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MFO

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C. O. C. H. 3. C. O. C. H. 3. N. N. O. H. C. H. H. 2. C. H. 2. C. O. C. H. H. 3. N. N. -. O. S. O. O. C. O. C. H. C. H. 3. C. H. 3. 2. 2. H. O. C. O. C. H. 3. N. +. H. N. C. H. 2. R. C. H. 2. ACTIVATION OF 2-AAF.

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MFO

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

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

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

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

  5. 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

  6. AFB1-dGuo Adduct Opposite dCyd

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

  8. Ring-opened formamido pyrimidine (Fapy) of AFB1 adduct at dGuo N7

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

  10. 3,N4-Etheno-dC opposite dGuo adduct

  11. FORMATION OF 2-AAF ADDUCT

  12. 2-AF-dGuo adduct at template junction

  13. Common direct acting alkylating agents

  14. deamination of nucleosides

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

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

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

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

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