How stereochemistry affects mutagenesis by N-deoxyguanosine adducts of 7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene: Configuration of the adduct bond is more important than those of the hydroxyl groups

Previous work has shown that the major adduct from the (+)-anti diol epoxide of benzo[a]-pyrene (B[a]P), which forms at N-deoxyguanosine [(+)- trans-anti-B[a]P-N-dG], is capable of inducing either predominantly G → T mutations (~95%) in a 5'-TGC-3 sequence context or predominantly GA mutations (~80%) in a 5'-CGT-3' sequence context. This is likely to be attributable to the major adduct being in a different mutagenic conformation in each case. In the next phase of this work, the questions to be addressed are what conformation is associated with what mutation and why? To help define what aspect of adduct structure is important to mutagenesis, the work herein reports on the mutations induced in a single sequence context by four stereoisomers of B[a]P-N-dG: (+)-trans-, (+)-cis-, (-)-trans-, and (-)- cis-. The (+)-trans- and (-)-cis-adducts show a remarkably similar mutational pattern with G → A mutations predominating (~80%). The (-)-trans- and (+)- cis-adducts also show a similar mutational pattern with a more even mixture of G → T, G → A, and G → C mutations. Each of these adducts has an adduct bond and three hydroxyl groups at four consecutive saturated carbons in the B[a]P moiety of the adduct; the stereochemistry at these four positions differs in each of the adducts. The (+)-trans- and (-)-cis-adducts are a pair sharing the S configuration for the adduct bond, although they are a mirror image vis-a-vis the hydroxyl groups. The (-)-trans- and (+)-cis-adducts share the opposite adduct bond stereochemistry (R) but differ in the stereochemistry of their hydroxyl groups. Thus, there is a correlation suggesting that anti-B[a]P-N-dG adduct mutagenesis is more dependent on the stereochemistry of the adduct bond than on the stereochemistry of the hydroxyl groups.