A crucial role of Nrf2 in in vivo defense against oxidative damage by an environmental pollutant, pentachlorophenol.
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 indices (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.
Umemura
Takashi
T
Division of Pathology, National Institute of Health Sciences, 1-18-1, Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan. umemura@nihs.go.jp
Kuroiwa
Yuichi
Y
Kitamura
Yasuki
Y
Ishii
Yuji
Y
Kanki
Keita
K
Kodama
Yukio
Y
Itoh
Ken
K
Yamamoto
Masayuki
M
Nishikawa
Akiyoshi
A
Hirose
Masao
M
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000469:Alkaline Phosphatase / Q000097:blood; D000818:Animals; D049109:Cell Proliferation; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D004249:DNA Damage; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D004032:Diet; D004305:Dose-Response Relationship, Drug; D004785:Environmental Pollutants / Q000633:toxicity*; D014453:Glucuronosyltransferase / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D051379:Mice; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D016660:NAD(P)H Dehydrogenase (Quinone); D009252:NADPH Dehydrogenase / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D009336:Necrosis; D009929:Organ Size / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D010416:Pentachlorophenol / Q000633:toxicity*
D004785:Environmental Pollutants; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D000080242:8-Hydroxy-2'-Deoxyguanosine; D010416:Pentachlorophenol; D019388:Cytochrome P-450 CYP1A2; D016660:NAD(P)H Dehydrogenase (Quinone); C491732:Nqo1 protein, mouse; D009252:NADPH Dehydrogenase; D014453:Glucuronosyltransferase; D000469:Alkaline Phosphatase; D003849:Deoxyguanosine