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Journal of Biochemistry Advance Access published online on October 29, 2009
Journal of Biochemistry, doi:10.1093/jb/mvp169
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© The authors 2009. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.

Suppression of AhR signaling pathway is associated with the downregulation of UDP-glucuronosyltransferases during BBN-induced urinary bladder carcinogenesis in mice

Katsuyuki Iida1,2, Junsei Mimura3, Ken Itoh3,*, Chikara Ohyama4, Yoshiaki Fujii-Kuriyama5, Toru Shimazui1, Hideyuki Akaza1 and Masayuki Yamamoto2,6,*

1Department of Urology, Institute of Clinical Medicine, 2Center for TARA and JST-ERATO Environmental Response Project, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba 305-8577, 3Department of Stress Response Science and 4Department of Urology, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki 036-8562, 5Center for TARA and JST-SORST, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, 305-8577, 6Departement of Medical Biochemistry, Tohoku University Graduate School of Medicine, 2-1 Seiryo-cho, Aoba-ku, Sendai 980-8575, Japan

* Co-corresponding authors Please send correspondence to Masayuki Yamamoto at Department of Medical Biochemistry, Tohoku University Graduate School of Medicine 2-1 Seiryo-cho, Aoba-ku, Sendai 980-8575, Japan TEL 81-22-717-8088; FAX 81-22-717-8090 E-mail: masi{at}mail.tains.tohoku.ac.jp Please send correspondence to Ken Itoh at Department of Stress Response Science, Hirosaki University Graduate School of Medicine 5 Zaifu-cho, Hirosaki 036-8562, Japan TEL: 81-172-39-5158; FAX: 81-172-39-5158 E-mail: itohk{at}cc.hirosaki-u.ac.jp

Received August 18, 2009; Accepted October 15, 2009


  Abstract

Downregulation of carcinogen detoxifying enzymes might be a critical factor in tumor formation by increasing the carcinogen concentration in the target organ. Previous reports revealed that the expression of UGT1A mRNA is either lost or decreased in certain human cancer tissues, including urinary bladder cancer. To elucidate this downregulation mechanism, we used an N-nitrosobutyl (4-hydroxybutyl) amine (BBN)-induced mouse urinary bladder carcinogenesis model. Similar to human cancer, the expressions of Ugt1a6, Ugt1a9 and total Ugt1a mRNA in the BBN-induced bladder cancer were markedly decreased compared with those of normal mice. BBN downregulated the basal Ugt1a mRNA expression in a time-dependent manner and this was reversible in the first 2 weeks of BBN treatment. However, after 4 weeks of BBN treatment the repression became persistent after the cessation of BBN treatment. AhR regulates the constitutive and inducible expression of Ugt1a mRNA. We found that the constitutive Ugt1a mRNA expression is decreased in the bladder of AhR knockout (KO) mice. Furthermore, BBN-induced Ugt1a downregulation was lost in AhR KO mice, and the canonical AhR target gene Cyp1a1 was similarly downregulated by BBN in the bladder. These results demonstrate that BBN repressed Ugt1a mRNA expression via suppression of AhR signaling pathway during BBN-induced carcinogenesis.

Key Words: UDP-glucuronosyltransferase, urinary bladder carcinogenesis, AhR


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