Evolution of a Major Drug Metabolizing Enzyme Defect in the Domestic Cat and Other Felidae Phylogenetic Timing and the Role of Hypercarnivory 英文参考文献.docVIP

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Evolution of a Major Drug Metabolizing Enzyme Defect in the Domestic Cat and Other Felidae Phylogenetic Timing and the Role of Hypercarnivory 英文参考文献.doc

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Evolution of a Major Drug Metabolizing Enzyme Defect in the Domestic Cat and Other Felidae Phylogenetic Timing and the Role of Hypercarnivory 英文参考文献

EvolutionofaMajorDrugMetabolizingEnzymeDefect intheDomesticCatandOtherFelidae:Phylogenetic TimingandtheRoleofHypercarnivory BinuShrestha1,2,J.MichaelReed2,PhilipT.Starks2,GretchenE.Kaufman3,JaredV.Goldstone4, MelodyE.Roelke5,StephenJ.O’Brien6,Klaus-PeterKoepfli6,LaurenceG.Frank7,MichaelH.Court1* 1Comparative and Molecular Pharmacogenomics Laboratory, Department of Molecular Physiology and Pharmacology, Tufts University School of Medicine, Boston, Massachusetts,UnitedStatesofAmerica,2DepartmentofBiology,TuftsUniversity,Medford,Massachusetts,UnitedStatesofAmerica,3DepartmentofEnvironmental and Population Health, Tufts Cummings School of Veterinary Medicine, North Grafton, Massachusetts, United States of America, 4Biology Department, Woods Hole Oceanographic Institution, Woods Hole, Massachusetts, United States of America, 5Laboratory of Genomic Diversity, SAIC-Frederick Incorporated, National Cancer InstituteatFrederick,Frederick,Maryland,UnitedStatesofAmerica,6LaboratoryofGenomicDiversity,NationalCancerInstituteatFrederick,Frederick,Maryland,United StatesofAmerica,7LivingwithLionsProject(Kenya),MuseumofVertebrateZoology,UniversityofCalifornia,Berkeley,California,UnitedStatesofAmerica Abstract The domestic cat (Felis catus) shows remarkable sensitivity to the adverse effects of phenolic drugs, including acetaminophenandaspirin,aswellasstructurally-relatedtoxicantsfoundinthedietandenvironment.Thisidiosyncrasy resultsfrompseudogenizationofthegeneencodingUDP-glucuronosyltransferase(UGT)1A6,themajorspecies-conserved phenoldetoxificationenzyme.Here,weestablishedthephylogenetictimingofdisruptiveUGT1A6mutationsandexplored thehypothesisthatgeneinactivationincatswasenabledbyminimalexposuretoplant-derivedtoxicants.Fixationofthe UGT1A6pseudogenewasestimatedtohaveoccurredbetween35and11millionyearsagowithallextantFelidaehaving dysfunctional UGT1A6. Out of 22 additional taxa sampled, representative of most Carnivora families, only brown hyena (Parahyaena brunnea) and northern el