeigncompoundscanincreasetheactivityofcertainmetabolicprocessescatalyzedenzymesorincreasethecontentofenzymes.Thisphenomenoniscalledenzymeinduction.Compoundswithinductiveeffectsarecalledinducers.Theresultcanpromotethebiotransformationprocessofotherforeigncompoundstoenhanceoraccelerateit.Duringtheinductionofmicrosomalmixed-functionoxidases,theproliferationoftheendoplasmicreticulumontheslipperysurfacewasalsoobserved;theenhancementofenzymeactivityandthepromotionofthemetabolictransformationofothercompoundsareallrelatedtothis.
Threemetabolicsaturationstate
Thesaturationstateofaforeigncompoundinthebody'smetabolismhasaconsiderableimpactonitsmetabolism,andthereforeitstoxiceffects.Forexample,brominatedbenzeneisfirstconvertedintobrominatedbenzeneepoxidewithlivertoxiceffectsinthebody;iftheinputdoseissmall,about75%ofbrominatedbenzeneepoxidecanbeconvertedintoglutathioneconjugates.Bromophenylsulfideacidisexcretedintheform;butifalargerdoseisinput,only45%ofthesidecanbeexcretedintheaboveform.Whenthedoseistoolarge,duetoinsufficientglutathione,evenglutathionedepletionoccurs,andthebindingreactionisreduced.Therefore,thereactionofunboundbromobenzeneepoxidewithDNAorRNAandproteinisenhanced,showingToxiceffects.
Fourotherinfluencingfactors
Mainlymanifestedinage,genderandnutritionalstatus.Thenutritionalstatusofprotein,ascorbicacid,riboflavin,vitaminAandvitaminEcanallaffecttheactivityofmicrosomalmixedfunctionoxidase.Inanimalexperiments,iftheproteinsupplyisinsufficient,theactivityofmicrosomalenzymeswilldecrease.Whenascorbicacidisdeficient,thehydroxylationreactionofanilineisweakened.Lackofriboflavincanreducetheactivityofazocompoundreductaseandenhancethecarcinogeniceffectofthecarcinogenbutteryellow.Thedecreaseintheactivityoftheabove-mentionedenzymesmayweakenorslowdowntheconversionprocessofforeigncompounds.
Theinfluenceofageonthemetabolictransformationprocessofforeigncompoundsismanifestedinthelivermicrosomalenzymefunctionatbirthandimmaturebodyisnotyetmature,anditbeginstodeclineafteroldage,anditsfunctionislowerthanthatofadult.Themetabolismanddetoxificationabilityofthecompoundisweak.Forexample,30daysafterthebirthofarat,themixedfunctionaloxidaseoflivermicrosomesreachestheadultlevel,andafter250daysitstartstodeclineagain.Theglucuronicacidbindingreactionweakenedinoldanimals,butthemonoamineoxidaseactivityofratsincreasedwithage.Undernormalcircumstances,theabilityofthebodytometabolizeandtransformforeigncompoundsinyoungandoldisweakerthanthatinadults,sothedamageeffectofforeigncompoundsisalsostronger.