Comparison of Ha-ras mutational spectra of N-methyidibenzo[c,g]carbazole and 7H-dibenzo[c,g]carbazole-induced mouse skin tumors

Carcinogenic N-heterocyclic aromatic hydrocarbons are formed during the inc omplete combustion of fossil fuels as well as cigarette smoke. N-Methyldibe nzo[c,g]carbazole (NMeDBC) and 7H-dibenzo[c,g]carbazole (DBC) are members o f this group. DBC induces mouse skin and liver tumors, whereas NMeDBC induc es only mouse skin tumors. The objective of this study was to elucidate the mechanism of action of these compounds in skin by assessing the Ha-ras mut ational spectra induced by a two-stage initiation-promotion protocol. NMeDB C (200 nmol) or DBC (200 nmol) was applied to the back skin of 24 female Hs d:ICR(Br) mice (12 per group) once. 12-O-tetradecanoylphorbol-13-acetate (T PA) (2 mug) was then applied twice weekly for 28 wk, Tumors were screened f or Ha-ras mutations using enriched polymerase chain reaction and mutations defined by dideoxy sequencing. In DBC animals 58% produced papillomas, of w hich 71 % had codon 61 mutations, 4% had codon 12 mutations, 4% had codon 1 3 mutations, and 21 % had no Ha-ras mutations. In NMeDBC animals 92% produc ed papillomas, of which 73% had codon 61 mutations and 27% had no Ha-ras mu tations. All of the codon 61 mutations, from both NMeDBC and DBC, were CAA- CTA transversions, The DBC-induced tumors with the codon 12 mutation had a GGA --> GAA transition, and the codon 13 mutation was a GGC --> GTC transve rsion. These results suggest that NMeDBC is a more potent tumor inducer tha n DBC, but the resulting Ha-ras mutations in each group were predominantly in codon 61, and, therefore, mutation induction in skin by each chemical ap pears to proceed by a similar mechanism. (C) 2001 Wiley-Uss, Inc.