... THE RELATION OFDIETARYNITROGEN CONSUMPTION TO THE RATEOFURICACIDSYNTHESISINNORMALANDGOUTYMAN1ByEDWARDJ.BIEN,T.F.Ytl,JEAND.BENEDICT,ALEXANDERB.GUTMAN,ANDDEWITTSTETTEN,JR.(From the DivsionofNutritionandPhysiology, the PublicHealthResearchInstituteof the CityofNewYork,Inc.,NewYork;DepartmentofMedicine, The MountSinaiHospital,NewYork)(SubmittedforpublicationJanuary15,1953;acceptedMay1,1953)Inearlierstudies the rateofincorporationofdietaryglycinenitrogenintouricacidwasmeas-uredinnormalandgoutymen(1,2). The ex-perimentalprocedureemployedwastoaddafixedquantity(100mg.perKg.ofbodyweight)ofglycine-N1to the dietandtodetermineboth the quantityofurinaryuricacidanditsisotopecon-tentduring the succeedingtimeintervals.Inviewof the increaseinurinaryuricacidex-cretionwhichfollowsincreased consumption ofdietaryprotein,ithasbeendeemedadvisable,insomeclinics,torestrict the proteinintakeingout.Itwasconsideredofinteresttoexplore the possiblerelationshipbetween the levelofproteinin the dietand the rateofincorporationofdietarygly-cinenitrogenintouricacidinordertoascertainwhetheranincreasein the rateofuricacidsyn-thesiswasindeeddemonstrablewhen the con-sumptionofdietaryproteinwasenhanced.MATERIALANDMETHODSOnenormal(E.B.)andonegoutysubject(D.R.)wereselectedforthisstudy.Bothhavealreadybeende-scribed(1), the goutysubjectbeingknowntoexcrete1Thisworkwascarriedoutwith the supportofagrant-in-aidfrom the NationalInstituteofArthritisandMeta-bolicDiseases,NationalInstitutesofHealth.excessivequantitiesofuricacidin the urineandtoin-corporateglycine-NUatanaugmentedratewhenmain-tainedonalowproteindiet(1).Twoexperimentswereconductedoneachsubject, the firstwhileonarelativelylowpurinediet(2), the sec-ondon the samedietfortifiedwithskimmedmilkpowder(Lonalac)toincrease the proteinintakesignificantly(TableI)withoutmaterialincreaseinfat,carbohydrateortotalcalories.Asuitableinterval,of10to12months,wasallowedtoelapsebetweenexperimentsoneachofthesesubjectsinordertoensureabsenceofdetectableisotopicenrichmentafter the initialfeedingofNu-labeledglycine,aswasdemonstratedineachinstance. The sub-jectsweremaintainedontheirrespectivedietsatleastoneweekbefore the doseofglycine-N1'wasadministered. The samedosageofglycine-N'wasusedinallex-periments(100mg.perKg.bodyweight).Allof the syntheticandanalyticalmethodsemployedwerethosepreviouslydescribed(1,2).RESULTSDespite the factthat the isotopicglycinemusthaveundergonesomewhatgreaterdilutionbynon-isotopicglycinepriortoabsorptionfrom the in-testinewhen the dietwasfortifiedwithprotein, the uricacidexcretedin the earlyperiodbybothofthesesubjectswasricherinisotopewhentheywereonahighproteinregimen(TableI,Figure1).ThisindicationthatincorporationofglycineTABLEIPercentofdoseofadministeredN16excretedasuricacidandastotalnitrogenbyanormal(E.B.)andagouty(D.R.)subjectoveraninedayperiodonarelativelylowandrelativelyhighproteindietDailyexcretionTotalNUricacidNB.mg.7.640.5*13.440.810.8i0.417.341.313144193120228i632327PercentofNfedexcretedasTotalNUricacidN(A)(B)33.00.12552.10.19544.60.45352.10.603*Averagedeviation.778SubjectE. ... THE RELATION OFDIETARYNITROGEN CONSUMPTION TO THE RATEOFURICACIDSYNTHESISINNORMALANDGOUTYMAN1ByEDWARDJ.BIEN,T.F.Ytl,JEAND.BENEDICT,ALEXANDERB.GUTMAN,ANDDEWITTSTETTEN,JR.