DNA adduct formation and mutation induction by nitropyrenes in Salmonella and Chinese hamster ovary cells: Relationships with nitroreduction and acetylation

Abstract

Nitrated pyrenes are environmental pollutants and potent mutagens in the Salmonella reversion assay. In this study reversion induction by 1-nitropyrene and 1,8-dinitropyrene in Salmonella typhimurium TA1538 and mutation induction by 1-nitropyrene in Chinese hamster ovary (CHO) cells were related to the extent of metabolism and DNA adduct formation. In suspension cultures of Salmonella typhimurium TA1538, 1,8-dinitropyrene was up to 40-fold more mutagenic than 1-nitropyrene, although both compounds were metabolized at similar rates with nitroreduction being the major pathway. The major metabolite formed from 1-nitropyrene after 2 hr of incubation was 1-nitrosopyrene, while 1-amino-8-nitropyrene was the major metabolite formed from 1,8-dinitropyrene. 1-Nitrosopyrene and 1-nitro-8-nitrosopyrene elicited mutation values consistent with their being intermediates in the activation pathways. However, subsequent to nitroreduction, 1,8-dinitropyrene appeared to be further activated by acetylation, while 1-nitropyrene was not. Each nitrated pyrene produced a major DNA adduct substituted at the C8-position of deoxyguanosine. Although 1,8-dinitropyrene was more mutagenic than 1-nitropyrene, both compounds induced a similar number of revertants per adduct. Incubation of 1-nitrosopyrene with CHO cells produced a rapid concentration- and time-dependent induction of mutations and the conversion of 1-nitrosopyrene to 1-aminopyrene. In contrast, 1-nitropyrene did not induce mutations and was not converted to 1-aminopyrene. Both compounds produced the same major adduct, but adduct formation by 1-nitropyrene was much lower than by 1-nitrosopyrene. These data indicate that nitroreduction and C8 deoxyguanosine adduct formation are strongly associated with mutation induction by 1-nitropyrene in Salmonella and CHO cells. With 1,8-dinitropyrene, however, mutation induction in Salmonella is dependent upon both nitroreduction and esterification.