HOW STEREOCHEMISTRY AFFECTS MUTAGENESIS BY N-2-DEOXYGUANOSINE ADDUCTSOF Y-9,10-EPOXY-7,8,9,10-TETRAHYDROBENZO[ALPHA]PYRENE - CONFIGURATIONOF THE ADDUCT BOND IS MORE IMPORTANT THAN THOSE OF THE HYDROXYL-GROUPS

Previous work has shown that the major adduct from the (+)-anti diol e poxide of benzo[a]-pyrene (B[a]P), which forms at N-2-deoxyguanosine [ (+)-trans-anti-B[a]P-N-2-dG], is capable of inducing either predominan tely G --> T mutations (similar to 95%) in a 5'-TGC-3 sequence context or predominantly G --> A mutations (similar to 80%) in a 5'-CGT-3' se quence 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 conformatio n is associated with what mutation and why? To help define what aspect of adduct structure is important to mutagenesis, the work herein repo rts on the mutations induced in a single sequence context by four ster eoisomers of B[a]P-N-2-dG: (+)-trans-, (+)-cis-, (-)-trans-, and (-)-c is-. The (+)-trans- and (-)-cis-adducts show a remarkably similar muta tional pattern with G --> A mutations predominating (similar to 80%). The(-)-trans- and (+)-cis-adducts also show a similar mutational patte rn 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 a t four consecutive saturated carbons in the B[a]P moiety of the adduct ; the stereochemistry at these four positions differs in each of the a dducts. The (+)-trans- and (-)-cis-adducts are a pair sharing the S co nfiguration for the adduct bond, although they are a mirror image vis- a-vis the hydroxyl groups. The (-)-trans- and (+)-cis-adducts share th e opposite adduct bond stereochemistry (R) but differ in the stereoche mistry of their hydroxyl groups. Thus, there is a correlation suggesti ng that anti-B[a]P-N-2-dG adduct mutagenesis is more dependent on the stereochemistry of the adduct bond than on the stereochemistry of the hydroxyl groups.