Genetic Resistance to Chemical Hepatocarcinogenesis in the DRH Rat Strain

摘要

Thecarcinogen-resistantinbredratstrainDRHestablishedfromclosed-colonyDonryuratsbyuseofselectivebrother-sistermatingover20generationsundercontinuousfeedingof3#8242;-methyl-4-dimethylaminoazobenzene(3#8242;-Me-DAB)maintainsahighlyresistantphenotypewithoutcarcinogenexposureformanyyears.WereportedthattheclonalexpansionofpreneoplasticglutathioneS-transferase-P(GST-P)-positivefociinducedby3#8242;-Me-DABwaslessextensiveintheliverofDRHratsthanintheliverofsusceptiblestrains,suchasDonryuandF344,althoughlevelsofDNAadductswerecomparableamongtheserats.ComparativestudiesoftheeventsafterinitiationindicatethatDRHratsareconstitutionallylesspronetocellulardamagecausedbycontinuousadministrationof3#8242;-Me-DABthanareparentalDonryurats.Consequently,thereducedgrowthresponseoftheliverduringthepromotionstagemaycontributetothelowsusceptibilitytodevelopmentoflivertumors.Geneticanalysisof(F344×DRH)F2ratsidentifiedtwoquantitativetraitloci,Drh1onchromosome1andDrh2onchromosome4,whichprovideresistancetothedevelopmentofGST-P-positivepreneoplasticfociinducedby3#8242;-Me-DABduringtheearlystageofitsadministration.TheresistancetoprogressiontohepatocellularcarcinomaisaffectedsolelybyDrh2.Theseobservationsindicatethatatleasttwogeneticlociarecriticallyinvolvedinthestepsleadingtochemicalhepatocarcinogenesis.TheDRHratisausefulexperimentalmodelwithwhichtostudygeneticsusceptibilityandresistancetochemicallyinducedlivercancers.