Relationships of DNA adduct formation, K-ras activating mutations and tumorigenic activities of 6-nitrochrysene and its metabolites in the lungs of CD-1 mice.

Abstract

6-Nitrochrysene (6-NC), an environmental pollutant and a potent mouse lung carcinogen, is activated by two major metabolic pathways to yield DNA adducts derived from either trans-1,2-dihydro-1,2-dihydroxy-6-aminochrysene (1,2-DHD-6-AC) or N-hydroxy-6-aminochrysene (N-OH-6-AC). While the former pathway has been shown to be the major activation pathway leading to DNA adducts in mice treated with 6-NC, the potential contribution of the minor nitroreduction pathway to tumorigenicity in this system is not clear. To evaluate the roles of these activation pathways and the resulting DNA adducts in mouse lung tumorigenesis, we studied DNA adduct formation, the induction of tumors and tumor K-ras mutational spectra in the lungs of male CD-1 mice treated with 6-NC and its metabolites. 6-NC, 6-AC and 1,2-DHD-6-AC produced predominantly a single chromatographically identical dG adduct, and 6-nitrosochrysene (6-NOC) gave a single major adduct that was most likely derived from reaction at the C8 position of deoxyadenosine. 6-NC-, 1,2-DHD-6-AC- and 6-NOC-treated mice developed both adenomas and adenocarcinomas in the lung, whereas only lung adenomas were observed in 6-AC-treated animals. K-ras mutations in adenomas resulting from 6-NC and its metabolites were primarily at G:C basepairs in codons 12 and 13, while adenocarcinomas had K-ras mutations distributed between codons 12, 13 and 61, and involved both G:C and A:T basepairs. The K-ras mutational spectra in codons 12 and 13 were similar in both adenomas and adenocarcinomas whereas a higher percentage of mutations at A:T in codon 61 was found in adenocarcinomas. These results support the conclusion that the 1,2-DHD-6-AC-derived adduct is associated with both adenoma and adenocarcinoma formation and is the primary lesion involved in the induction of mouse lung tumors by 6-NC. The major adduct detected after 6-NOC treatment, which is derived from N-OH-6-AC, is apparently less efficient as an inducer of mouse lung tumors and is associated more specifically with adenocarcinoma formation.