Chloride Ions Catalyze the Formation of Cis Adducts in the Binding of Anti- Benzo[a]Pyrene Diol Epoxide to Nucleic Acids

The alkylation of DNA by racemic 7r,8t-dihydroxy-9t,10t-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (anti-BPDE) exhibits a strong preference for formation of trans adducts between the N2deoxyguanosine alkylation site and the (+)-enantiomer of anti-BPDE. In the presence of 10 mM buffer with no added salt, 98% of the adducts formed with native calf thymus DNA result from trans opening of the epoxide ring. The strong selectivity for trans adduct formation obtained with duplex DNA at low salt concentration is found to a lesser degree with poly(G) but is nearly absent with dAMP. When DNA adducts are formed in 10 mM MgCl2or 1 M NaCl, the proportion of cis adducts increases to ≈7 and ≈26%, respectively. At low salt, 10 mM MgCl2, and 1 M NaCl, deoxyguanosine adducts are approximately 1%, 6%, and 24% cis, whereas deoxyadenosine adducts are approximately 11%, 14%, and 37% cis, respectively. NaCl also increases the proportion of cis adducts formed with poly(G) and dAMP. It is proposed that the increase in cis-adduct formation due to salt results from SN1 attack of chloride ion on the BPDE carbocation, forming a trans chlorohydrin, followed by SN2 attack of DNA.