ACTIVATION OF 2-AAF glucuronidation, excretion glucuronide, excretion H 2 N O 3 S - R + MFO N-hydroxylation hydroxylamine acyl transferase sulfotransferase MFO C-hydroxylation R= H, CH3CO- nitrenium transient glucuronidation, excretion covalent DNA binding, mutagenesis, carcinogenesis

RELATION BETWEEN DNA DAMAGE AND MUTATION DNA +activated compound lesion processing/repair no effect mutation RELATION BETWEEN DNA DAMAGE AND MUTATION

ADDUCT FORMATION O d Nu transition state for opening of bay region epoxide heavy lines indicate the p- aromatic system

ORIENTATION OF (±)-trans-anti-DIOLEPOXIDE ADDUCTS OF BP AT Gua N2

Adduct of (-)-trans-anti-BPDE with N6-dAdo opposite dThyd axis 5 face of dAdo Looking down helix axis sequence of modified DNA 5′ -GCTC(A*)CGAG-3′ 3′ -CGAT T GCTC-5′ Looking perpendicular to helix axis

AFB1-dGuo Adduct Opposite dCyd

Reactions of AFB1-dGuo adduct H 3 H O hydrolysis H H O H O O O O O O C H depurination 3 formamidopyrimidine (Fapy) H O H O H O N O H N H N N N 2 O P H apurinic site

Ring-opened formamido pyrimidine (Fapy) of AFB1 adduct at dGuo N7 DEOXYRIBONUCLEIC ACID 11-MAY-98 1HM1 TITLE THE SOLUTION NMR STRUCTURE OF A THERMALLY STABLE FAPY ADDUCT TITLE 2 OF AFLATOXIN B1 IN AN OLIGODEOXYNUCLEOTIDE DUPLEX REFINED TITLE 3 FROM DISTANCE RESTRAINED MOLECULAR DYNAMICS SIMULATED TITLE 4 ANNEALING, MINIMIZED AVERAGE STRUCTURE COMPND MOL_ID: 1; COMPND 2 MOLECULE: FAPY ADDUCT OF AFLATOXIN B1 MODIFIED DNA DUPLEX; COMPND 3 CHAIN: A, B; COMPND 4 ENGINEERED: YES; COMPND 5 OTHER_DETAILS: CHAIN A, GUA 5 -> FAG, FAPY ADDUCT OF COMPND 6 AFLATOXIN B1\: 2'-DEOXY-N7-(8,9-DIHYDRO)-8- COMPND 7 (2,6-DIAMINO-4-OXO-3,4-DIHYDROPYRIMIDYL-5-FORMAMIDO-9- COMPND 8 (HYDROXY-AFLATOXIN B1)-GUANOSINE SOURCE MOL_ID: 1; SOURCE 2 SYNTHETIC: YES KEYWDS AFLATOXIN B1, FAPY, FORMAMIDOPYRIMIDINE, INTERCALATION, DNA KEYWDS 2 DUPLEX, NMR, SOLUTION STRUCTURE, DNA ADDUCT, KEYWDS 3 DEOXYRIBONUCLEIC ACID EXPDTA NMR, MINIMIZED AVERAGE STRUCTURE AUTHOR H.MAO,Z.DENG,F.WANG,T.M.HARRIS,M.P.STONE REVDAT 1 14-OCT-98 1HM1 0 JRNL AUTH H.MAO,Z.DENG,F.WANG,T.M.HARRIS,M.P.STONE JRNL TITL AN INTERCALATED AND THERMALLY STABLE FAPY ADDUCT OF JRNL TITL 2 AFLATOXIN B1 IN A DNA DUPLEX: STRUCTURAL REFINEMENT JRNL TITL 3 FROM 1H NMR JRNL REF BIOCHEMISTRY V. 37 4374 1998 Ring-opened formamido pyrimidine (Fapy) of AFB1 adduct at dGuo N7

ADDUCT OF 2-CHLOROOXIRANE WITH dGuo AND OTHER dNUCLEOSIDES  = “etheno”

