TY - JOUR
T1 - Increased susceptibility to hepatocarcinogenicity of Nrf2-deficient mice exposed to 2-amino-3-methylimidazo[4,5-f]quinoline
AU - Kitamura, Yasuki
AU - Umemura, Takashi
AU - Kanki, Keita
AU - Kodama, Yukio
AU - Kitamoto, Sachiko
AU - Saito, Koichi
AU - Itoh, Ken
AU - Yamamoto, Masayuki
AU - Masegi, Toshiaki
AU - Nishikawa, Akiyoshi
AU - Hirose, Masao
PY - 2007/1/1
Y1 - 2007/1/1
N2 - 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.
AB - 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.
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U2 - 10.1111/j.1349-7006.2006.00352.x
DO - 10.1111/j.1349-7006.2006.00352.x
M3 - Article
C2 - 17083568
AN - SCOPUS:33751322162
VL - 98
SP - 19
EP - 24
JO - Cancer Science
JF - Cancer Science
SN - 1347-9032
IS - 1
ER -