DNA Adduct Formation by 1-Nitropyrene 4,5- and 9,10-Oxide

Abstract

1-Nitropyrene is an environmental pollutant with both mutagenic and tumorigenic properties (reviewed in reference 1). This nitropolycyclic aromatic hydrocarbon is metabolized in vivo by either oxidative or reductive pathways, or by a combination of the two. Reduction of 1-nitropyrene leads to the formation of N-hydroxy-l-aminopyrene, an electrophilic metabolite that reacts with DNA to give N-(deoxyguanosin-8-yl)-1-aminopyrene (dG-C8-AP). This adduct is associated with the induction of mutations in Salmonella typhimurium and Chinese hamster ovary (CHO) cells (2–6), and evidence has been presented for its formation in vivo (7–11). Although 1-nitropyrene undergoes nitro-reduction in vivo, the major metabolic pathways appear to be oxidative (reviewed in reference 1), and these may lead to the DNA adducts that have been detected in addition to dG-C8-AP (8–11). 1-Nitropyrene 4,5-oxide and 1-nitropyrene 9,10-oxide are prime candidates for the ring-oxidized 1-nitropyrene metabolites that produce some of these unidentified DNA adducts. Both oxides display strong mutagenicity in Salmonella typhimurium (12) and CHO cells (13). In addition, Djuric et al. (14) demonstrated their binding to DNA by direct reaction and after nitroreduction by the mammalian nitroreductase, xanthine oxidase. In this study, we have examined the DNA adducts formed by 1-nitropyrene 4,5-and 9,10-oxide following reaction with calf thymus DNA, both in the presence and absence of xanthine oxidase and hypoxanthine, and have compared these adducts to those responsible for the mutagenicity of the oxides in CHO cells.