toxikologie

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,anditrunsthroughtheideaof​​preventionasthemainstay.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.

Klasifikace

Z obsahu výzkumu ji lze rozdělit na tři části: deskriptivní toxikologii, toxikologii mechanismů a toxikologii řízení (také nazývaná regulační toxikologie).

Podle standardních oborů jej lze rozdělit na: forenzní toxikologii, klinickou toxikologii, manažerskou toxikologii nebo regulační toxikologii, výzkumnou toxikologii atd.

Z aplikované toxikologie lze rozdělit na: toxikologii potravin, průmyslovou toxikologii, pesticidní toxikologii, vojenskou toxikologii, toxikologii záření, toxikologii životního prostředí, ekotoxikologii a další odvětví.

Výzkumné předměty lze rozdělit na: toxikologii hmyzu, veterinární toxikologii, humánní toxikologii a fytotoxikologii.

Z oblasti výzkumu to lze rozdělit na: farmaceutickou toxikologii, toxikologii životního prostředí, toxikologii potravin, průmyslovou toxikologii, klinickou toxikologii, forenzní toxikologii, analytickou toxikologii, vojenskou toxikologii, toxikologii řízení atd.

Z výzkumných cílových orgánů nebo systémů to lze rozdělit na: toxikologii orgánů, toxikologii jater, toxikologii ledvin, oční toxikologii, ototoxikologii, neurotoxikologii, reprodukční toxikologii, imunotoxikologii atd..

1. Koncept

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.Hygienickotoxikologické výzkumné metody

Jeden pokus na zvířatech

1.Metoda experimentu Invivo

Usuallyperformedinwholeanimals,Theexperimentalanimalisexposedtoacertaindoseofthetestedforeigncompoundaccordingtotheactualcontactmethodofthehumanbodyforacertainperiodoftime,andthenthepossiblemorphologicalorfunctionalchangesoftheanimalareobserved.Experimentsmostlyusemammals,suchasrats,mice,guineapigs,rabbits,hamsters,dogs,andmonkeys.Thegeneraltoxicityofforeigncompoundsisusuallytested,suchasacutetoxicitytest,sub-chronictoxicitytestandchronictoxicitytest.

2.Invitroexperimentální metody

Mostusefreeorgans,primaryculturedcells,celllinesandorganelles.Theorganperfusiontechnologycanbeusedtoperfusetheliver,kidneys,lungs,andbrains,sothattheisolatedorganscanmaintainalivingconditionforacertainperiodoftime,contactwiththetestedforeigncompounds,andobservethemorphologicalandfunctionalchangesoftheorgans.Atthesametime,itcanalsoobservethemetabolismofthetestsubstanceintheorgans;freecellsandorganellesaremostlyusedforpreliminaryscreeningofthevariousdamageeffectsofforeigncompoundsonthebody,themechanismofactionandthein-depthstudyofthemetabolictransformationprocess,whichhavemanyadvantages.

Theabove-mentionedstudiesattheoverall,organ,cellularandsubcellularlevelseachhavecertaincharacteristicsandlimitations.Inactualwork,themostappropriatemethodshouldbeusedmainlyaccordingtothepurposeandrequirementsofexperimentalresearch.Andmutualauthentication.

Dva populační průzkumy

Inordertoverifytheresultsofanimalexperimentsonhumans,populationsurveysaresometimesrequired.Accordingtotheresultsofanimalexperimentsandthenatureoftheforeigncompounds,appropriateobservationindicatorsareselectedandthepopulationsurveyisconductedbyepidemiologicalmethods.Thecharacteristicofpopulationsurveyisthatitcanobtainthedatadirectlyobservedinthehumanbody,butitissusceptibletotheinfluenceandinterferenceofmanyotherconfoundingfactors;theresultsandevaluationmustberemovedfromthefalseandthetruth,fromtheoutsidetotheinside,andcomprehensivelyconsideredandanalyzedwiththeresultsofanimalexperiments.Amorerealisticconclusion.

1.Toxicita

Toxicityistheabilityofasubstancetocausedamagetothebody.Highlytoxicsubstances,aslongasrelativelysmallamounts,cancausecertaindamagetothebody;whilelesstoxicsubstancesrequirealargeramounttobecometoxic.Thelevelofsubstancetoxicityisonlyofrelativesignificance.Inacertainsense,aslongasitreachesacertainamount,anysubstanceistoxictothebody;ingeneral,ifitislessthanacertainamount,nosubstanceistoxic;thekeyistheamountofsuchsubstanceincontactwiththebody.Inadditiontothenumberofsubstancesincontactwiththebody,itisalsorelatedtothephysicalandchemicalpropertiesofthesubstanceitselfandthewayinwhichitcomesintocontactwiththebody.

