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CATEGORIES OF DAMAGE

CATEGORIES OF DAMAGE. 1. Bulky covalent adducts causing distortion of the helix. 2. Sterically benign covalent adducts (do not distort DNA) that may be promutagenic. 3. Alteration of nucleobase structure without formation of covalent adducts. electrophile. d-. o. d+. d+. Nu. nucleophile.

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CATEGORIES OF DAMAGE

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  1. CATEGORIES OF DAMAGE 1. Bulky covalent adducts causing distortion of the helix. 2. Sterically benign covalent adducts (do not distort DNA) that may be promutagenic. 3. Alteration of nucleobase structure without formation of covalent adducts.

  2. electrophile d- o d+ d+ Nu nucleophile ELECTROPHILE/NUCLEOPHILE DICHOTOMY in the formation of DNA adducts ~60 o sp3 carbon internal angle 109 o internal angle of epoxide ~60 o

  3. BP DIOLEPOXIDE GEOMETRICAL ISOMERS H H O O H H H H H O H O H O H H H O syn anti trans HYDRATION OF CYCLIC EPOXIDE

  4. MIRROR CHIRALITY (OPTICAL ISOMERISM)

  5. OPTICAL AND GEOMETRIC ISOMERS OF BP DIOLEPOXIDE * H * H O H O H _ (+) -7,8-dihydrodiol H H O O H H H H H O H O H O H H H O _ _ -syn -anti (+) (+)

  6. ACTIVATION OF AFB1 Carcinogenic potency determined by: 1. Intrinsic activity of ultimate active metabolite 2. Proportion of metabolic pathway leading to ultimate active metabolite

  7. ACTIVATION OF VINYL CHLORIDE C l C H 2 H vinyl chloride (monomer for PVC-based plastics) P450 1 C l O DNA adducts? 2 2-chlorooxirane, chloroethylene oxide (CEO) nonenzymatic rearrangement O C l DNA adducts? C H 2 H chloroacetaldehyde

  8. ACTIVATION OF DIMETHYLNITROSAMINE GENERAL STRUCTURE gem aminohydrin -

  9. 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

  10. DNA + activated compound lesion Processing or mis-repair by cell mutation no effect RELATION BETWEEN DNA DAMAGE AND MUTATION Repair by cell

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

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

  13. 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

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