bhmt 8 - dr amy yaskodramyyasko.com/wp-content/uploads/2010/06/39-a1-bhmt8.pdf · lead inhibits...
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• Acutestressnorepinephrineincrease
• ThisinturnleadstoanincreaseintyrosinehydroxylasebutNOTindopaminergicnuclei
• Neteffectisincreasednorepinephrinerela:vetodopamine.
BrainRes.1991Mar22;544(1):26‐32.RelatedAr:cles,Links
EffectsofstressandadrenalectomyontyrosinehydroxylasemRNAlevelsinthelocusceruleusbyinsituhybridiza@on.
SmithMA,BradyLS,GlowaJ,GoldPW,HerkenhamM.
Sec:ononFunc:onalNeuroanatomy,NIMH,Bethesda,MD20892.
Thelocusceruleus‐norepinephrinesystemisoneoftheprincipaleffectorsofthestressresponse.Acutestressinducesnorepinephrinesynthesisandrelease,andnoradrenergiccellscompensatebyincreasingtheac:vityoftyrosinehydroxylase,therate‐limi:ngenzymeincatecholaminesynthesis.Hereweuseinsituhybridiza:onhistochemistrytoshowtheeffectsofacuteandchronicintermiYentstressontheexpressionoftyrosinehydroxylasemRNAintheratlocusceruleus.RestraintstressincreasedtyrosinehydroxylasemRNAinthelocusceruleusbutnotindopaminergicnucleisuchasthesubstan:anigraorventraltegmentalarea.OnehouroffootshockorrestraintcausedarapidincreaseinlocusceruleustyrosinehydroxylasemRNAwhichreturnedtobasallevelswithin24h.ChronicintermiYentstress(1hourofrestraintorfootshockperdayfor14days)producednochangeintyrosinehydroxylasemRNA.NeitheradrenalectomynordexamethasonereplacementsignificantlyaffectedmRNAexpression.Thesefindingsindicatethatacutestress
canincreasetheexpressionoftyrosinehydroxylasemRNAinthelocusceruleusbutthatadapta:onoccurstorepeatedstress,andthattheexpressionoftyrosinehydroxylasemRNAinthelocusceruleusisindependentofdirectglucocor:coidmodula:on.
Rememberthatsulfurcontainingaminoacidsincreasenorepinephrine,rela6onshiptoCBSupregula6ons
BHMT8appearstoincreasenorepinephrinerela@vetodopamine;alsoreflectedinbehaviors
Leadinhibitsthisenzyme
Caspers,ML.Inhibi6onobyleadofphenylethanolamineNmethyltransferase.BiochemPharmacol.31(11):1985.1982
IncreasedCBSac:vitycanleadtoastressresponseduetosulfureffectsoncor:sollevels.
Wherethenorepinephrinereceptorisinhibitedbyhighsulfur,thisleadstoasitua:onwithhighcircula:ngnorepinephrine.
dopamine norepinephrineCopper/VitaminC
DBH
Lead
Mercury
Excessmanganese
H2S(hydrogensulfide)
Sulfides
Sulfadrugs
epinephrine
PNMT
SAMe
Methyla:onpathway
Inhibitedbylead
•CBS•SUOX•Lowmolybdenum
Norepinephrinereceptorisinhibitedby
highsulfur
KidneyInt2001Jun;59(6):2267‐72Dimethylglycineaccumulatesinuremiaandpredictselevatedplasmahomocysteineconcentra@ons.McGregorDO,DellowWJ,LeverM,GeorgePM,RobsonRA,ChambersST
BACKGROUND:Hyperhomocysteinemiaisariskfactorforatherosclerosisthatiscommoninchronicrenalfailure(CRF),butitscauseisunknown.Homocysteinemetabolismislinkedtobetaine‐homocysteinemethyltransferase
(BHMT),azincmetalloenzymethatconvertsglycinebetaine(GB)toN,Ndimethylglycine(DMG).DMGisaknownfeedbackinhibitorofBHMT.WepostulatedthatDMGmightaccumulateinCRFandcontributetohyperhomocysteinemiabyinhibi:ngBHMTac:vity.METHODS:Plasmaandurineconcentra:onsofGBandDMGweremeasuredin33dialysispa:ents(15con:nuousambulatoryperitonealdialysisand18hemodialysis),33pa:entswithCRF,and33age‐matchedcontrols.Concentra:onsoffas:ngplasmatotalhomocysteine(tHcy),redcellandserumfolate,vitaminsB(6)andB(12),serumzinc,androu:nebiochemistrywerealsomeasured.Groupswerecompared,anddeterminantsofplasmatHcywereiden:fiedbycorrela:onsandstepwiselinearregression.RESULTS:PlasmaDMGincreasedasrenalfunc:ondeclinedandwastwofoldtothreefoldelevatedindialysispa:ents.PlasmaGBdidnotdifferbetweengroups.Thefrac:onalexcre:onofGB(FE(GB))wasincreasedtenfold,andFED(MG)wasdoubledinCRFpa:entscomparedwithcontrols.PlasmatHcycorrelatedposi:velywithplasmaDMG,theplasmaDMG:GBra:o,plasmacrea:nine,andFE(GB)andnega:velywithserumfolate,zinc,andplasmaGB.Inthemul:pleregressionmodel,onlyplasmacrea:nine,plasmaDMG,ortheDMG:GBra:owasindependentpredictorsoftHcy.CONCLUSIONS:DMGaccumulatesinCRFandindependentlypredictsplasmatHcyconcentra:ons.ThesefindingssuggestthatreducedBHMTac:vityisimportantinthepathogenesisofhyperhomocysteinemiainCRF.PMID:11380830,UI:21275836
AddressingStress:DMG
H2Sleadstoanincreaseinnorepinephrineandserotonin,rela@onshiptoaggression,hyperac@vityanddiversionofmethyla@oncycle
•AMen6onSupport•AmmoniaSupport•DMG•SAMe