Carcinogenesis, Vol 18, 2029-2033, Copyright © 1997 by Oxford University Press
JM Peters, RC Cattley and FJ Gonzalez
Chronic administration of peroxisome proliferators to mice and rats results
in hepatomegaly and ultimately carcinogenesis. The mechanism underlying the
carcinogenic effect of nongenotoxic peroxisome proliferators is not well
understood. To determine whether nongenotoxic carcinogenesis is receptor
mediated, we evaluated the effect of the prototypical peroxisome
proliferator Wy-14,643 on replicative DNA synthesis and carcinogenesis in
the PPAR alpha-null mouse line. Male mice (F4, Sv/129 ter) of both
genotypes (+/+) and (-/-) were fed either a control diet or one containing
0.1% Wy-14,643 for either 1 week, 5 weeks, or 11 months. Wild-type mice fed
the Wy-14,643 diet for 1 or 5 weeks showed increased hepatic labeling by
bromodeoxyuridine (BrDU) compared to untreated controls. In contrast, there
was no increase in hepatic BrDU labeling index in (-/-) mice fed the
Wy-14,643 diet for the same time periods compared to controls. After 11
months, 100% of the (+/+) mice fed the Wy-14,643 diet had multiple
hepatocellular neoplasms, including adenomas and carcinomas, while the
(-/-) mice fed the Wy-14,643 diet were unaffected. This work demonstrates
that the effects of Wy-14,643 on replicative DNA synthesis and
hepatocarcinogenesis are mediated by PPAR alpha.
ARTICLES
Role of PPAR alpha in the mechanism of action of the nongenotoxic carcinogen and peroxisome proliferator Wy-14,643
Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
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O. Moennikes, S. Stahl, P. Bannasch, A. Buchmann, and M. Schwarz WY-14,643-mediated promotion of hepatocarcinogenesis in connexin32-wild-type and connexin32-null mice Carcinogenesis, September 1, 2003; 24(9): 1561 - 1565. [Abstract] [Full Text] [PDF]
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M. Iida, C. H. Anna, J. Hartis, M. Bruno, B. Wetmore, J. R. Dubin, S. Sieber, L. Bennett, M. L. Cunningham, R. S. Paules, et al. Changes in global gene and protein expression during early mouse liver carcinogenesis induced by non-genotoxic model carcinogens oxazepam and Wyeth-14,643 Carcinogenesis, April 1, 2003; 24(4): 757 - 770. [Abstract] [Full Text] [PDF]
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J. M. Dufour, M.-N. Vo, N. Bhattacharya, J. Okita, R. Okita, and K. H. Kim Peroxisome Proliferators Disrupt Retinoic Acid Receptor Alpha Signaling in the Testis Biol Reprod, April 1, 2003; 68(4): 1215 - 1224. [Abstract] [Full Text] [PDF]
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A. K. Bauer, B. Faiola, D. J. Abernethy, R. Marchan, L. J. Pluta, V. A. Wong, K. Roberts, A. K. Jaiswal, F. J. Gonzalez, B. E. Butterworth, et al. Genetic Susceptibility to Benzene-induced Toxicity: Role of NADPH: Quinone Oxidoreductase-1 Cancer Res., March 1, 2003; 63(5): 929 - 935. [Abstract] [Full Text] [PDF]
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 S. Gu, S. L. Ripp, R. A. Prough, and T. E. Geoghegan Dehydroepiandrosterone Affects the Expression of Multiple Genes in Rat Liver Including 11beta -Hydroxysteroid Dehydrogenase Type 1: A cDNA Array Analysis Mol. Pharmacol., March 1, 2003; 63(3): 722 - 731. [Abstract] [Full Text] [PDF]
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M. D. Wheeler, O. M. Smutney, J. F. Check, I. Rusyn, R. Schulte-Hermann, and R. G. Thurman Impaired Ras membrane association and activation in PPARalpha knockout mice after partial hepatectomy Am J Physiol Gastrointest Liver Physiol, February 1, 2003; 284(2): G302 - G312. [Abstract] [Full Text] [PDF]
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R. A. Roberts Evidence for Cross Talk between PPAR{alpha} and p38 MAP Kinase Toxicol. Sci., August 1, 2002; 68(2): 270 - 274. [Full Text] [PDF]
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S. Hasmall, G. Orphanides, N. James, W. Pennie, K. Hedley, A. Soames, I. Kimber, and R. Roberts Downregulation of Lactoferrin by PPAR{alpha} Ligands: Role in Perturbation of Hepatocyte Proliferation and Apoptosis Toxicol. Sci., August 1, 2002; 68(2): 304 - 313. [Abstract] [Full Text] [PDF]
