| Abstract: | Incubation of suspension cultures of Chinese hamster ovary (CHO) cells with 1-nitropyrene for as long as 2.5 h failed to induce mutations at the hypoxanthine-guanine phosphoribosyl transferase (HGPRT) locus, while incubation with 1-nitrosopyrene, a reduced derivative of 1-nitropyrene, resulted in a strong mutagenic response. Examination of the metabolites produced during these incubations indicated that 1-nitrosopyrene was rapidly reduced to 1-aminopyrene while 1-nitropyrene was not detectably metabolized. Both compounds produced a single major DNA adduct, N-(deoxyguanosin-8-yl)-1-aminopyrene, in the CHO cells and a strong linear relationship was found between mutation induction and the extent of DNA binding. The low level of adducts produced by 1-nitropyrene was consistent with the weak mutagenic response produced by this compound. These results indicate that both 1-nitropyrene and 1-nitrosopyrene are reduced to a reactive electrophile, presumably N-hydroxy-1-aminopyrene, which produces potentially mutagenic DNA damage in CHO cells. Comparison of the relationship between N-(deoxyguanosin-8-yl)-1-aminopyrene formation and mutation induction in CHO cells with the levels of 1-nitropyrene-induced DNA damage associated with positive responses in other assays of genetic toxicity and with the number of mutations associated with the DNA adducts produced by other agents in CHO cells suggests that the CHO/HGPRT assay may be relatively insensitive to 1-nitropyrene-induced DNA damage. The poor capability of CHO cells in reducing 1-nitropyrene and the relative insensitivity of the assay to the DNA damage produced by this compound may contribute to the weak mutagenic response of 1-nitropyrene in CHO cells. |
