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ToxSci Advance Access published online on May 5, 2007
Toxicological Sciences, doi:10.1093/toxsci/kfm104
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© The Author 2007. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

WY-14,643-induced cell proliferation and oxidative stress in mouse liver are independent of NADPH oxidase

Courtney G. Woods*, Amanda M. Burns*, Blair U. Bradford*, Pamela K. Ross*, Oksana Kosyk*, James A. Swenberg*, Michael L. Cunningham{dagger} and Ivan Rusyn*

* Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, NC {dagger} National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC

Send all correspondence to: Dr. Ivan Rusyn, 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. Phone# (919) 843-2596; FAX# (919) 843-2596; E-mail: iir{at}unc.edu

Received February 2, 2007; revision received May 2, 2007; accepted May 2, 2007


  Abstract

Long term exposure of rodents to peroxisome proliferators leads to increases in peroxisomes, cell proliferation, oxidative damage, suppressed apoptosis, and ultimately results in the development of hepatic adenomas and carcinomas. Peroxisome proliferator activated receptor (PPAR){alpha} was shown to be required for these pleiotropic responses; however, Kupffer cells, resident liver macrophages, were also identified as playing a role in peroxisome proliferator-induced effects, independently of PPAR{alpha}. Previous studies showed that oxidants from NADPH 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% w/w) for 1 week, 5 weeks or 5 months along with Ppar{alpha}-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{alpha} -null mice. Through 5 months of treatment, the p47phox–null and wild type mice exhibited peroxisome proliferator-induced adverse liver effects, along with increased oxidative DNA damage and increased cell proliferation, a response that is potentially mediated through NF{kappa}B. Suppressed apoptosis caused by WY-14,643 was dependent on both NADPH oxidase and PPAR{alpha}. 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{alpha}; peroxisome proliferators; carcinogenesis.


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[Abstract] [Full Text] [PDF]


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