ToxSci Advance Access originally published online on May 5, 2007
Toxicological Sciences 2007 98(2):366-374; doi:10.1093/toxsci/kfm104
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WY-14,643–Induced Cell Proliferation and Oxidative Stress in Mouse Liver are Independent of NADPH Oxidase
* Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, North Carolina 27599-7431
National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709
1 To whom correspondence should be addressed at 0031 Michael Hooker Research Center, CB #7431, Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7431. Fax: (919) 843-2596. E-mail: iir{at}unc.edu.
Received February 2, 2007; accepted May 2, 2007
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Abstract |
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Long-term exposure of rodents to peroxisome proliferators leads to increases in peroxisomes, hepatocellular proliferation, oxidative damage, suppressed apoptosis, and ultimately results in the development of hepatic adenomas and carcinomas. Peroxisome proliferators–activated receptor (PPAR)
was shown to be required for these pleiotropic responses; however, Kupffer cells, resident liver macrophages, were also identified as playing a role in peroxisome proliferators–induced effects, independently of PPAR. Previous studies showed that oxidants from NADPH (nicotinamide adenine dinucleotide phosphate, reduced) oxidase mediate acute effects of peroxisome proliferators in rodent liver. To determine if Kupffer cell oxidants are also involved in chronic effects, NADPH oxidase–deficient (p47phox-null) mice were fed 4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio acetic acid (WY-14,643)–containing diet (0.1% wt/wt) for 1 week, 5 weeks, or 5 months along with Ppar-null and wild type mice. As expected, no change in liver size, cell replication rates, or other phenotypic effects of peroxisome proliferators were observed in Ppar-null mice. Through 5 months of treatment, the p47phox-null and wild type mice exhibited peroxisome proliferators–induced adverse liver effects, along with increased oxidative DNA damage and increased cell proliferation, a response that is potentially mediated through nuclear factor kappa B (NFkB). Suppressed apoptosis caused by WY-14,643 was dependent on both NADPH oxidase and PPAR. Collectively, these findings suggest that involvement of Kupffer cells in WY-14,643–induced parenchymal cell proliferation and oxidative stress in rodent liver is an acute phenomenon that is not relevant to long-term exposure, but they are still involved in chronic apoptotic responses. These results provide new insight for understanding the mode of hepatocarcinogenic action of peroxisome proliferators.
Key Words: Kupffer cells; PPAR; peroxisome proliferators; carcinogenesis.
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