RELATIONSHIPS OF DNA ADDUCT FORMATION, K-RAS ACTIVATING MUTATIONS ANDTUMORIGENIC ACTIVITIES OF 6-NITROCHRYSENE AND ITS METABOLITES IN THE LUNGS OF CD-1 MICE

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-ami nochrysene (1,2-DHD-6-AC) or N-hydroxy-6-aminochrysene (N-OH-6-AC). Wh ile the former pathway has been shown to be the major activation pathw ay leading to DNA adducts in mice treated with 6-NC, the potential con tribution of the minor nitroreduction pathway to tumorigenicity in thi s system is not clear. To evaluate the roles of these activation pathw ays and the resulting DNA adducts in mouse lung tumorigenesis, we stud ied DNA adduct formation, the induction of tumors and tumor K-ras muta tional spectra in the lungs of male CD-1 mice treated with 6-NC and it s metabolites. 6-NC, 6-AC and 1,2-DHD-6-AC produced predominantly a si ngle chromatographically identical dG adduct, and 6-nitrosochrysene (6 -NOC) gave a single major adduct that was most likely derived from rea ction 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 l ung, whereas only lung adenomas were observed in 6-AC-treated animals. K-ras mutations in adenomas resulting from 6-NC and its metabolites w ere primarily at G:C basepairs in codons 12 and 13, while adenocarcino mas 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 c odons 12 and 13 were similar in both adenomas and adenocarcinomas, whe reas 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 adenocarcinom a formation and is the primary lesion involved in the induction of mou se lung tumors by 6-NC. The major adduct detected after 6-NOC treatmen t, 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.