The induction of phase 2 detoxifying
enzymes, such as
UDP-glucuronosyltransferases (UGTs), in response to an array of naturally occurring and synthetic agents, such as
oltipraz (4-methyl-5-[2-pyrazinyl]-1,2-dithiole-3-
thione), provides an effective means of protection against a variety of
carcinogens.
Transcription factor Nrf2 is an essential regulator of the inducible expression of detoxifying
enzyme genes by chemopreventive agents. In this study, we investigated in Nrf2-deficient mice the susceptibility to the urinary bladder-specific
carcinogen N-nitrosobutyl(4-hydroxybutyl)amine (BBN) and the chemopreventive efficacy of
oltipraz. The incidence of urinary bladder
carcinoma by BBN was significantly higher in Nrf2-/- mice than in wild-type mice; invasive
carcinoma was found in 24.0 and 38.5% of wild-type and Nrf2-/- mice, respectively.
Oltipraz induced the phase 2
enzymes responsible for BBN detoxification in the liver and urinary bladder in an Nrf2-dependent manner. As expected, therefore,
oltipraz decreased the incidence of urinary bladder
carcinoma by BBN in wild-type mice but had little effect in Nrf2-/- mice. In wild-type mouse liver,
oltipraz significantly induced BBN glucuronidation and decreased the urinary concentration of
N-nitrosobutyl(3-carboxypropyl)amine, a proximate
carcinogen of BBN. Importantly, BBN was found to suppress the expression of UGT1A specifically in the urinary bladder. This suppression was counteracted by
oltipraz in wild-type mice but not in Nrf2-/- mice. These results show that Nrf2 and its downstream target genes are responsible for BBN detoxification. Furthermore,
oltipraz prevents
carcinogenesis by BBN by enhancing detoxification of this
carcinogen in the liver and urinary bladder.