2. Dávka

Doseisanimportantfactorindeterminingthedamageeffectofforeigncompoundsonthebody.Theconceptofdoseisrelativelybroad,anditcanrefertotheamountgiventothebody,ortheamountofforeigncompoundsincontactwiththebody,theamountofforeigncompoundsabsorbedintothebody,andtheconcentrationorcontentofforeigncompoundsinthetargetorgan'ssiteofactionorbodyfluids.Sincetheinternaldoseisnoteasytodetermine,thegeneralconceptofdosereferstotheamountofforeigncompoundgiventothebodyortheamountofbodycontact.Theunitofdosageisexpressedastheamountofforeigncompoundexposedperunitbodyweight,forexample,mg/kgbodyweight.

1.Letaldóza

Thelethaldoseisthedosethatcancausethebodytodie.However,inagroup,thenumberofdeadindividualsvariestoalargeextent,andtherequireddosesarealsoinconsistent.Therefore,lethaldosehasthefollowingdifferentconcepts.

⑴.Absolutní letální dávka (LD100) se vztahuje na nejnižší dávku, která může způsobit všechna úmrtí ve skupině.

⑵.Střední smrtelná dávka (LD50) se vztahuje na dávku, která je nutná k tomu, aby způsobila 50 % úmrtí ve skupině jednotlivců, také nazývaná smrtelná střední dávka. Jednotka LD50 isg/kg tělesné hmotnosti.

2. Maximální úroveň účinku (maximální úroveň žádného účinku)

Themaximumno-effectlevelmeansthataforeigncompoundcomesintocontactwiththebodyinacertainwayorroutewithinacertainperiodoftime.Accordingtothecurrentlevelofknowledge,usingthemostsensitivetestmethodsandobservationindicators,ithasnotbeenpossibletoobservethehighestdoseofanydamagingeffectonthebody.

Thedeterminationofthemaximumnon-effectdoseisbasedontheresultsofsubchronictoxicityorchronictoxicitytests,andisthemainbasisforassessingthedamageeffectofforeigncompoundsonthebody.Basedonthis,theacceptabledailyimtarie(intake,ADI)andthemaximumallowableconcentration(MAC)ofaforeigncompoundcanbeformulated.ADIreferstothedailyintakeoftheforeigncompoundforthelifeofhumanswithoutcausinganydamagingeffects.MACreferstotheconcentrationatwhichaforeigncompoundcanexistintheenvironmentwithoutcausinganydamagetothehumanbody.

3. Minimální účinná dávka (minimální úroveň účinku)

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.

Tři. Efekt a odezva

Oneeffectreferstothebiologicalchangesthatcanbecausedbyacertaindoseofforeigncompoundsincontactwiththebody.Thedegreeofthischangeisexpressedinunitsofmeasurement,suchasseveral,milligrams,units,etc.

Thesecondresponseisthatafteracertaindoseofaforeigncompoundcomesintocontactwiththebody,itexhibitsacertaineffectandreachesacertaindegreeofratio,ortheratioofthenumberofindividualsthatproduceaneffectinacertaingroup,generallyin%Orratiorepresentation.

Čtyři. Vztah dávka-odpověď a vztah dávka-odpověď

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.

Pět. Poškození a neškodlivé účinky

Onenon-damagingeffectsaregenerallyconsideredthatnon-damagingeffectsdonotcausechangesinthebody'sfunctionmorphology,growthanddevelopmentandlifespan;donotcausecertainfunctionsofthebodyThedecreaseincapacitydoesnotcausedamagetothebody'sabilitytocompensatefortheadditionalstressstate.Allbiologicalchangesinthebodyshouldbewithinthebody’scompensatorycapacity.Whenthebodyceasestobeexposedtotheexotoxiccompound,thebody’sabilitytomaintainhomeostasisshouldnotbereduced.Sensibilityshouldnotincreaseeither.Steadystateisatendencyorabilityofthebodytokeepitsinternalenvironmentstableandunchanging.

TwodamagingeffectsThedamagingeffectsareoppositetothenon-damagingeffects,andshouldhavethefollowingcharacteristics:

1.Thenormalshapeofthebodyandthegrowthanddevelopmentprocessareseverelyaffected,andthelifespanwillalsobeshortened.

2.Thefunctionalcapacityofthebodyorthecompensatoryabilityoftheextrastressstateisreduced.

3. Schopnost těla udržovat stabilitu se snižuje.

4.Tělo je citlivější na nepříznivé účinky některých dalších faktorů.

