Adenine-DNA adduct derived from the nitroreduction of 6-nitrochrysene is more resistant to nucleotide excision repair than guanine-DNA adducts.

Previous studies in rats, mice, and in vitro systems showed that 6-NC can be metabolically activated by two major pathways: (1) the formation of N-hydroxy-6-aminochrysene by nitroreduction to yield three major adducts, N-(dG-8-yl)-6-AC, 5-(dG-N(2)-yl)-6-AC, and N-(dA-8-yl)-6-AC, and (2) the formation of trans-1,2-dihydroxy-1,2-dihydro-6-hydroxylaminochrysene (1,2-DHD-6-NHOH-C) by a combination of nitroreduction and ring oxidation pathways to yield N-(dG-8-yl)-1,2-DHD-6-AC, 5-(dG-N(2)-yl)-1,2-DHD-6-AC and N-(dA-8-yl)-1,2-DHD-6-AC. These DNA lesions are likely to cause mutations if they are not removed by cellular defense mechanisms before DNA replication occurs. Here, we compared for the first time, in HeLa cell extracts in vitro, the relative nucleotide excision repair (NER) efficiencies of DNA lesions derived from simple nitroreduction and from a combination of nitroreduction and ring oxidation pathways. We show that the N-(dG-8-yl)-1,2-DHD-6-AC adduct is more resistant to NER than the N-(dG-8-yl)-6-AC adduct by a factor of ∼2. Furthermore, the N-(dA-8-yl)-6-AC is much more resistant to repair since its NER efficiency is ∼8-fold lower than that of the N-(dG-8-yl)-6-AC adduct. On the basis of our previous study and the present investigation, lesions derived from 6-NC and benzo[a]pyrene can be ranked from the most to the least resistant lesion as follows: N-(dA-8-yl)-6-AC > N-(dG-8-yl)-1,2-DHD-6-AC > 5-(dG-N(2)-yl)-6-AC ≃ N-(dG-8-yl)-6-AC ≃ (+)-7R,8S,9S,10S-benzo[a]pyrene diol epoxide-derived trans-anti-benzo[a]pyrene-N(2)-dG adduct. The slow repair of the various lesions derived from 6-NC and thus their potential persistence in mammalian tissue could in part account for the powerful carcinogenicity of 6-NC as compared to B[a]P in the rat mammary gland.