This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Marsman, D. S. Articles by Popp, J. A. Search for Related Content PubMed PubMed Citation Articles by Marsman, D. S. Articles by Popp, J. A.

Relationship of Hepatic Peroxisome Proliferation and Replicative DNA Synthesis to the Hepatocarcinogenicity of the Peroxisome Proliferators Di(2-ethylhexyl)phthalate and [4-Chloro-6-(2,3-xylidino)-2-pyrimidinylthio]acetic Acid (Wy-14,643) in Rats

Chemical Industry Institute of Toxicology, Research Triangle Park, North Carolina 27709

The mechanism of hepatocarcinogenesis caused by peroxisome proliferators (PP) is poorly understood, making it difficult to predict the carcinogenicity of PP to rodents or other species. It has been suggested that the carcinogenic potential of individual PP in rodents is correlated with the degree of PP-induced hepatic peroxisome proliferation. To evaluate this possible correlation, di(2-ethylhexyl)phthalate (DEHP) at 1.2% and [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio]acetic acid (Wy-14,643) at 0.1% were fed to male F-344 rats for up to 365 days and hepatocytic peroxisome proliferation and DNA replication were measured. All rats fed Wy-14,643 for 365 days had numerous grossly visible nodules in comparison to none in the livers of DEHP-fed or control rats. Despite this difference in the induction of tumors, both DEHP and Wy-14,643 increased the peroxisomal volume density 4- to 6-fold from 8 to 365 days of treatment. Peroxisomal ß-oxidation enzyme activities were increased 8-fold by both DEHP and Wy-14,643 after 18 days. At later time points (77 to 365 days), these enzyme activities were about 25% higher in livers of Wy-14,643- than DEHP-fed rats. DEHP or Wy-14,643 increased absolute liver weights 50 to 75% above controls after 18 to 365 days of feeding. Labeling of hepatocyte nuclei with a single injection of tritiated thymidine revealed a rapid burst in replicative DNA synthesis in both DEHP and Wy-14,643-fed rats, with a return to control levels by 4 days. Additional rats were implanted with 7-day osmotic pumps containing tritiated thymidine. With this more extended method of labeling a 5- to 10-fold increase in replicative DNA synthesis was observed in rats receiving Wy-14,643 for 39 to 365 days as compared to DEHP-fed rats or controls. In conclusion, when performed under conditions similar to the tumorigenicity studies, the degree of peroxisome proliferation correlated poorly with the relative hepatocarcinogenicity of DEHP and Wy-14,643. However, a strong correlation was observed between the relative hepatocarcinogenicity of DEHP and Wy-14,643 and the ability to induce a persistent increase in replicative DNA synthesis. These data emphasize the possible importance of cell replication in the mechanism of PP-induced hepatocarcinogenesis.

¹ To whom requests for reprints should be addressed, at CIIT, P.O. Box 12137, Research Triangle Park, NC 27709.

² Present address: College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27606. R.C.C. was supported in part by grant CA 07945 from the Public Health Service, US Department of Health and Human Services.

³ Present address: Glaxo Inc., 5 Moore Drive, Research Triangle Park, NC 27709.

Received 2/23/88. Revised 7/12/88. Accepted 9/ 1/88.

This article has been cited by other articles:

				A. Al Kholaifi, A. Amer, B. Jeffery, T. J. B. Gray, R. A. Roberts, and D. R. Bell Species-Specific Kinetics and Zonation of Hepatic DNA Synthesis Induced by Ligands of PPAR{alpha} Toxicol. Sci., July 1, 2008; 104(1): 74 - 85. [Abstract] [Full Text] [PDF]

				T. Makino, K. Ishikawa, I. Igarashi, T. Yamoto, S. Manabe, and H. Nakayama Relationship between GST Yp Induction and Hepatocyte Proliferation in Rats Treated with Phase II Drug Metabolizing Enzyme Inducers Toxicol Pathol, April 1, 2008; 36(3): 420 - 427. [Abstract] [Full Text] [PDF]

				C. G. Woods, A. M. Burns, B. U. Bradford, P. K. Ross, O. Kosyk, J. A. Swenberg, M. L. Cunningham, and I. Rusyn WY-14,643 Induced Cell Proliferation and Oxidative Stress in Mouse Liver are Independent of NADPH Oxidase Toxicol. Sci., August 1, 2007; 98(2): 366 - 374. [Abstract] [Full Text] [PDF]

