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 Kasai, H. Articles by Reddy, J. K. Search for Related Content PubMed PubMed Citation Articles by Kasai, H. Articles by Reddy, J. K.

Formation of 8-Hydroxydeoxyguanosine in Liver DNA of Rats following Long-Term Exposure to a Peroxisome Proliferator¹

Biology Division, National Cancer Center Research Institute, Tsukiji 5-1-1, Chuo-ku, Tokyo 104, Japan [H. K., Y. O., S. N.] and Department of Pathology, Northwestern University Medical School, Chicago, Illinois 60611 [M. S. R., J. K. R.]

The mechanism by which nongenotoxic peroxisome proliferators induce hepatocellular carcinomas in rats and mice remains intriguing. The available experimental evidence suggests that the proliferation of peroxisomes and induction of peroxisome-associated enzymes results in oxidative stress which then leads to tumorigenesis. However, so far no direct evidence for oxidative DNA damage in livers of peroxisome proliferator-treated animals has been established. In the present study we have examined the DNA obtained from the livers of rats treated with ciprofibrate, a potent peroxisome proliferator, for variable periods of time for 8-hydroxydeoxyguanosine (8-OH-dG), an adduct that results from the damage of DNA caused by hydroxyl radical. Administration of ciprofibrate in diet at a concentration of 0.025% for 16, 28, 36, or 40 weeks resulted in progressive increases in the levels of 8-OH-dG. At 16, 28, and 40 weeks of ciprofibrate treatment, the 8-OH-dG in the liver DNA was significantly increased as compared to controls. This increase in 8-OH-dG levels is attributed to persistent peroxisome proliferation resulting from chronic ciprofibrate treatment as no increase in 8-OH-dG was found in liver DNA of rats that received a single large dose of ciprofibrate. The results of this study clearly demonstrate, for the first time, that persistent proliferation of peroxisomes leads to specific oxidative DNA damage.

¹ This work was supported in part by grants from the Ministry of Education, Science and Culture, Japan, and by NIH Grants R37 GM23750 and CA-36130.

² To whom requests for reprints should be addressed, at Department of Pathology, Northwestern University Medical School, 303 East Chicago Avenue, Chicago, IL 60611.

Received 7/28/88. Revised 10/31/88. Revised 2/14/89. Accepted 2/20/89.

This article has been cited by other articles:

				H. Wanibuchi, M. Wei, M. R. Karim, K. Morimura, K. Doi, A. Kinoshita, and S. Fukushima Existence of No Hepatocarcinogenic Effect Levels of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline with or without Coadministration with Ethanol Toxicol Pathol, April 1, 2006; 34(3): 232 - 236. [Abstract] [Full Text] [PDF]

				J. K. Reddy Peroxisome Proliferators and Peroxisome Proliferator-Activated Receptor {alpha}: Biotic and Xenobiotic Sensing Am. J. Pathol., June 1, 2004; 164(6): 2305 - 2321. [Full Text] [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]

				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]

				K. Meyer, J.-S. Lee, P. A. Dyck, W.-Q. Cao, M.S. Rao, S. S. Thorgeirsson, and J. K. Reddy Molecular profiling of hepatocellular carcinomas developing spontaneously in acyl-CoA oxidase deficient mice: comparison with liver tumors induced in wild-type mice by a peroxisome proliferator and a genotoxic carcinogen Carcinogenesis, May 1, 2003; 24(5): 975 - 984. [Abstract] [Full Text] [PDF]

				H. Tsuda, S. Fukushima, H. Wanibuchi, K. Morimura, D. Nakae, K. Imaida, M. Tatematsu, M. Hirose, K. Wakabayashi, and M. A. Moore Value of GST-P Positive Preneoplastic Hepatic Foci in Dose-Response Studies of Hepatocarcinogenesis: Evidence for Practical Thresholds with Both Genotoxic and Nongenotoxic Carcinogens. A Review of Recent Work Toxicol Pathol, January 1, 2003; 31(1): 80 - 86. [Abstract] [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]

				I. Rusyn, M. F. Denissenko, V. A. Wong, B. E. Butterworth, M. L. Cunningham, P. B. Upton, R. G. Thurman, and J. A. Swenberg Expression of base excision repair enzymes in rat and mouse liver is induced by peroxisome proliferators and is dependent upon carcinogenic potency Carcinogenesis, December 1, 2000; 21(12): 2141 - 2145. [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. Chen, M. Gokhale, B. Schofield, S. Odwin, and J. D. Yager Inhibition of TGF-{beta}-induced apoptosis by ethinyl estradiol in cultured, precision cut rat liver slices and hepatocytes Carcinogenesis, June 1, 2000; 21(6): 1205 - 1211. [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]

				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]

				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. B. BECKMAN and B. N. AMES The Free Radical Theory of Aging Matures Physiol Rev, April 1, 1998; 78(2): 547 - 581. [Abstract] [Full Text] [PDF]

				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]