agents that influence drug metabolism

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1、AgentsThatInfluenceDrugMetabolismGarlicConsumptioninChinaandItalylinkedtolowerGIcancersSulfurcompoundsinhibitcancersofcolon,breast,esophagus,lung,skinPrimarilyactsthroughmodulationofPhase1(activation)andPhase2(detoxification)enzymesAlliumsativumOrganosulfurCompoundsinGarlicMemberoft

2、heplantgenusAlliumOver20differentcompoundsingarlicarebeingtestedforcancerinhibition.Diallylsulfidewasthefirstorganosulfurcompoundknowntoinhibitexperimentally-inducedcancer.Proposedmechanismsofchemoprotectionlieinmodificationofcarcinogenmetabolismand/ordetoxification.AlliinLipophilic

3、compoundsdiallylsulfidediallyldisulfidemethylpropylsulfidedipropyldisulfidedimethyltrisulfidemethylpropyltrisulfidemethylpropylthiosulfinateWatersolublecompoundsL-cysteineS-allyl-l-cysteineS-methyl-l-cysteineL-methionineAllicinAllinaseCyp2e1OnesubsetofmanycytochromesP450Maintaskisto

4、activatecompounds;eliminatethemfromthebodyThisenzymemetabolizesmanysmallmolecularweightcompoundsEthanol,nitrosamines,hydrazinesCYP2E1andColonCancerDimethylhydrazine(DMH)ModelCH3-NH-NH-CH31,2-DimethylhydrazineCH3-N=N-CH3azomethaneCH3-N=N-CH3azoxymethaneCH3-N=N-CH2OHmethylazoxymethano

5、lOCH3-NNmethyldiazoniumLIVERH3C+N2COLONSpontaneousbreakdownCYP2E1CYP2E1TypicalChemopreventionAssaysinRodentsChemopreventiveactivityofoil-solubleOSCsinACFassay(M.Wargovich,1997)GarlicCompoundsandPhaseIIEnzymesAntiproliferativeorGrowthSuppressingAgents:ModulationofCellSignalingCOXIn

6、hibitorsReduceColorectalCarcinogenesis–ObservationalDataBIOLOGICALROLEOFPROSTANOIDSNSAIDsInhibitACFsintheColonToxicityofNSAIDsIbuprofenDiclofenacNaproxenKetoprofenIndomethacinPiroxicam-++/-++/-++++++++++++++++CompoundToxicity*InhibitACF?*Clinicalmanifestations:Colitis,perforation,fi

7、stulae,GIbleedingPepticandsmallbowelulcers,strictures*P<0.05;n=12/groupVehicle15050015005005101520253035Latetreatment(days55-80)CelecoxibPiroxicam*(mg/kgdiet)*CelecoxibInhibitsTumorMultiplicityintheMINMouseModelMultiplicity(tumors/animal)101520253035Vehicle50015005005Earlytreatment

8、(days30-80)Celecoxi