Coenzyme competition and precursor specificity during teratogenesis induced by 6-aminonicotinamide☆

[摘要] Theteratogenicmechanismofthenicotinamideanalog6-aminonicotinamide(6-AN),isthoughttobeinhibitionofenergyexchangereactionswhichinturnselectivelyinterferewithsynthesisofmucopolysaccharides.Nicotinamideand6-ANwereadministeredsinglyorincombinationforstudyingmicromeliaintheembryonicchicklimb.Thesecoenzymecompetition,protection,andreversibilityexperimentssuggestthatcellsof4-dayembryosreadilyaccepteithernicotinamideor6-AN.Preloadingwithnicotinamide1–24hourspriortoexposureto6-ANpreventedteratogenicityof6-AN.Anexcessofnicotinamideupto2timesthemaximalprotectivedosegiven2hoursormoreafter6-ANdidnotoffsettheteratogenicityof6-AN.Onceexposedeitherto6-ANortonicotinamidethecellsdonotreadilyaccepteitheralternatemolecule.Thismutualexclusivityenableddemonstrationthat6-ANis80%effectiveasateratogenin4-daychickembryoswithin2hoursafteritsadministration.Durationoftheeffectivenessofastandarddoseof6-ANgiventoa4-dayembryowasstudiedbya30-minuteterminallabelwith35S-sulfate.Maximuminhibitionwasseen3daysaftertreatmentandrecoverytocontrolvaluesoccurredinabout412days.Becauselimbteratogenicityisaresultofatypicalchondrogenesisandbecausetheexperimentsabovewereperformedonmixedtissuesofwholeembryosorwholelimbs,earlyrudimentsoftibiaat9,10,and11dayswereisolatedandtestedwith6-ANandlabeledprecursors.Itwasfoundthat2hoursofexposureofbonerudimentsto6-ANwassufficienttodemonstrateselectiveinhibitionof35Sincorporationwhileaminoacidincorporationremainedsimilartocontrols.Theeffectof6-ANinthelimbofthechickembryoisprompt,demonstrablein2hoursandtemporarilyirreversible.Recoveryisseenin4to5days,butdistortionofthecartilagemodelresultsinmicromelia.

[学科分类] 生物科学（综合）