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

Abstract

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 IQtreated 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(-/ (1) and also in cigarette smoke condensate (2) . IQ is carcinogenic to the liver, colon, small intestine, Zymbal's gland, clitoral gland and skin in F344 rats, (3) to the liver, forestomach and lung in CDF 1 mice, (4) and to the liver in B6C3F 1 mice (5) in long-term experiments. Recently, we have found that rat lung is also a target of IQ carcinogenicity.-(6) Its carcinogenesis is considered to involve mainly IQ bioactivation, that is phase I hepatic CYP1A1/2-mediated N-hydroxylation followed by phase II (mainly N-acetyltransferase and sulfotransferase) esterification of N-hydroxylamines to reactive ester derivatives that bind to DNA covalently. (7,8) In addition, it was suggested recently that oxidative stress may also participate in HCA carcinogenesis, based on the findings that induction of preneoplastic or neoplastic lesions following HCA exposure was significantly inhibited when given simultaneously with antioxidants in rats, (9,10) and that superoxide anion radicals were generated during metabolism of HCA by NADPH/cytochrome P-450 reductase in vitro using a spin-trapping method.(11) We have demonstrated enhancement of IQ-induced colon tumor development due to cotreatment with NaNO 2 and the participation of oxidative stress such as oxidative DNA damage and lipid peroxidation in this phenomenon. However, IQ-induced liver tumors were only slightly increased by the addition of NaNO 2 , the relation to oxidative stress being equivocal.(12) Thus, IQ causes carcinogenesis in a b...

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