(From the DivsionofNutritionandPhysiology, the PublicHealthResearchInstituteof the CityofNewYork,Inc.,NewYork;DepartmentofMedicine, The MountSinaiHospital,NewYork)(SubmittedforpublicationJanuary15,1953;acceptedMay1,1953)Inearlierstudies the rateofincorporationofdietaryglycinenitrogenintouricacidwasmeas-uredinnormalandgoutymen(1,2). The ex-perimentalprocedureemployedwastoaddafixedquantity(100mg.perKg.ofbodyweight)ofglycine-N1to the dietandtodetermineboth the quantityofurinaryuricacidanditsisotopecon-tentduring the succeedingtimeintervals.Inviewof the increaseinurinaryuricacidex-cretionwhichfollowsincreased consumption ofdietaryprotein,ithasbeendeemedadvisable,insomeclinics,torestrict the proteinintakeingout.Itwasconsideredofinteresttoexplore the possiblerelationshipbetween the levelofproteinin the dietand the rateofincorporationofdietarygly-cinenitrogenintouricacidinordertoascertainwhetheranincreasein the rateofuricacidsyn-thesiswasindeeddemonstrablewhen the con-sumptionofdietaryproteinwasenhanced.MATERIALANDMETHODSOnenormal(E.B.)andonegoutysubject(D.R.)wereselectedforthisstudy.Bothhavealreadybeende-scribed(1), the goutysubjectbeingknowntoexcrete1Thisworkwascarriedoutwith the supportofagrant-in-aidfrom the NationalInstituteofArthritisandMeta-bolicDiseases,NationalInstitutesofHealth.excessivequantitiesofuricacidin the urineandtoin-corporateglycine-NUatanaugmentedratewhenmain-tainedonalowproteindiet(1).Twoexperimentswereconductedoneachsubject, the firstwhileonarelativelylowpurinediet(2), the sec-ondon the samedietfortifiedwithskimmedmilkpowder(Lonalac)toincrease the proteinintakesignificantly(TableI)withoutmaterialincreaseinfat,carbohydrateortotalcalories.Asuitableinterval,of10to12months,wasallowedtoelapsebetweenexperimentsoneachofthesesubjectsinordertoensureabsenceofdetectableisotopicenrichmentafter the initialfeedingofNu-labeledglycine,aswasdemonstratedineachinstance. The sub-jectsweremaintainedontheirrespectivedietsatleastoneweekbefore the doseofglycine-N1'wasadministered. The samedosageofglycine-N'wasusedinallex-periments(100mg.perKg.bodyweight).Allof the syntheticandanalyticalmethodsemployedwerethosepreviouslydescribed(1,2).RESULTSDespite the factthat the isotopicglycinemusthaveundergonesomewhatgreaterdilutionbynon-isotopicglycinepriortoabsorptionfrom the in-testinewhen the dietwasfortifiedwithprotein, the uricacidexcretedin the earlyperiodbybothofthesesubjectswasricherinisotopewhentheywereonahighproteinregimen(TableI,Figure1).ThisindicationthatincorporationofglycineTABLEIPercentofdoseofadministeredN16excretedasuricacidandastotalnitrogenbyanormal(E.B.)andagouty(D.R.)subjectoveraninedayperiodonarelativelylowandrelativelyhighproteindietDailyexcretionTotalNUricacidNB.mg.7.640.5*13.440.810.8i0.417.341.313144193120228i632327PercentofNfedexcretedasTotalNUricacidN(A)(B)33.00.12552.10.19544.60.45352.10.603*Averagedeviation.778SubjectE. ... B.(1)E.B.(2)D.R.(1)D.R.