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Nrf2 is essential for the chemopreventive efficacy of oltipraz against urinary bladder carcinogenesis

Katsuyuki Iida1, Ken Itoh, Yoshito Kumagai

  • 1Department of Urology, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.

Cancer Research
|September 18, 2004
PubMed

Insights

Nuclear factor erythroid 2-related factor 2 (Nrf2) is crucial for detoxifying carcinogens like N-nitrosobutyl(4-hydroxybutyl)amine (BBN). The chemopreventive agent oltipraz enhances this detoxification, protecting against BBN-induced bladder cancer in mice.

Area of Science:

  • Biochemistry
  • Toxicology
  • Cancer Prevention

Background:

  • Phase 2 detoxifying enzymes, like UDP-glucuronosyltransferases (UGTs), protect against carcinogens.
  • Nuclear factor erythroid 2-related factor 2 (Nrf2) regulates the expression of these detoxifying enzymes.
  • Oltipraz is a synthetic agent known to induce phase 2 enzymes.

Purpose of the Study:

  • To investigate the role of Nrf2 in susceptibility to the urinary bladder carcinogen N-nitrosobutyl(4-hydroxybutyl)amine (BBN).
  • To evaluate the chemopreventive efficacy of oltipraz in Nrf2-deficient mice exposed to BBN.

Main Methods:

  • Utilized Nrf2-deficient (Nrf2-/-) and wild-type (WT) mice.
  • Administered BBN to induce urinary bladder carcinoma.
  • Assessed the chemopreventive effects of oltipraz on BBN-induced carcinogenesis and detoxification pathways.

Main Results:

  • Nrf2-/- mice exhibited significantly higher incidence of urinary bladder carcinoma following BBN exposure compared to WT mice.
  • Oltipraz induced BBN-detoxifying phase 2 enzymes in a Nrf2-dependent manner.
  • Oltipraz reduced BBN-induced bladder cancer in WT mice but not in Nrf2-/- mice, by enhancing BBN glucuronidation and counteracting UGT1A suppression.

Conclusions:

  • Nrf2 and its downstream genes are essential for the detoxification of BBN.
  • Oltipraz exerts chemopreventive effects against BBN-induced carcinogenesis by enhancing carcinogen detoxification in an Nrf2-dependent manner.

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