3,N4-Etheno-dC opposite dGuo adduct DEOXYRIBONUCLEIC ACID 19-JAN-99 1B6X TITLE 3,N4-ETHENO-2'-DEOXYCYTIDINE OPPOSITE GUANINE IN AN 11-MER TITLE 2 DUPLEX, SOLUTION STRUCTURE FROM NMR AND MOLECULAR DYNAMICS, TITLE 3 4 STRUCTURES COMPND MOL_ID: 1; COMPND 2 MOLECULE: 11-MER DNA DUPLEX; COMPND 3 CHAIN: A, B; COMPND 4 ENGINEERED: YES SOURCE MOL_ID: 1; SOURCE 2 SYNTHETIC: NON-BIOLOGICAL SEQUENCE KEYWDS DEOXYRIBONUCLEIC ACID, ETHENODC, EDC, EXOCYCLIC LESION EXPDTA NMR, 4 STRUCTURES AUTHOR D.CULLINAN,F.JOHNSON,A.P.GROLLMAN,M.EISENBERG, AUTHOR 2 C.DE LOS SANTOS REVDAT 2 06-APR-99 1B6XA 3 3,N4-Etheno-dC opposite dGuo adduct

FORMATION OF 2-AAF ADDUCT

2-AF-dGuo adduct at template junction DEOXYRIBONUCLEIC ACID 19-JUL-99 1C0Y TITLE SOLUTION STRUCTURE OF THE [AF]-C8-DG ADDUCT POSITIONED TITLE 2 OPPOSITE DA AT A TEMPLATE-PRIMER JUNCTION COMPND MOL_ID: 1; COMPND 2 MOLECULE: DNA (5'-D(*AP*AP*CP*GP*CP*TP*AP*CP*CP*AP*TP*CP*C) COMPND 3 -3'); COMPND 4 CHAIN: A; COMPND 5 ENGINEERED: YES; COMPND 6 BIOLOGICAL_UNIT: MONOMER; COMPND 7 OTHER_DETAILS: N ATOM OF AF-GROUP LINKED TO C8 ATOM OF G 4; COMPND 8 MOL_ID: 2; COMPND 9 MOLECULE: DNA (5'-D(*GP*GP*AP*TP*GP*GP*TP*AP*GP*C)-3'); COMPND 10 CHAIN: B; COMPND 11 ENGINEERED: YES; COMPND 12 BIOLOGICAL_UNIT: MONOMER SOURCE MOL_ID: 1; SOURCE 2 SYNTHETIC: YES; SOURCE 3 MOL_ID: 2; SOURCE 4 SYNTHETIC: YES KEYWDS DNA DUPLEX, AMINOFLUORENE ADDUCT, CARCINOGEN ADDUCT, KEYWDS 2 TEMPLATE-PRIMER JUNCTION, DEOXYRIBONUCLEIC ACID EXPDTA NMR, 6 STRUCTURES AUTHOR Z.GU,A.GORIN,B.E.HINGERTY,S.BROYDE,D.J.PATEL REVDAT 1 31-AUG-99 1C0Y 0 JRNL AUTH Z.GU,A.GORIN,B.E.HINGERTY,S.BROYDE,D.J.PATEL JRNL TITL SOLUTION STRUCTURES OF THE [AF]-C8-DG ADDUCT JRNL TITL 2 POSITIONED OPPOSITE DA AT A TEMPLATE-PRIMER JRNL TITL 3 JUNCTION JRNL REF BIOCHEMISTRY V. 38 10855 1999

Common direct acting alkylating agents

deamination of nucleosides

REACTIVE ALDEHYDES FROM LIPID PEROXIDATION AND TRICYCLIC ADDUCTS malondialdehyde (enol form) N d R 1,N 2 -propeno dG (M1G) acrolein C 3 crotonaldehyde 4-hydroxy-2-nonenal 4 isomers 4-hydroxy-2,3-epoxynonanal -etheno dG + -propano dG, two isomers

PRODUCTS OF ATTACK OF HYDROXYL RADICAL ON NUCLEOBASES 2 O d R 5-hydroxy dCyd 5,6-dihydroxy-5,6-dihydro dCyd C 3 dThyd glycol PRODUCTS OF ATTACK OF HYDROXYL RADICAL ON NUCLEOBASES , r e u c t i o n - Z I z F a p y G 8 x

PRODUCTS OF 4' AND 5',5'' DEOXYRIBOSE HYDROGEN ABSTRACTION phosphoglycolate base propenal nucleotide 5'-aldehyde furfural aerobic anaerobic both R O 3 P H C ' PRODUCTS OF 4' AND 5',5'' DEOXYRIBOSE HYDROGEN ABSTRACTION R, R'= DNA strand - B 4' 5',5''

Oxidation of 8-oxodGuo by singlet oxygen (1O2)