Effect of DNA sequence and cytosine methylation on the stereoisomerism and yield of adducts formed by benzo[c]phenanthrene and dibenz[a,j]anthracene diol epoxides

The widespread environmental pollutants, polycyclic aromatic hydrocarbons (PAHs), are changed to dihydrodiol epoxides in living systems. Bay-region diol epoxides, as ultimate carcinogens of the PAHs, react with the exocyclic nitrogens of purines of DNA (N-6 of A or N-2 of G). Most PAH diol epoxides make a mixture of adducts that may differ in carcinogenicity, and factors that alter the composition of the mixture may alter the overall carcinogenicity of the mixture. Changes in DNA base sequence were found to alter systematically the ratio of S vs. R configured dA adducts formed by the (+)-(4S,3R,2S,1R) diol epoxide isomer of benzo[c]phenanthrene (BcPh) (Cheh et al., Biochemistry 33, 12911(1994)). This dissertation probed whether S vs. R adduct ratio varied systematically with DNA sequence when other diol epoxides, dG as well as dA targets and methylated vs. nonmethylated cytosine nearest neighbors were employed. With other BcPhDE isomers, changes in sequence were also seen to alter both adduct S vs. R ratio and adduct yield systematically. The decreasing ratio of S vs. R dA adducts as the sequence changed from 5 '-GAT > CAT > TAC > TAG, that was observed with the (4S,3R,2S,1R)-BcPhDE isomer, was also seen with the (+)-(4S,3R,2R,1S)-BcPhDE isomer. The (-)-(4R,3S,2R,1S)-BcPhDE isomer exhibited decreasing S/R dA adduct formation following the pattern 5'-CAT > TAG >> GAT > or ∼ TAC. With BcPhDE isomers, it was observed that methylation of nearest neighbor C to target A systematically affected the S/R dA adduct ratio and had variable effects on adduct yield, but on average the yield increased by about 40%. With (+)-(4R,3S,2S,1R)-dibenz[a,j]anthracene diol epoxides (DBADE), a pattern of S/R dG adduct ratio dependent on the identity of nearest neighbors was not observed. Methylation of a nearest neighbor C also systematically altered the S/R dG adduct ratios, and often greatly increased the adduct yields. With (-)-(4R,3S,2R,1S) DBADE, there also was no obvious pattern linking S/R dG ratios and nearest neighbors.