Chapter11MetabolismofNon-nutritionalSubstancesBiotransformationinliverMetabolismofbileacidsBiosynthesisofhemeMetabolismofbilepigmentsSectionⅠBiotransformationofliverSomenon-nutrientsubstancescanbeconvertedtomorepolarmetabolitesbyvariouschemicalreactionssuchasoxidation,reduction,hydrolysis,andconjugation,whicharethenexcretedfromthebody.Theseprocessesmainlyoccurinliver.Sourcesofnon-nutrients:*endogenous:hormones,neurotransmitters,amine,ammoniaandbilepigment…

*exogenous:drugs,foodadditives,toxicityandenvironmentalpollutants,etc.Significanceofbiotransformation:

1.Increasesolubility

(polarity).Facilitatetheirexcretionfromthebody.(excretedintheurineandbile)2.Decreaseoreliminatebiologicalactivityandtoxicity3.Butsomematerialsbecomelesssolubleandmoretoxic，increasetheirbiologicalactivity.(Dualismofdetoxicificationandtoxicification)biotransformationDetoxification

Majortypesofbiotransformationreactions(1)Phase1reactions:

oxidationreductionhydrolysis

(2)Phase2reactions:

conjugation(1)CytochromeP450Monooxygenase(mixed-functionoxidase,orhydroxylase)inmicrosome

MonooxygenasesincorporateoneatomfromO2intoaproductandreducetheotheratomtowater.RH+NADPH+H++O2→R-OH+NADP++H2OThistypeofenzymeisusedinhydroxylationofsteroidhormones,bileacid,andbiotransformationinliver,etc.1.Oxidationreaction

NADPH

MonooxygenaseNADPH-CytP450reductase(FAD,Fe-S)

CytP450

(2)Monoamineoxidase,MAO(inmitochondria)RCH2NH2+O2+H2O→RCHO+NH3+H2O2(amine)(aldehyde)RCHO+NAD++H2O→RCOOH+NADH+H+(aldehyde)aldehydedehydrogenase(3)Alcoholdehydrogenase(ADH,cytosol)andAldehydedehydrogenase(ALDH,Mitandcytosol)ALDHMEOS(P450):alcohol-p450monooxygenase(microsomalethanoloxidizingsystem)2.

Reductionreaction*Nitroreductase,Azoredictase(NADH

orNADPH)3.Hydrolyzedreaction*Hydrolases(incytosolandER)Esterase,amidase,glucosidase

aspirinsalylicacid

4.Conjugation

*Conjugationofglucuronicacid(mostimportant)Activateddonor:

uridinediphosphateglucuronicacid(UDPGA)

Enzyme:

UDP

glucuronyltransferase(UGT)

*Conjugationofsulfate

Donor:3'-phosphoadenosyl-5'-phosphosulphate(PAPS)Enzyme:Sulfatetransferase

*Acetylationacetyl-CoA,acetyltransferase

*Conjugationofglutathione

GSH-S-transferase(GST)*Methylation

S-adenosylmethionine(SAM),methyltransferase*ConjugationofGly

acylCoAligaseandacyl-CoA:aminoacidN-acyltransferaseFactorsthataffectbiotransformation(1)Age,sex,nutritionstate,diseasesandheredity(2)InducersandinhibitorsSectionⅡ

BileandBileacidmetabolismI.Bile:

BilehepaticbilegallbladderbileComponentsbileacidsproteinslecithincholesterolbilepigmentsseveralionswaterII.Classificationofbileacid1731224OHCholicacid(3,7,12)*Freebileacid:cholicacidchenodeoxycholicaciddeoxycholicacidlithocholicacid*Conjugatedbileacid:glycocholicacidtaurocholicacidglycochenodeoxycholicacidtaurochenodeoxycholicacidglycodeoxycholicacidtaurodeoxycholicacidPrimaryfreebileacidSecondaryfreebileacidPrimaryconjugatedbileacid

SecondaryconjugatedbileacidOHOHCholicacid(3,7,12)Chenodeoxycholicacid(3,7)PrimarybileacidCholicacidChenodeoxycholicacidDeoxycholicacidlithocholicacidSecondarybileacid7α-dehydroxyl

7α-dehydroxylⅢ.FunctionsofbileacidsFacilitatedigestionandabsorptionofdietarylipidsandfat-solublevitaminsBileacidsandphospholipidssolubilizecholesterolinthebile,therebypreventingtheprecipitationofcholesterolinthegallbladder.(Bilesalts+lecithin)︰cholesterol→10:1Ⅳ.MetabolismofbileacidandenterohepaticcirculationofbileacidFormationofprimarybileacids(inliver)therate-limitingstepGlycocholicacidTaurocholicacid膽汁酸生成的調(diào)節(jié)膽固醇7α－羥化酶(膽汁酸合成的限速酶)HMG－CoA還原酶(膽固醇合成的關(guān)鍵酶)肝膽汁酸－－高膽固醇飲食－增加膽固醇7α-羥化酶基因表達(dá)＋甲狀腺素＋糖皮質(zhì)激素生長激素＋Formationofsecondarybileacids(inintestine)Enterohepaticcirculationofbileacids:UtilizethelimitedbileacidsforthedigestionandabsorptionoflipidsPassiveabsorptionActiveabsorptionLiverCholesterolBilesaltsDietaryFatEmulsifiesdietaryfatFatgetsabsorbed>95%Enterohepatic

circulation<5%(inthestools)AffectofDietaryFiberDrugs:ionexchangeresins

(cholestyramine)BloodCholesterolStoredinthegallbladderIncreases?OverviewofbilesaltmetabolismSectionⅢ.Biosynthesisofheme