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S. P. Anderson, C. S. Dunn, R. C. Cattley, and J.C. Corton Hepatocellular proliferation in response to a peroxisome proliferator does not require TNF{alpha} signaling Carcinogenesis, November 1, 2001; 22(11): 1843 - 1851. [Abstract] [Full Text] [PDF]
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T. E. Akiyama, C. J. Nicol, C. Fievet, B. Staels, J. M. Ward, J. Auwerx, S. S. T. Lee, F. J. Gonzalez, and J. M. Peters Peroxisome Proliferator-activated Receptor-alpha Regulates Lipid Homeostasis, but Is Not Associated with Obesity. STUDIES WITH CONGENIC MOUSE LINES J. Biol. Chem., October 12, 2001; 276(42): 39088 - 39093. [Abstract] [Full Text] [PDF]
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R. Ge, W. Wang, P. M. Kramer, S. Yang, L. Tao, and M. A. Pereira Wy-14,643-Induced Hypomethylation of the c-myc Gene in Mouse Liver Toxicol. Sci., July 1, 2001; 62(1): 28 - 35. [Abstract] [Full Text] [PDF]
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A. Kiss, R. Ortiz-Aguayo, R. Sharp, G. Merlino, S. S. Thorgeirsson, F. J. Gonzalez, and J. M. Peters Evidence that reduction of hepatocyte growth factor (HGF) is not required for peroxisome proliferator-induced hepatocyte proliferation Carcinogenesis, June 1, 2001; 22(6): 975 - 979. [Abstract] [Full Text] [PDF]
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 M. PIBIRI, G. M. LEDDA-COLUMBANO, C. COSSU, G. SIMBULA, M. MENEGAZZI, H. SHINOZUKA, and A. COLUMBANO Cyclin D1 is an early target in hepatocyte proliferation induced by thyroid hormone (T3) FASEB J, April 1, 2001; 15(6): 1006 - 1013. [Abstract] [Full Text] [PDF]
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I. Rusyn, M. B. Kadiiska, A. Dikalova, H. Kono, M. Yin, K. Tsuchiya, R. P. Mason, J. M. Peters, F. J. Gonzalez, B. H. Segal, et al. Phthalates Rapidly Increase Production of Reactive Oxygen Species in Vivo: Role of Kupffer Cells Mol. Pharmacol., April 1, 2001; 59(4): 744 - 750. [Abstract] [Full Text]
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J. W. Lawrence, G. K. Wollenberg, and J. G. DeLuca Tumor necrosis factor {{alpha}} is not required for WY14,643-induced cell proliferation Carcinogenesis, March 1, 2001; 22(3): 381 - 386. [Abstract] [Full Text] [PDF]
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W. Parzefall, W. Berger, E. Kainzbauer, O. Teufelhofer, R. Schulte-Hermann, and R. G. Thurman Peroxisome proliferators do not increase DNA synthesis in purified rat hepatocytes Carcinogenesis, March 1, 2001; 22(3): 519 - 523. [Abstract] [Full Text] [PDF]
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R. T. Miller, L. A. Scappino, S. M. Long, and J. C. Corton Role of Thyroid Hormones in Hepatic Effects of Peroxisome Proliferators Toxicol Pathol, January 1, 2001; 29(1): 149 - 155. [Abstract] [PDF]
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S. C. Hasmall, D. A. West, K. Olsen, and R. A. Roberts Role of hepatic non-parenchymal cells in the response of rat hepatocytes to the peroxisome proliferator nafenopin in vitro Carcinogenesis, December 1, 2000; 21(12): 2159 - 2165. [Abstract] [Full Text] [PDF]
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R. A. Gupta, J. Tan, W. F. Krause, M. W. Geraci, T. M. Willson, S. K. Dey, and R. N. DuBois Prostacyclin-mediated activation of peroxisome proliferator-activated receptor delta in colorectal cancer PNAS, November 21, 2000; 97(24): 13275 - 13280. [Abstract] [Full Text] [PDF]
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C. Chen, G. E. Hennig, H. E. Whiteley, J. C. Corton, and J. E. Manautou Peroxisome Proliferator-Activated Receptor Alpha-Null Mice Lack Resistance to Acetaminophen Hepatotoxicity following Clofibrate Exposure Toxicol. Sci., October 1, 2000; 57(2): 338 - 344. [Abstract] [Full Text] [PDF]
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C. Rodríguez, V. Noé, A. Cabrero, C. J. Ciudad, and J. C. Laguna Differences in the Formation of PPARalpha -RXR/acoPPRE Complexes between Responsive and Nonresponsive Species upon Fibrate Administration Mol. Pharmacol., July 1, 2000; 58(1): 185 - 193. [Abstract] [Full Text]
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