In Vivo Mutagenicity and Carcinogenicity of Heterocyclic Amines in Transgenic Ro

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2-Amino-3, 8-dimethylimidazo[4,5-f]quinoxaline (MeIQx)and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine are mutagenic and carcinogenic heterocyclic amines found in cooked meat. The in vivo mutagenicity of these compounds were examined in mice and rats harboring the lacZ or lacI mutation reporter gene (Muta Mice and Big Blue rats). Bitransgenic mice over-expressing the c-myc oncogene were also examined. C57Bl/ lacZ and bitransgenic c-myc (albumin promoter)/ lacZ mice were bred and weaned onto an AIN-76 based diet containing 0.06% (w/w) MeIQx or onto control diet. After 30 weeks on diet, only male bitransgenic mice on MeIQx developed hepatocellular carcinoma (100% incidence) indicating that there was synergism between c-myc over-expression and MeIQx. By 40 weeks, hepatic tumor incidence was 100 %/75% (17%/0%) and 44%/17% (0%/0%) in male/female c-myc/ lacZ and C57Bl/ lacZ mice given MeIQx (or control) diet, respectively, indicating that either MeIQx or c-myc over-expression alone eventually induced hepatic tumors. At either time point, mutant frequency in the lacZ gene was at least 40-fold higher in MeIQx-treated mice than in control mice of either strain. These findings suggest that MeIQx-induced hepatocarcinogenesis is associated with MeIQx-induced mutations. Elevated mutant frequency in MeIQx-treated mice also occurred concomitant with the formation of MeIQx-guanine adducts as detected by the 32P-postlabeling assay. Irrespective of strain or diet, sequence analysis of the lacZ mutants from male mouse liver showed that the principal sequence alteration was a single guanine-base substitution. Adenine mutations, however, were detected only in animals on control diet. MeIQx-fed mice harboring the c-myc oncogene showed a 1.4-2.6-fold higher mutant frequency in the lacZ gene than mice not carrying the transgene. Although there was a trend toward higher adduct levels in c-myc mice, MeIQx-DNA adduct levels were not significantly different between c-myc/ lacZ and C57Bl/ lacZ mice after 30 weeks on diet. Thus, it appeared that factors in addition to MeIQx-DNA adduct levels, such as the enhanced rate of proliferation associated with c-myc over-expression, may have accounted for a higher mutant frequency in c-myc mice. In the control diet groups, the lacZ mutant frequency was significantly higher in c-myc/ lacZ mice than in C57Bl/ lacZ mice. The findings are consistent with the notion that c-myc over-expression is associated with an increase in mutagenesis. The c-myc over-expression appears to synergistically enhance gene mutations and hepatocarcinogenicity by MeIQx.