Slide 1Slide 2Slide 3Slide 4Slide 5Slide 6Slide 7Slide 8Slide 9Slide 10Slide 11Slide 12Slide 13Slide 14Slide 15Slide 16Slide 17Slide 18Slide 19Slide 20Slide 21P450 catalytic cycle“compound I”“compound 0”FeIIIFeIIFeIIO2FeIIIO2-.FeIVO.+O2-2FeIIIFeIIIOOHFeIIIRRRRRRRe-e-H+2H+H2OR(O)H2O2, RCO3H,PhIOperoxide shuntR(O) O2-.RO22O2 + 2H+ H2O2 + 02H202 + Mn+ M(n+1)+ + HO- + HO•SOD-•Hydroxyl radical from action of superoxide dismutase followed by Fenton chemistryFenton reactionQuinone redox cycling is a source of reactive oxygen species (ROS)NADHNADO2OOquinoneOHO2NADH NADOO.semiquinoneOHcatechol H2O2,O2-OH.H2O2,O2-OH.LIPID PEROXIDATION RADICAL CHAINαββ-CLEAVAGE TO UNSATURATED ALDEHYDESFormation of MalondialdehydeOOO HOmalondialdehyde (enol form)NNNONNd R1,N2-propeno dGONO HNNONNd RNH ONNONNd RacroleinC H3ONH3CO HNNONNd RcrotonaldehydeOO HNO HNNONNd RH O4-hydroxy-2-nonenal4 isomersOO HO4-hydroxy-2,3-epoxynonanalNONNd RNNNONNd RNNO1,N2-etheno dG4 isomers++1,N2-propano dG, two isomersOH(M1G)R =CH2CH3NROHOHNNONNNHOOHNRHOOHOHNNONNOHOOHHNNNONNNHOOHHCHOCHRHO+dGuo from initial 2,3-epoxy-4-hydroxynonanal adductsHNNNNH2NOdRHNNNHNH2NOdROHNNNHNHH2NOdRHONNNHdROH2NONNHdROH2NH2NHOHOHO8-oxodGuoFapyGuodIzdZHydroxyl radical oxidation of dGuoNNNH2OdROHOHHHHNNOOdROHOHCH3HNNNH2OHOdR5-hydroxy dCyd5,6-dihydroxy-5,6-dihydrodCyddThyd glycolProducts of Hydroxyl Radical Oxidation of BasesHNNNNOdRH2NHNNNHNOdRH2NONNNHOdRH2N2-amino-5-[(2’-deoxyribosyl)-amino]-4H- imidazol-4-one dIzNOH2NH2NONHdR2,2-diamino-4-[(2’-deoxyribosyl)- amino]-5(2H)-oxazolone dZH2O1-electron oxidation products of dGuoNHNHNHNdRH2NOOHguanidinohydantoinGh-e--e-HNNNNHNNNHNNNHHNNHNNHOdRH2NOOH2NdRdROHNOONHdRNHH2NOOHdGuo8-oxodGuospiroiminodihydantoinSpguanidinohydantoinGhpH > 5.8pH < 5.81O2Oxidation of dGuo by singlet oxygenphosphoglycolatebase propenalnucleotide 5'-aldehydefurfuralaerobic anaerobicbothRO3POHOOCH3HOPO3R'OOHOHOPO3R'OOCH3HOOPRODUCTS OF 4' AND 5',5'' DEOXYRIBOSE HYDROGEN ABSTRACTIONR, R'= DNA strandRO3POHOPO3R'OOHOHOHOOO-ORO3POBHHOOBHOPO3R'OOHOOHCHOPO3R'OOOHCHOHOO4'5',5''Formation of base propenalReaction of base propenal with dGuo to form M1GHNNNNOBH2NOMichael additionHNNNNNHOOBHHNNNNNHOONNNNONOHHNNNNONM1GM1G FROM BASE PROPENALONNNNNH2OHNNNNNHOHONNNNNONNNHNNHOkinetinfurfuralKINETIN FROM OXIDATIVE DNA DAMAGECation radicals from 1-electron oxidation of BP and 6-MePBbenzo[a]pyrene cation radical 6-methylbenzo[a]pyrene cation radicalAdducts of the cation radicals of BP and 7,12-DMBA with dAdo and dGuoPathway for formation of adducts of dGuo from the cation radical of DMBAPathway to adducts of dAdo from 1-electron oxidation of dibenzo[a,l]pyrene“ene-diyne” class of antineoplastic drugsH1´ abstraction from deoxyriboseFrom: Chem. Rev. 1998, 98,