Reactivity of benzo[a]pyrene-7,8-dione with DNA. Evidence for the formation of deoxyguanosine adducts

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Abstract
Polycyclic aromatic hydrocarbon (PAH) o-quinones are products of the dihydrodiol dehydrogenase-catalyzed oxidation of trans-dihydrodiols which are proximate carcinogens. The PAH o-quinones are highly reactive molecules and have the potential to alkylate DNA. In this study, the reactivity of [3H](+/−)-trans-7,8-dihydroxy-anti-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene ([3H](+/−)-anti-BPDE), [3H]benzo[a]pyrene-7,8-dione ([3H]BPQ) and [3H](+/−)-trans-7,8-dihydroxy-7,8-dihydrobenzo[a] pyrene ([3H](+/−)-B[a]P-diol) with DNA were compared. (+/−)-anti-BPDE reacted equally well with native, deproteinated and deproteinated/sheared calf thymus DNA. In each case DNA adducts were formed which upon digestion to deoxyribonucleosides comigrated on reverse-phase (RP)-HPLC with adducts synthesized by reacting (+/−)-anti-BPDE with oligo-p(dG)10. (+/−)-anti-BPDE also reacted with plasmid (pGEM-3) DNA to yield multiple adducts one of which comigrated with the (+)-anti-BPDE-deoxyguanosine adduct. Under identical conditions [3H]BPQ reacted preferentially with native calf thymus DNA but displayed low reactivity with deproteinated and deproteinated/sheared calf thymus DNA. RP-HPLC analysis of deoxyribonucleoside—BPQ adducts indicated that the predominant adduct formed comigrated with a standard synthesized by reacting BPQ with oligo-p(dG)10. BPQ also reacted with pGEM-3 DNA to yield multiple adducts one of which comigrated with the BPQ—deoxyguanosine adduct. Reactions between [3H]BPQ and poly(dA), poly(dT), poly(dC) and oligo-p(dG)10 indicated that BPQ preferentially formed deoxyguanosine adducts. In this study, [3H]BPQ and [3H](+/−)-anti-BPDE covalently labeled native calf thymus DNA to an equal extent, however, less [3H]BPQ was recovered as deoxyguanosine adducts. By contrast, no covalent modification of calf thymus DNA, pGEM-3 DNA or oligonucleotides was observed with [3H](+/−)-B[a]P-diol. These studies indicate that BPQ has the potential to be genotoxic in vitro; that reactivity is heightened in the presence of protein or circular DNA and that the major adduct formed is a deoxyguanosine adduct.

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