				C. G. Woods, J. P. Vanden Heuvel, and I. Rusyn Genomic Profiling in Nuclear Receptor-Mediated Toxicity Toxicol Pathol, June 1, 2007; 35(4): 474 - 494. [Abstract] [Full Text] [PDF]

				Q. Yang, S. Ito, and F. J. Gonzalez Hepatocyte-restricted constitutive activation of PPAR{alpha} induces hepatoproliferation but not hepatocarcinogenesis Carcinogenesis, June 1, 2007; 28(6): 1171 - 1177. [Abstract] [Full Text] [PDF]

				R. A. Roberts, P. E. Ganey, C. Ju, L. M. Kamendulis, I. Rusyn, and J. E. Klaunig Role of the Kupffer Cell in Mediating Hepatic Toxicity and Carcinogenesis Toxicol. Sci., March 1, 2007; 96(1): 2 - 15. [Abstract] [Full Text] [PDF]

				A. Tedgui and Z. Mallat Cytokines in Atherosclerosis: Pathogenic and Regulatory Pathways Physiol Rev, April 1, 2006; 86(2): 515 - 581. [Abstract] [Full Text] [PDF]

				H. P. Glauert, A. Eyigor, J. C. Tharappel, S. Cooper, E. Y. Lee, and B. T. Spear Inhibition of Hepatocarcinogenesis by the Deletion of the p50 Subunit of NF-{kappa}B in Mice Administered the Peroxisome Proliferator Wy-14,643 Toxicol. Sci., April 1, 2006; 90(2): 331 - 336. [Abstract] [Full Text] [PDF]

				O. S. Gardner, B. J. Dewar, and L. M. Graves Activation of Mitogen-Activated Protein Kinases by Peroxisome Proliferator-Activated Receptor Ligands: An Example of Nongenomic Signaling Mol. Pharmacol., October 1, 2005; 68(4): 933 - 941. [Abstract] [Full Text] [PDF]

				B. Knight, B. B. Yeap, G. C. Yeoh, and J. K. Olynyk Inhibition of adult liver progenitor (oval) cell growth and viability by an agonist of the peroxisome proliferator activated receptor (PPAR) family member {gamma}, but not {alpha} or {delta} Carcinogenesis, October 1, 2005; 26(10): 1782 - 1792. [Abstract] [Full Text] [PDF]

				D. E. Amacher, R. Adler, A. Herath, and R. R. Townsend Use of Proteomic Methods to Identify Serum Biomarkers Associated with Rat Liver Toxicity or Hypertrophy Clin. Chem., October 1, 2005; 51(10): 1796 - 1803. [Abstract] [Full Text] [PDF]

				G.M. Ledda-Columbano, M. Pibiri, F. Molotzu, C. Cossu, L. Sanna, G. Simbula, A. Perra, and A. Columbano Induction of hepatocyte proliferation by retinoic acid Carcinogenesis, November 1, 2004; 25(11): 2061 - 2066. [Abstract] [Full Text] [PDF]

				D. J. Hoivik, C. W. Qualls Jr, R. C. Mirabile, N. F. Cariello, C. L. Kimbrough, H. M. Colton, S. P. Anderson, M. J. Santostefano, R. J. O. Morgan, R. R. Dahl, et al. Fibrates induce hepatic peroxisome and mitochondrial proliferation without overt evidence of cellular proliferation and oxidative stress in cynomolgus monkeys Carcinogenesis, September 1, 2004; 25(9): 1757 - 1769. [Abstract] [Full Text] [PDF]

				R. L. Brent Utilization of Animal Studies to Determine the Effects and Human Risks of Environmental Toxicants (Drugs, Chemicals, and Physical Agents) Pediatrics, April 1, 2004; 113(4/S1): 984 - 995. [Abstract] [Full Text] [PDF]

				R. C. Cattley Peroxisome Proliferators and Receptor-Mediated Hepatic Carcinogenesis Toxicol Pathol, February 1, 2004; 32(2_suppl): 6 - 11. [Abstract] [PDF]

				J. C. Tharappel, A. Nalca, A. B. Owens, L. Ghabrial, E. C. Konz, H. P. Glauert, and B. T. Spear Cell Proliferation and Apoptosis Are Altered in Mice Deficient in the NF-{kappa}B p50 Subunit after Treatment with the Peroxisome Proliferator Ciprofibrate Toxicol. Sci., October 1, 2003; 75(2): 300 - 308. [Abstract] [Full Text] [PDF]

