TY - JOUR
T1 - Inducibility of cytochrome P450 1A1 and chemical carcinogenesis by benzo[a]pyrene in AhR repressor-deficient mice
AU - Hosoya, Tomonori
AU - Harada, Nobuhiko
AU - Mimura, Junsei
AU - Motohashi, Hozumi
AU - Takahashi, Satoru
AU - Nakajima, Osamu
AU - Morita, Masanobu
AU - Kawauchi, Shimako
AU - Yamamoto, Masayuki
AU - Fujii-Kuriyama, Yoshiaki
N1 - Funding Information:
We thank Yuko Kikuchi, Naomi Kaneko, Reiko Kawai, Mitsuru Okano and Masayoshi Noguchi for help during the experiments. We also thank Dr. Keisuke Yamashita and Ms. Yoko Nemoto for discussion and for clerical work, respectively. This work was supported in part by a grant from Solution Oriented Research for Science and Technology, Japan Science and Technology Agency and by a grant for Scientific Research from the Ministry of Health, Labor and Welfare of Japan.
PY - 2008/1/18
Y1 - 2008/1/18
N2 - AhR repressor (AhRR) is an AhR-related bHLH-PAS transcription factor. It is known to repress AhR transcription activity in a competitive manner. To examine AhRR functions in mice, we produced AhRR-deficient mice by gene knockout. AhRR(-/-) mice were born in normal Mendelian proportions, grew well, and were fertile. AhR(-/-) mice exhibited higher levels of Cyp1a1 (Cytochrome P450 1A1) mRNA induction in the skin, stomach and spleen than wild-type mice, while expression of Cyp1a1 mRNA was not significantly altered in the liver, lung, heart or other tissues, suggesting that "super-induction" of Cyp1a1 mRNA expression in AhRR(-/-) mice occurs in a tissue specific manner. AhRR(-/-) mice displayed a delayed response to skin carcinogenesis caused by benzo[a]pyrene. Since CYP1A1 is involved in the metabolic activation and detoxification of chemical carcinogens, these results suggest that overexpression of CYP1A1 shifts the balance of the metabolic activities in the skin of AhRR(-/-) mice in favor of the detoxification of carcinogens.
AB - AhR repressor (AhRR) is an AhR-related bHLH-PAS transcription factor. It is known to repress AhR transcription activity in a competitive manner. To examine AhRR functions in mice, we produced AhRR-deficient mice by gene knockout. AhRR(-/-) mice were born in normal Mendelian proportions, grew well, and were fertile. AhR(-/-) mice exhibited higher levels of Cyp1a1 (Cytochrome P450 1A1) mRNA induction in the skin, stomach and spleen than wild-type mice, while expression of Cyp1a1 mRNA was not significantly altered in the liver, lung, heart or other tissues, suggesting that "super-induction" of Cyp1a1 mRNA expression in AhRR(-/-) mice occurs in a tissue specific manner. AhRR(-/-) mice displayed a delayed response to skin carcinogenesis caused by benzo[a]pyrene. Since CYP1A1 is involved in the metabolic activation and detoxification of chemical carcinogens, these results suggest that overexpression of CYP1A1 shifts the balance of the metabolic activities in the skin of AhRR(-/-) mice in favor of the detoxification of carcinogens.
KW - AhR
KW - AhR receptor
KW - CYP1A1
KW - Chemical carcinogenesis
KW - Gene targeting
KW - Metabolic activation
KW - Polyaromatic hydrocarbon
KW - Super-induction
KW - Transcription
KW - Transcription repression
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U2 - 10.1016/j.bbrc.2007.11.016
DO - 10.1016/j.bbrc.2007.11.016
M3 - Article
C2 - 18022386
AN - SCOPUS:36548999681
SN - 0006-291X
VL - 365
SP - 562
EP - 567
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
IS - 3
ER -