Itshouldbepointedoutthatbothdamagingandnon-damagingeffectsbelongtothebiologicaleffectsofforeigncompoundsinthebody.Inbiologicaleffects,changesinquantityoftencausequalitativechanges,sodamagingandnon-damagingeffectsThedamageeffectonlyhasacertainrelativesignificance.Inaddition,theobservableindicatorsfordeterminingdamagingandnon-damagingeffectshavealsobeencontinuouslydeveloped.

Six.Normalvalues​​Thedeterminationofdamagingandnon-damagingeffectsofteninvolvesthenormalrangeofmanyindicatorsofthebody,andsometimesitisnecessarytodeterminethenormalvalue.First,itmustbeclearthat"normalvalue"onlyhasarelativemeaning.Inactualwork,accordingtothecurrentlevelofknowledge,individualswhoareconsidered"healthy"or"normal"willbemeasuredforanobservationindex,andtheaveragevalue±2standarddeviationswillbeusedasthenormalvaluerange.Statisticalmethodscanbeusedtodeterminewhetherthechangeofthisindicatordeviatesfromthenormalvaluerange.Whenacertainobservationindicatormeetsoneofthefollowingconditions,itcanbeconsideredashavingdeviatedfromthenormalvaluerangeandbelongstoadamagingeffectoranon-damagingeffect.

⒈Ve srovnání s kontrolní skupinou je statisticky významný rozdíl (P<0,05) a jeho hodnota není v normálním rozsahu.

⒉Ve srovnání s kontrolní skupinou je statisticky významný rozdíl (P<0,05), ale jeho hodnoty jsou v obecně uznávaném rozsahu "normálních hodnot"; ale pokud se kontakt zastaví, takový rozdíl, pokud to pokračuje po určitou dobu, má škodlivý účinek.

⒊Comparedwiththecontrolgroup,thereisastatisticallysignificantdifference(P<0.05),butitsvalueiswithinthegenerallyrecognized"normalvalue"range;butifthebodyisinafunctionalorbiochemicalresponseInanexcitedstate,thisdifferenceismoreobvious,whichisadamagingeffect.

1.Koncepce biologické dopravy

Theabsorption,distributionandmetabolismofforeigncompoundsinthebodyarecollectivelyreferredtoasbiologicaltransport.

Zadruhé, mechanismus biologické přepravy

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.

Druhá filtrace

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.

Difúze čtyř nosných

Forforeigncompoundsthatarenoteasilysolubleinlipids,theprocessinwhichthecarriermovesfromahighconcentrationtoalowconcentrationisused.Sincetheconcentrationgradientcannotbereversedfromlowconcentrationtohighconcentration,metabolicenergyisnotconsumed.Duetotheuseofthecarrier,thebiofilmhasacertaindegreeofinitiativeorselectivity,butitcannotreversetheconcentrationgradient,soitbelongstothenatureofdiffusion,andcanalsobecalledfacilitatingdiffusionorpromotingdiffusion.Water-solubleglucoseentersthebloodfromthegastrointestinaltract,enterstheredbloodcellsfromtheplasma,andentersthenervetissuefromtheblood,allofwhicharediffusedthroughthecarrier.

Wupping a fagocytóza

Liquidorsolidforeigncompoundsaresurroundedbytheprotrudingbiofilm,andthenthesurroundeddropletsorlargerparticlesareincorporatedintothecelltoachievetransportThepurposeoftheformeriscalledpinocytosisandthelatteriscalledphagocytosis.Eliminationofforeignbodiesinthebody,suchasthephagocytosisofmicroorganismsbywhitebloodcells,andtheeliminationoftoxicforeignbodiesbyhepaticreticuloendothelialcellsareallrelatedtothis.

3.Koncepce absorpce a způsob absorpce

Koncept absorpce

Absorptionisthewaythatforeigncompoundsenterthebloodthroughthebody’sbiologicalmembranesprocess.

Druhá cesta absorpce

1.Absorpce gastrointestinálním traktem

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.Vstřebává se dýchacím traktem

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.Absorpce kůží

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.

Absorpci pokožky mohou ovlivnit také příměs, teplota, vlhkost a poškození kůže.

Four.Theconceptofdistributionandthemainfactorsaffectingthedistribution

Koncept distribuce

Distributionistheabsorptionofforeigncompoundsintothebloodorotherbodyfluids.Theprocessofdispersingtheflowofbloodorlymphtothecellsofvarioustissuesthroughoutthebody.

Dva hlavní faktory ovlivňující distribuci

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.

