ToxSci Advance Access published online on December 13, 2005
Toxicological Sciences, doi:10.1093/toxsci/kfj076
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1 Division of Pathology, National Institute of Health Sciences, 1-18-1, Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan
* To whom correspondence should be addressed. Our goal was to elucidate roles of Nrf2 in in vivo defense against pentachlorophenol (PCP), an environmental pollutant and hepatocarcinogen in mice. We examined oxidative stress and cell proliferation, along with other hepatotoxicological parameters, in the livers of nrf2-deficient (wild:+/+, heterozygous:+/-, homozygous:-/-) animals fed PCP in their diet at doses of 0, 150, 300, 600 or 1200 ppm for 4 weeks. For measurement of methoxyresorufin-O-demethylase (CYP 1A2), NAD(P):quinone oxidoreductase 1 (NQO1) and UDP-glucuronosyltransferase (UDP-GT), an additional study was performed with all but the 150 ppm dose. Significant elevation of 8-hydroxydeoxyguanosine (8-OH-dG) levels in the liver DNA was observed only in -/- mice treated with PCP at 1200 ppm. Levels of thiobarbituric-acid reactive substances (TBARS) were also raised significantly compared to those of the relevant +/+ mice. Bromodeoxyuridine labeling indicies (BrdU-LIs) of hepatocytes in -/- mice were significantly higher at all doses than those in the relevant +/+ mice. Relative liver weights were unchanged in mice lacking Nrf2, whereas liver weight in +/+ and +/- mice was increased. Significant elevations of serum ALP activity, but not ALT and AST activity, occurred at 600 ppm and above in -/- mice compared to the relevant +/+ mice. Histopathologically, centrilobular hepatocyte necrosis was severe in the -/- mice that received 600 ppm. Although CYP 1A2 activity was elevated in all treated mice, increases in NQO1 levels and UDP-GT activities did not occur only in -/- mice. These data suggest that Nrf2 plays a key role in prevention of PCP-induced oxidative stress and cell proliferation.
Received October 7, 2005
Accepted November 18, 2005
Environmental Toxicology
A Crucial Role of Nrf2 in In Vivo Defense Against Oxidative Damage by an Environmental Pollutant, Pentachlorophenol
Takashi Umemura 1 *,
Yuichi Kuroiwa 1,
Yasuki Kitamura 1,
Yuji Ishii 2,
Keita Kanki 1,
Yukio Kodama 3,
Ken Itoh 4,
Masayuki Yamamoto 4,
Akiyoshi Nishikawa 1,
and
Masao Hirose 1
2 Division of Pathology, National Institute of Health Sciences, 1-18-1, Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan; Faculty of Pharmaceutical Science, Department of Analytical Chemistry, Hoshi University, 2-4-41 Ebara, Shinakawa-ku, Tokyo 142-8501, Japan
3 Division of Toxicology, National Institute of Health Sciences, 1-18-1, Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan
4 Center for Tsukuba Advanced Research Alliance and Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8577, Japan
Takashi Umemura, E-mail: umemura{at}nihs.go.jp
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