title: 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: 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.
authors.affiliation: Onco-Pathology, Department of Pathology and Host-Defense, Faculty of Medicine, Kagawa University, Kagawa 761-0793.
authors.forename: Hijiri
authors.initials: H
authors.lastname: Takeuchi
authors.forename: Kousuke
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authors.lastname: Saoo
authors.forename: Keiko
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authors.lastname: Yamakawa
authors.forename: Yoko
authors.initials: Y
authors.lastname: Matsuda
authors.forename: Masanao
authors.initials: M
authors.lastname: Yokohira
authors.forename: Yu
authors.initials: Y
authors.lastname: Zeng
authors.forename: Totshiya
authors.initials: T
authors.lastname: Kuno
authors.forename: Yukari
authors.initials: Y
authors.lastname: Totsuka
authors.forename: Mami
authors.initials: M
authors.lastname: Takahashi
authors.forename: Keiji
authors.initials: K
authors.lastname: Wakabayashi
authors.forename: Katsumi
authors.initials: K
authors.lastname: Imaida