				F. Yadetie, A. Laegreid, I. Bakke, W. Kusnierczyk, J. Komorowski, H. L. Waldum, and A. K. Sandvik Liver gene expression in rats in response to the peroxisome proliferator-activated receptor-{alpha} agonist ciprofibrate Physiol Genomics, September 29, 2003; 15(1): 9 - 19. [Abstract] [Full Text] [PDF]

				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]

				M. Fischer, M. You, M. Matsumoto, and D. W. Crabb Peroxisome Proliferator-activated Receptor {alpha} (PPAR{alpha}) Agonist Treatment Reverses PPAR{alpha} Dysfunction and Abnormalities in Hepatic Lipid Metabolism in Ethanol-fed Mice J. Biol. Chem., July 18, 2003; 278(30): 27997 - 28004. [Abstract] [Full Text] [PDF]

				J. A. Kramer, E. A.G. Blomme, R. T. Bunch, J. C. Davila, C. J. Jackson, P. F. Jones, K. L. Kolaja, and S. W. Curtiss Transcription Profiling Distinguishes Dose-Dependent Effects in the Livers of Rats Treated with Clofibrate Toxicol Pathol, June 1, 2003; 31(4): 417 - 431. [Abstract] [PDF]

				G. M. Ledda-Columbano, M. Pibiri, D. Concas, F. Molotzu, G. Simbula, C. Cossu, and A. Columbano Sex difference in the proliferative response of mouse hepatocytes to treatment with the CAR ligand, TCPOBOP Carcinogenesis, June 1, 2003; 24(6): 1059 - 1065. [Abstract] [Full Text] [PDF]

				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]

				M. L. O'Brien, M. L. Cunningham, B. T. Spear, and H. P. Glauert Peroxisome Proliferators Do Not Activate the Transcription Factors AP-1, Early Growth Response-1, or Heat Shock Factors 1 and 2 in Rats or Hamsters Toxicol. Sci., September 1, 2002; 69(1): 139 - 148. [Abstract] [Full Text] [PDF]

				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]

				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]

				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]

				L. B. Biegel, M. E. Hurtt, S. R. Frame, J. C. O'Connor, and J. C. Cook Mechanisms of Extrahepatic Tumor Induction by Peroxisome Proliferators in Male CD Rats Toxicol. Sci., March 1, 2001; 60(1): 44 - 55. [Abstract] [Full Text] [PDF]

				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]

				I. Rusyn, S. Yamashina, B. H. Segal, R. Schoonhoven, S. M. Holland, R. C. Cattley, J. A. Swenberg, and R. G. Thurman Oxidants from Nicotinamide Adenine Dinucleotide Phosphate Oxidase Are Involved in Triggering Cell Proliferation in the Liver Due to Peroxisome Proliferators Cancer Res., September 1, 2000; 60(17): 4798 - 4803. [Abstract] [Full Text]

				J. S. Isenberg, L. M. Kamendulis, J. H. Smith, D. C. Ackley, G. Pugh Jr., A. W. Lington, and J. E. Klaunig Effects of Di-2-Ethylhexyl Phthalate (DEHP) on Gap-Junctional Intercellular Communication (GJIC), DNA Synthesis, and Peroxisomal Beta Oxidation (PBOX) in Rat, Mouse, and Hamster Liver Toxicol. Sci., July 1, 2000; 56(1): 73 - 85. [Abstract] [Full Text] [PDF]

				J. M. Peters, I. Rusyn, M. L. Rose, F. J. Gonzalez, and R. G. Thurman Peroxisome proliferator-activated receptor {alpha} is restricted to hepatic parenchymal cells, not Kupffer cells: implications for the mechanism of action of peroxisome proliferators in hepatocarcinogenesis Carcinogenesis, April 1, 2000; 21(4): 823 - 826. [Abstract] [Full Text] [PDF]

				I. G. Shabalina, T. Panaretakis, A. Bergstrand, and J. W. Depierre Effects of the rodent peroxisome proliferator and hepatocarcinogen, perfluorooctanoic acid, on apoptosis in human hepatoma HepG2 cells Carcinogenesis, December 1, 1999; 20(12): 2237 - 2246. [Abstract] [Full Text] [PDF]

