© 1989 Oxford University Press
research-article |
Relationship of oxidative damage to the hepatocarcinogenicity of the peroxisome proliferators di(2-ethylhexyl)phthalate and Wy-14,643
Chemical Industry Institute of Toxicology Research Triangle Park, NC 27709
1National Institute of Environmental Health Sciences Research Triangle Park, NC 27709
2Biomedical Science Department, General Motors Research Laboratories Warren, MI 48090, USA
Quantitative comparisons of the time course of biochemical and morphological changes induced by peroxisome proliferators resulting in low and high incidences of hepatic cancer have not been conducted previously under bioassay conditions. [4-Chloro-6-(2,3 xylidino)-2-pyrimidyl-thio]acetic acid (Wy-14,643) at 0.1% in the diet produced a much higher incidence of hepatic cancer in male rats than 1.2% di(2-ethylhexyl)phthalate (DEHP) in the diet. Both diets, however, caused similar degrees of peroxisome proliferation. To investigate this difference in carcinogenicity, H2O2-detoxification mechanisms and indices of oxidative damage were evaluated in male F-344 rats fed 1.2% DEHP or 0.1% Wy-14,643 for up to one year. DEHP or Wy-14,643 treatment increased hepatic catalase activity 
25% from 8 to 365 days. DEHP or Wy-14,643 treatment decreased hepatic glutathione peroxidase activity by 50% from 8 to 365 days. Glutathione concentrations were not affected by 151 days of DEHP or Wy-14,643 feeding. The similar effects of DEHP and Wy on H2O2 detoxification enzymes and glutathione concentrations suggests that these factors are not responsible for the widely different carcinogenicities of Wy-14,643 and DEHP. Hepatic vitamin E concentrations were 50% lower in rats receiving Wy-14,643 for 151 days as compared to rats fed DEHP or control diets. Lipofuscin, which was contained within lysosomes, was increased 3-fold after 39 days of DEHP and remained at this level up to 365 days of treatment. In comparison, lipofuscin was increased 4-fold after 18 days of Wy-14,643 and continued to accumulate in a linear manner reaching values 30-fold over controls after 365 days of treatment. DEHP treatment for 39–365 days increased the activities of the lysosomal enzymes 
-fucosidase, ß-galactosidase and N-acetylglucosaminidase 50–100%. The same enzyme activities were increased 4-fold after 39–365 days of Wy-14,643. Lysosomal cathepsin B activity was unchanged by DEHP but doubled by 151 and 365 days of Wy-14,643. Acid phosphatase activity was unchanged by DEHP but increased by 50% after 151 and 365 days of Wy-14, 643. In addition, conjugated dienes were increased (45%) only in rats receiving Wy-14,643 for 151 and 365 days. These data show for the first time that the magnitude and time course of lipofuscin deposition, induction of lysosomal enzymes and conjugated diene accumulation, is correlated closely with the degree of carcinogenicity. Wy-14,643-induced decreases in hepatic vitamin E concentrations could contribute to the observed accumulation of conjugated dienes at later time points. The data suggest that lipofuscin accumulation is an early biomarker that is quantitatively predictive of the carcinogenicity of the peroxisome proliferators DEHP and Wy-14,643.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  H. E. Hollingshead, R. L. Killins, M. G. Borland, E. E. Girroir, A. N. Billin, T. M. Willson, A. K. Sharma, S. Amin, F. J. Gonzalez, and J. M. Peters Peroxisome proliferator-activated receptor- /{delta} (PPAR /{delta}) ligands do not potentiate growth of human cancer cell lines Carcinogenesis, December 1, 2007; 28(12): 2641 - 2649. [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]
|
|
|
|
 |
|
 A. J. Stauber, H. Brown-Borg, J. Liu, M. P. Waalkes, A. Laughter, R. A. Staben, J. C. Coley, C. Swanson, K. A. Voss, J. J. Kopchick, et al. Constitutive Expression of Peroxisome Proliferator-Activated Receptor {alpha}-Regulated Genes in Dwarf Mice Mol. Pharmacol., March 1, 2005; 67(3): 681 - 694. [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]
|
|
|
|
|
|
K. D. Oakes, M. E. McMaster, A. C. Pryce, K. R. Munkittrick, C. B. Portt, L. M. Hewitt, D. D. MacLean, and G. J. Van Der Kraak Oxidative Stress and Bioindicators of Reproductive Function in Pulp and Paper Mill Effluent Exposed White Sucker Toxicol. Sci., July 1, 2003; 74(1): 51 - 65. [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]
|
|
|
|
 |
|
 J. G. Fischer, H. P. Glauert, T. Yin, M. L. Sweeney-Reeves, N. Larmonier, and M. C. Black Moderate Iron Overload Enhances Lipid Peroxidation in Livers of Rats, but Does Not Affect NF-{kappa}B Activation Induced by the Peroxisome Proliferator, Wy-14,643 J. Nutr., September 1, 2002; 132(9): 2525 - 2531. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. L. O'Brien, T. P. Twaroski, M. L. Cunningham, H. P. Glauert, and B. T. Spear Effects of Peroxisome Proliferators on Antioxidant Enzymes and Antioxidant Vitamins in Rats and Hamsters Toxicol. Sci., April 1, 2001; 60(2): 271 - 278. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Regulations and Advisories Toxicology and Industrial Health, September 1, 1999; 15(8): 718 - 742. [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]
|
|
|
|
 |
|
 J. Ashby, A. Brady, C.R. Elcombe, B.M. Elliott, J. Ishmael, J. Odum, J.D. Tugwood, S. Kettle, and I.F.H. Purchase Mechanistically-based Human Hazard Assessment of Peroxisome Proliferator-induced Hepatocarcinogenesis Human and Experimental Toxicology, January 1, 1994; 13(2_suppl): S1 - S117. [PDF]
|
|
|
|
 |
|
 I. C. Munro, G. L. Carlo, J. C. Orr, K. G. Sund, R. M. Wilson, E. Kennepohl, B. S. Lynch, and M. Jablinske A Comprehensive, Integrated Review and Evaluation of the Scientific Evidence Relating to the Safety of the Herbicide 2,4-D International Journal of Toxicology, September 1, 1992; 11(5): 559 - 664. [Abstract] [PDF]
|
|
|
|
|
|
S. Green Receptor-Mediated Non-Genotoxic Carcinogenesis: New Models for Risk Assessment? Human and Experimental Toxicology, January 1, 1991; 10(6): 390 - 395. [PDF]
|
|