M=methylP=propionateV=vinylSubstituents:ABCDHemeMethenylbridge1.Biosynthesisofheme(inliver,bonemarrow)Gly,succinyl-CoA,Fe2+Materials:Site:inmitochondriaandcytosol

Processes:1)ALAsynthesis2)PBGsynthesis3)UPGandCPGsynthesis4)Hemesynthesis

（ALA）ALAsynthase(Coenzyme:Pyridoxalphosphate)Theprocessesofhemesynthesis(keyenzyme)inmitochondriaHemefeedbackinhibitionΘ

ALAdehydrase

(ALAentersthecytosol)(PBG)膽色素原3NH2NH24CO2deaminaseLineartetrapyrrolecosynthasedecarboxylaseUroporphyrinogenIIICoproporphyrinogenIIIFe2+ferrochalataseglobinHbCoproporphyrinogenIII(intoMit)6H2CO2decarboxylaseoxidaseProtoporphyrinIXHemeProtoporphyrinogenIntocytosol原卟啉原IX原卟啉原IXMaterials:succinyl-CoA,glycineandFe2+.

Theinitialreactionandthelastthreeoccurinmitochondria;Theintermediatestepsoccurinthecytosol.Synthesizedmainlyinliverandbonemarrowbutmatureredbloodcellslackmitochondriaandareunabletosynthesizeheme.keyenzyme:ALAsynthase(coenzyme:pyridoxalphosphate.Summary2.Regulationofhemesynthesis1)ALAsynthase

(Themajorregulatorystep)

(-)Gly+succinyl-CoAALAheme(-)

(+)

VitB6,MHbsterolhormonefeedbackinhibition2)ALAdehydraseandferrochelataseTheyaresensitivetoheavymetal,suchasplumbum.Soplumbumtoxicosiscanleadtoinhibitionofhemesynthesisandanemia.Ironabsent→anemia3)Erythropoietin,(EPO)

ItisthemajorregulatorofRBCgeneration.

EPOissynthesizedbythekidneyandisreleasedintothebloodstream.ItcombineswithprogenitorsofRBCviaaspecificreceptor.*EPOpromotessynthesisofhemeandHb.*EPO

promotesproliferationanddifferentiationofRBCprogenitors.Porphyria(卟啉癥)

Disordersthatarisefromdefectsintheenzymesofhemebiosynthesisaretermedtheporphyriasanditcauseselevationsofintermediatesinhemesynthesisintheserumandurine.Theporphyriasarebothinheritedandacquireddisordersinhemesynthesis.

Hb80%globinhemeaminoacidbiliverdinbilirubinbilinogenbilinbilepigmentSectionⅣ

MetabolismofbilepigmentandjaundiceMb,Cyt,Catalase,Peroxidase,etc.Bilepigmentarecatabolicproductsofiron-containingporphyrincompounds1.HemeDegradation

M=methyl,P=proprionic,V=vinylLiver,spleen6-氫鍵fat-solubletoxicDCABHemeoxygenase(HO-1,2,3)HO-1isinducible,whereasHO-2isconstitutive.Bilirubin:themostpotentantioxidantintheserumofmammals.ThenormalconcentrationsofBRissufficienttoalleviateoxidativestress,toinhibitROSgeneration.Highnormalconcentrationsofbilirubin(>1mg/dL)inadultscorrelateswithbettercardio-vascularfunctionandlessinflammation.Biliverdinreductasecycle:bilirubin,actingasanantioxidant,isitselfoxidizedtobiliverdinandthenrecycledbybiliverdinreductasebacktobilirubin.Thisredoxcyclemayconstitutetheprincipalphysiologicfunctionofbilirubin.CO:secondmessengerAmodelforantioxidantcytoprotectionconferredbybiliverdinreductase(BVR).激活PKG,PKG磷酸化其底物可引起血管舒張等效應(yīng)CO的信使功能與cGMP有關(guān)CO(Unconjugatedbilirubin)increasingthesolubilityofbilirubinandfacilitatingitstransportationinblood.increasingthesizeofbilirubinandlimitingitspenetrabilitytomembrane2.Transportationofbilirubininblood3.BilirubinInliver(1)Takeup

Bilirubin(2)Conjugation(3)ExcretionBilirubin+Y.ZPrABilirubin-YPr.ZPrBilirubin+UDP-GA

bilirubin-GAbileductintestineUDP-GAtransferase(ligandin)