⑴Biéra krve a mozku

Aspecialfunctionalstructurecomposedofcapillaryendothelialcellsandpiamaterthatgathersastrocytessurroundingcapillaries¾¾;blood-brainbarrier.Theimportanceoftheblood-brainbarrieristoensuretheexchangeofnormalmetabolitesbetweenbloodandbraintissue,preventtheentryofunneededsubstances,andmaintainthenormalfunctionofthebrain.Generally,foreigncompoundscanpenetrateonlywhentheyhavelowmolecularweightandhighfatsolubility.However,ionized,ionic,andwater-solublechemicalsaredifficulttopassthroughtheblood-brainbarrier.Forexample,inorganicmercuryisnoteasytoenterthebraintissue,whilemethylmercuryeasilypenetratestheblood-brainbarrier,causingdamagetothecentralnervoussystem.

⑵Placentární bariéra

Inadditiontotheexchangeofnutrients,oxygen,carbondioxideandmetabolitesbetweenthemotherandthefetus,theplacentaalsopreventssomeforeigncompoundsfromenteringthroughtheplacentafromthemotherThefunctionoftheembryotoensurethenormalgrowthanddevelopmentofthefetus.Theanatomicalbasisoftheplacentalbarrieriscomposedofseverallayersofcellslocatedbetweenthematernalbloodcirculationsystemandtheembryo.Differentspeciesofanimalsandthesamespecieshavedifferentlevelsofplacentalcellsatdifferentstagesofpregnancy.Forexample,pigsandhorseshave6layers,ratsandguineapigshaveonlyonelayer;rabbitshave6layersatthebeginningofpregnancyandonlyhaveonelayerattheendofpregnancy.Thinnerplacenta,thatis,thosewithfewercelllayers,arerelativelyeasytopenetrateforeigncompounds.Forexample,ratplacentaisthinnerthanhumans,andforeigncompoundsareeasilypenetrated.Therefore,itmaybemorecomplicatedtoperformteratogenictestswithpregnantrats.

Themechanismofmostforeigncompoundspassingthroughtheplacentaissimplediffusion,andnutrientsnecessaryforembryonicdevelopmententertheembryothroughactivetransport.

V. Koncept vylučování a hlavní cesty

OneexcretionconceptExcretionistheprocessbywhichforeigncompoundsandtheirmetabolitesaretransportedoutsidethebody,andisthelastpartoftheentireprocessofbodymaterialmetabolismLink.

Dva hlavní způsoby vylučování

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. Vylučování žlučí játry

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.Vylučuje se s vydechovaným dechem plícemi

Manygaseousforeigncompoundscanbeexcretedthroughtherespiratorytract.Suchascarbonmonoxide,certainalcoholsandvolatileorganiccompoundscanbeexcretedthroughthelungs.Themainmechanismofitsexcretionthroughthelungsissimplediffusion,andthespeedofexcretionismainlydeterminedbythesolubilityofthegasintheblood,thebreathingrateandthespeedofbloodflowingthroughthelungs.Gaseswithlowsolubilityintheblood,suchasnitrousoxide,areexcretedfaster;whilesubstanceswithhighsolubilityintheblood,suchasethanol,areexcretedslowlythroughthelungs,theeffectofbreathingspeedisslightlydifferentfordifferentcompounds.Forexample,etherhasahighsolubilityintheblood,anditisexcretedveryquicklythroughthelungsduringhyperventilation.Thedischargeofsomegasesthatarenoteasilysolubleinblood(suchassulfurhexafluoride)isalmostunaffectedbyhyperventilation.

Theforeigncompoundsdissolvedinthesecretionoftherespiratorytractandtheparticulatematteringestedbymacrophageswillbedischargedalongwiththesecretiononthesurfaceoftherespiratorytract.

4. Jiné cesty vylučování

Foreigncompoundscanalsobeexcretedthroughotherpathways.Forexample,itisexcretedthroughthegastrointestinaltract,alongwithsweatandsaliva,andalongwithmilk.Althoughtheproportionofthisexcretionpathwayintheentireexcretionprocessisnotimportant,somehavespecialtoxicologicalsignificance.Forexample,excretionwithmilk.Manyforeigncompoundscanentermilkbysimplediffusion.Organochlorinepesticides,ether,polyhalogenatedbiphenyls,caffeineandcertainmetalscanbeexcretedwithmilk.Ifacertainsubstanceisinrepeatedcontactwiththemotherforalongperiodoftime,itislikelytobeconcentratedinthemilk.Theimportantsignificanceliesinthedamagetothebaby;becausecalculatedbytheunitweight,theforeigncompoundingestedbythebabythroughthemilkisoftenlargerthanthegeneralpopulation.