(2)Proteinintakeg.488468108PercentofexcretedNilinuricacid(100B/A)0.380.371.021.16DIETARYNITROGENANDRATEOFURICACIDSYNTHESIS00.2.oi.DAYSFIG.1. THE ABUNDANCEOFN1INDAILYURINARYURICACIDFROMANORMALANDAGOUTYSUBJECT The concentrationofN'asatompercentexcesshasbeenplottedagainst-timeindays.Eachsubjectwasstud-iedtwice,firstwhileonalowproteindiet,thenwhileonahighproteindiet.nitrogenintouricacidismorerapidwhenonahighproteindietisconfirmedby the morerapid50,25tA~~~~~~TOTALNITROGENoiL-o0hiURICACID0046SDAYSFIG.2. THE ExCRETIONoFN'ASURINARYTOTALNITROGENANDURICACIDBYANORMALSUBJECTONAHIGHANDONALOWPROrEINDIET The percentageof the totaldoseofadministeredNlthatwasexcretedhasbeenplottedcumulatively.declineinisotopeconcentrationinuricacidin the latterperiodof the experiment.Atthistime the glycineabsorbedfrom the intestinaltractis,ofcourse,predominantlyglycine-N".Thesedata,togetherwithtotalN15excretiondata,havealsobeenplottedascumulativeper-centagesof the N15fedwhichwasexcretedastotalurinarynitrogenandasuricacid(Figures2and3).Itwillbenotedthatinbothsubjectsanappreciablygreaterfractionof the administeredglycinenitrogenwasexcretedin the totalnitrogenFIG.3. THE EXCRETIONOFN"ASURINARYTOTALNITROGENANDURICACIDBYAGOUTYSUBJECTONAHIGHANDONALowPROTEINDIET The percentageof the totaldoseofadministeredN1'thatwasexcretedhasbeenplottedcumulatively.of the urinewhenahighproteindietwasfed.ThisincreaseintotalN15excretionproducedbydietarychangeisroughlyparalleledby the in-creaseinuricacid-N"1excretion.Indeed,in the normalsubject(E.B.,TableI) the percentofexcretedN15whichwasfoundinuricacidap-pearedtobeindependentof the quantityofproteiningested.Achangeinproteinintakewhichalmostdoubled the totalurinarynitrogenexcretionpro-ducednosignificantalterationinthispercentage.(0.38and0.37).In the goutysubject(D.R.)a779E.J.BIEN,T.F.YU,J.D.BENEDICT,A.B.GUTMAN,ANDD.STETTEN,JR.considerablylargerpercentof the excretedN15wasrecoveredinuricacid(1.02and1.16onlowandhighproteindiets).Itisquestionablewhether the changeofdiethadanysignificantinfluenceon the percentageinthisinstance.Whenonadietfortifiedwithprotein,both the normaland the goutysubjectincorporateddietaryglycinenitrogen,andpresumablyotherdietaryconstituents,morerapidlyintouricacidthanwhenonaprotein-poordiet.Theyalsoapparentlyde-liverednitrogenfromglycinetoureamorerapidlywhen the dietwasprotein-richandthesetwoproc-esseswereacceleratedinapproximatelyparallelfashion.Itishardlynecessarytopointoutthattheseobservationsaretoofewtopermitofanydefinitiveconclusions. The presentresultswould,however,appeartosupport the validityofrestrictionofdietaryproteininsituations,liketophaceousgout,whereitwouldappeardesirabletoreducetoaminimum the rateofuricacidsynthesis.SUMMARYGlycine-Nl"hasbeenfedinastandardexperi-menttoonegoutyandonenormalsubject,and the abundanceofN15intotalurinarynitrogenandinurinaryuricacidhasbeenstudied.Eachsubjectwasstudiedfirstwhileonalowproteindietandagainwhileonahighproteindiet.Bothin the normalandin the goutysubject,uricacidsynthesiswasfoundtobeacceleratedwhen the dietwasfortifiedwithprotein.Thisaccelera-tionwasapproximatelyparalleledbyanaccelera-tioninothermetabolicpathwaysofglycine.REFERENCES1.Benedict,J.D.,Roche,M.,Yu,T.F.,Bien,E.J.,Gut-man,A.B.,andStetten,D.,Jr.,Incorporationofglycinenitrogenintouricacidinnormalandgoutyman.Metabolism,1952,1,3.2.Benedict,J.D.,Yu,T.F.,Bien,E.J.,Gutnan,A.B.,andStetten,D.,Jr.,Afurtherstudyof the utiliza-tionofdietary...