Nrf2 is essential for the chemopreventive efficacy of oltipraz against urinary bladder carcinogenesis.
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.
Iida
Katsuyuki
K
Department of Urology, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
Itoh
Ken
K
Kumagai
Yoshito
Y
Oyasu
Ryoichi
R
Hattori
Kazunori
K
Kawai
Koji
K
Shimazui
Toru
T
Akaza
Hideyuki
H
Yamamoto
Masayuki
M
D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D002085:Butylhydroxybutylnitrosamine / Q000493:pharmacokinetics; D002273:Carcinogens / Q000493:pharmacokinetics; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D020022:Genetic Predisposition to Disease; D020719:Glucuronides / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D008658:Inactivation, Metabolic; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D051267:NF-E2-Related Factor 2; D011719:Pyrazines / Q000494:pharmacology*; D013871:Thiones; D013876:Thiophenes; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D001743:Urinary Bladder / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D001749:Urinary Bladder Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D000099148:UGT1A1 Enzyme
D016588:Anticarcinogenic Agents; D002085:Butylhydroxybutylnitrosamine; D002273:Carcinogens; D004268:DNA-Binding Proteins; D020719:Glucuronides; D014453:Glucuronosyltransferase; D051267:NF-E2-Related Factor 2; D011719:Pyrazines; D013871:Thiones; D013876:Thiophenes; D015534:Trans-Activators; D000099148:UGT1A1 Enzyme; C495636:Nfe2l2 protein, mouse; C026209:oltipraz