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.
Kitamura
Yasuki
Y
Division of Pathology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo, Japan.
Umemura
Takashi
T
Kanki
Keita
K
Kodama
Yukio
Y
Kitamoto
Sachiko
S
Saito
Koichi
K
Itoh
Ken
K
Yamamoto
Masayuki
M
Masegi
Toshiaki
T
Nishikawa
Akiyoshi
A
Hirose
Masao
M
D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D018736:DNA Adducts / Q000187:drug effects / Q000378:metabolism; D005260:Female; D014453:Glucuronosyltransferase / Q000187:drug effects / Q000378:metabolism; D005982:Glutathione Transferase / Q000187:drug effects / Q000378:metabolism; D008113:Liver Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D051267:NF-E2-Related Factor 2 / Q000235:genetics* / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology; D018809:Proliferating Cell Nuclear Antigen / Q000187:drug effects / Q000378:metabolism; D011804:Quinolines / Q000633:toxicity*; D012737:Sex Factors
D002273:Carcinogens; D018736:DNA Adducts; D051267:NF-E2-Related Factor 2; D018809:Proliferating Cell Nuclear Antigen; D011804:Quinolines; C029216:2-amino-3-methylimidazo(4,5-f)quinoline; D014453:Glucuronosyltransferase; D005982:Glutathione Transferase