1.Pojem biotransformace

Theprocessbywhichforeigncompoundsundergoaseriesofchemicalchangesinthebodyandformtheirderivativesanddecompositionproductsiscalledbiotransformation,ormetabolictransformation.Theresultingderivativesaremetabolites.Afterbiologicaltransformationofforeigncompounds,somecanachievedetoxificationandreducetoxicity.However,somecanincreaseitstoxicity,andevenproduceteratogenicandcarcinogeniceffects.Therefore,metabolictransformationshouldnotonlyberegardedasadetoxificationprocess,butthemetabolicprocesshasadualityinthetoxicityofforeigncompounds.

Zadruhé, typ biotransformační reakce

Oxidace

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-dealkylační a S-dealkylační reakce: podobně jako N-dealkylační reakce, ale po oxidaci je odstraněna alkylová skupina spojená s kyslíkovým atomem nebo sulfuratomem.

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.

Dvě redukční reakce

Externalcompoundscontainingnitro,azoandcarbonylgroups,aswellasdisulfidesandsulfoxidecompounds,canbereducedinthebody,suchasnitrobenzeneandNitrobenzenecanbereducedtoformaniline.CarbontetrachloridecanbecatalyzedandreducedbyNADPH-cytochromeP-450reductaseinthebodytoformtrichloromethanefreeradicals(CCl3+),whichcandamagethelipidstructureoflivercellmembranesandcauseliversteatosisandnecrosis.Arsenicinpentavalentarseniccompoundscanalsobereducedtotrivalentarsenic.Trivalentarseniccompoundshavehighersolubilityinwater,sotheyaremoretoxicthanpentavalentarseniccompounds.

Třihydrolýza

Manyforeigncompounds,suchasesters,amidesandphosphatesubstitutionscontainingesterbondsareeasilyhydrolyzed.Therearemanyhydrolyticenzymesinplasma,liver,kidney,intestinalmucosa,muscleandnervetissue,aswellasinmicrosomes.Esteraseisaubiquitoushydrolase.Esteraseandamidasecanhydrolyzeestersandamines,respectively.

Thehydrolysisreactionisthemainmetabolicmodeofmanyorganophosphoruspesticidesinthebody,suchasdichlorvos,parathion,dimethoateandmalathionafterhydrolysis,thetoxicitydecreasesordisappears.Someinsectsareresistanttomalathion,thatis,duetothehighcarboxylesteraseactivityintheirbodies,itisveryeasytolosetheactivityofmalathion.Inaddition,pyrethroidinsecticidesarealsodetoxifiedbyhydrolyticenzymedegradation.

Čtyřvazná reakce

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.Hydrocyanicacidcanbecombinedwithcysteine​​andexcretedbysalivaandurine.

⒌Acetylbindstoaromaticaminesinforeigncompounds,forexample,anilinecanreactwithacetyl-CoAthroughitsaminogroup,andacetyltransferasecatalyzesaromaticaminestoformtheiracetylderivatives.Inaddition,aliphaticaminedrugshavesimilarreactions.ThesourceofacetylaseAisthemetabolitesofsugar,fatandprotein.

⒍MethylbindingThereactionofbiogenicamineswithmethylgroupsinthebody,alsoknownasmethylation.Themethylgroupcomesfrommethionine.ThemethylgroupofmethionineisactivatedbyATPtobecomeS-adenosylmethionine,whichiscatalyzedbymethyltransferasetocombinethebiogenicamineswiththemethylgroupfordetoxificationandexcretion.Inthedetoxificationofforeigncompounds,methylbindingdoesnotoccupyanimportantposition.

Dva. Faktory ovlivňující biotransformaci

Jedendruhovýrozdílajednotlivérozdíly

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.

Stav tři metabolické saturace

Thesaturationstateofaforeigncompoundinthebody'smetabolismhasaconsiderableimpactonitsmetabolism,andthereforeitstoxiceffects.Forexample,brominatedbenzeneisfirstconvertedintobrominatedbenzeneepoxidewithlivertoxiceffectsinthebody;iftheinputdoseissmall,about75%ofbrominatedbenzeneepoxidecanbeconvertedintoglutathioneconjugates.Bromophenylsulfideacidisexcretedintheform;butifalargerdoseisinput,only45%ofthesidecanbeexcretedintheaboveform.Whenthedoseistoolarge,duetoinsufficientglutathione,evenglutathionedepletionoccurs,andthebindingreactionisreduced.Therefore,thereactionofunboundbromobenzeneepoxidewithDNAorRNAandproteinisenhanced,showingToxiceffects.

Čtyři další ovlivňující faktory

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.