Tumorigenesis of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), but not enhancing effects of concomitant high-fat diet, on lung carcinogenesis in female A/J mice

Abstract

Abstract. It has been reported that 2-amino-3,8-dimethylimidazo [4,5-f]quinoxaline (MeIQx) induces liver tumors and to a lesser extent lung lesions, lymphomas and leukemias in cDF 1 mice. since a number of case control studies have pointed to a positive association between fat consumption and lung cancer, we examined the lung carcinogenic potential of MeIQx treatment concomitant with a high-fat diet using female A/J mice. groups 1 and 2 were fed a diet supplemented with MeIQx at a concentration of 600 ppm. groups 1 and 3 received a diet containing 20% corn oil and group 4 was fed the basal diet alone. After 1 week, 10 mice in each group were sacrificed for measurement of cytochrome P450 (cyP)1A2 mrnA in the liver and lung. the remaining mice were maintained on their respective diets until termination, 32 weeks after the initial MeIQx treatment, when lung proliferative lesions were analyzed. the incidences and multiplicities of hyperplasias and adenomas in MeIQx-treated groups (groups 1 and 2) were significantly higher than in the groups without MeIQx treatment, with a significant increase in the incidences and multiplicities of adenomas + carcinomas, as well as hyperplasia + adenomas + carcinomas (lung proliferative lesions). lung carcinomas were observed in 1 mouse in each of the MeIQx-treated groups.However, the high-fat diet (groups 1 and 3) did not affect the incidences or multiplicities of lung proliferative lesions. expression levels of cyP1A2 mrnA after MeIQx treatment significantly increased >3-fold in livers, but no significant change was noted in the lungs, where levels were very low at 1/210 and 1/923 the values for livers. In conclusion, following a 32-week period, we confirmed the lung tumorigenic potential of MeIQx which possibly occurs due to proximate carcinogens activated by cyP1A2 in the liver. However, we failed to detect any influence of a high-fat diet.

Different threshold levels for 2-amino-3,8 dimethylimidazo[4,5-f]quinoxaline (MelQx) initiation of lung and colon carcinogenesis and the effects of an additional initiation by 4 (methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in A/J mice

“…The formation of lung lesions with the administration of MeiQx alone was less than two lesions per mouse on average in terms of multiplicity at 600 ppm (16). By contrast, with nnK alone, on average more than six lesions per mouse were found (experiment 2-1, basal diet with nnK group, summarized in Table iii).…”

“…No significant differences were observed between the incidence and multiplicity of lung macroscopic lesions with up to 100 ppm of MeiQx exposure. However, lung lesions were increased at a dose of 600 ppm in our previous study using the same protocol (16). Since the incidences of hyperplasia and adenoma separately were not altered, histopathological examination for multiplicity was not performed.…”

“…in the present study, in experiment 1, macroscopic and microscopic lung lesions were not induced in the treated mice receiving MeIQx at ≥100 ppm for 32 weeks. However, our previous study using the same protocol demonstrated that a dose of 600 ppm significantly increased lung neoplastic lesions (16). Therefore, the noel was set at 100 ppm for lung tumorigenesis.…”

“…on the other hand, proliferative lesions were induced by MeiQx in a dextran sulfate sodium model for tumor promotion, suggesting initiation activity of MeiQx in the colon (14). We also reported lung tumorigenesis for MeiQx in a/J mice (15,16), a strain which is commonly considered to be highly susceptible to the induction of lung lesions (15,17). 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (nnK) is a tobacco-specific N-nitrosamine genotoxic carcinogen with an important role in tobacco-related human lung cancer, given its strong potential to induce lung carcinogenesis in rodents (18).…”

Dietary Fatty Acids and Cancer

“…In experimental animal models, dietary fat enhanced BPor BOP-induced carcinogenesis in hamsters [183,292], whereas in mice a high-fat diet did not affect spontaneous carcinogenesis in one study [267] and produced different results in 2amino-3, 8-dimethylimidazo [4,5-f] quinoxaline [MeIQx]induced tumors [293,294]. Tumor metastasis of Lewis lung carcinoma cells was increased by high-fat diets [295 -297].…”