Increased susceptibility to hepatocarcinogenicity of Nrf2‐deficient mice exposed to 2‐amino‐3‐methylimidazo[4,5‐ f ]quinoline

To elucidate the roles of the transcription factor NF‐E2‐related factor (Nrf2) in hepatocarcinogenesis induced by 2‐amino‐3‐methylimidazo[4,5‐ f ]quinoline (IQ), a mutagenic and carcinogenic heterocyclic amine, Nrf2‐deficient mice were treated with 300 p.p.m. IQ in their diet for 1, 4 or 52 weeks. In the long‐term experiment, the multiplicity and incidence of liver tumors in male and female IQ‐treated Nrf2 deficient (–/–) mice were significantly higher than those in their counterpart wild‐type (+/+) mice exposed to IQ. In the short‐term experiment, although IQ exposure to Nrf2 (+/+) mice of both sexes did not modify UDP‐glucuronosyltransferase values, glutathione S‐transferase values were significantly increased due to IQ treatment, in contrast to no alteration in male and female Nrf2 (–/–) mice. Levels of oxidative stress markers such as 8‐hydroxydeoxyguanosine and thiobarbituric acid reactive substances in the livers of all treated mice were not changed by IQ treatment. IQ‐specific DNA adduct levels were elevated only in female Nrf2 (–/–) mice, although the increase was not significant. IQ treatment caused an increase in proliferating cell nuclear antigen labeling indices only in male Nrf2 (–/–) mice. The present data clearly show that Nrf2 (–/–) mice of both sexes are susceptible to IQ hepatocarcinogenicity, which might result from IQ accumulation due to failure of metabolizing enzyme induction. In addition, inconsistent results concerning IQ‐specific adducts and proliferating cell nuclear antigen labeling indices in male and female Nrf2 (–/–) mice suggest the existence of different contributions of Nrf2 to IQ hepatocarcinogenesis between mice of the two sexes. ( Cancer Sci 2007; 98: 19–24)