				M. L. Rose, R. C. Cattley, C. Dunn, V. Wong, X. Li, and R. G. Thurman Dietary glycine prevents the development of liver tumors caused by the peroxisome proliferator WY-14,643 Carcinogenesis, November 1, 1999; 20(11): 2075 - 2081. [Abstract] [Full Text] [PDF]

				I. Rusyn, C. A. Bradham, L. Cohn, R. Schoonhoven, J. A. Swenberg, D. A. Brenner, and R. G. Thurman Corn oil rapidly activates nuclear factor-{kappa}B in hepatic Kupffer cells by oxidant-dependent mechanisms Carcinogenesis, November 1, 1999; 20(11): 2095 - 2100. [Abstract] [Full Text] [PDF]

				Regulations and Advisories Toxicology and Industrial Health, September 1, 1999; 15(8): 718 - 742. [PDF]

				A. R. Soames, S. Cliffe, I. Pate, and J. R. Foster Quantitative Analysis of the Lobular Distribution of S-Phase in Rat Liver Following Dietary Administration of Di(2-ethylhexyl)phthalate Toxicol Pathol, July 1, 1999; 27(4): 436 - 440. [Abstract] [PDF]

				M. L. Rose, J. Madren, H. Bunzendahl, and R. G. Thurman Dietary glycine inhibits the growth of B16 melanoma tumors in mice Carcinogenesis, May 1, 1999; 20(5): 793 - 798. [Abstract] [Full Text] [PDF]

				M. L. Rose, C. A. Rivera, B. U. Bradford, L. M. Graves, R. C. Cattley, R. Schoonhoven, J. A. Swenberg, and R. G. Thurman Kupffer cell oxidant production is central to the mechanism of peroxisome proliferators Carcinogenesis, January 1, 1999; 20(1): 27 - 33. [Abstract] [Full Text] [PDF]

				K. Motojima, P. Passilly, J. M. Peters, F. J. Gonzalez, and N. Latruffe Expression of Putative Fatty Acid Transporter Genes Are Regulated by Peroxisome Proliferator-activated Receptor alpha  and gamma  Activators in a Tissue- and Inducer-specific Manner J. Biol. Chem., July 3, 1998; 273(27): 16710 - 16714. [Abstract] [Full Text] [PDF]

				C. L. Rokos and B. J. Ledwith Peroxisome Proliferators Activate Extracellular Signal-regulated Kinases in Immortalized Mouse Liver Cells J. Biol. Chem., May 16, 1997; 272(20): 13452 - 13457. [Abstract] [Full Text] [PDF]

				T. Miyamoto, A. Kaneko, T. Kakizawa, H. Yajima, K. Kamijo, R. Sekine, K. Hiramatsu, Y. Nishii, T. Hashimoto, and K. Hashizume Inhibition of Peroxisome Proliferator Signaling Pathways by Thyroid Hormone Receptor. COMPETITIVE BINDING TO THE RESPONSE ELEMENT J. Biol. Chem., March 21, 1997; 272(12): 7752 - 7758. [Abstract] [Full Text] [PDF]

				B. J. Ledwith, C. J. Pauley, L. K. Wagner, C. L. Rokos, D. W. Alberts, and S. Manam Induction of Cyclooxygenase-2 Expression by Peroxisome Proliferators and Non-tetradecanoylphorbol 12,13-Myristate-type Tumor Promoters in Immortalized Mouse Liver Cells J. Biol. Chem., February 7, 1997; 272(6): 3707 - 3714. [Abstract] [Full Text] [PDF]

				X. Ma, D. A. Stoffregen, G. D. Wheelock, J. A. Rininger, and J. G. Babish Discordant Hepatic Expression of the Cell Division Control Enzyme p34cdc2 Kinase, Proliferating Cell Nuclear Antigen, p53 Tumor Suppressor Protein, and p21Waf1 Cyclin-Dependent Kinase Inhibitory Protein after WY14,643 ([4-Chloro-6-(2,3-xylidino)-2-pyrimidinylthio]Acetic Acid) Dosing to Rats Mol. Pharmacol., January 1, 1997; 51(1): 69 - 78. [Abstract] [Full Text]

				A. Bayly, N. French, C Dive, and R. Roberts Non-genotoxic hepatocarcinogenesis in vitro: the FaO hepatoma line responds to peroxisome proliferators and retains the ability to undergo apoptosis J. Cell Sci., January 2, 1993; 104(2): 307 - 315. [Abstract] [PDF]