This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Saved Citations Download to citation manager Add to My Marked Citations Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Citing Articles via Scopus Google Scholar Articles by Torrey, C. E. Articles by Santostefano, M. J. Search for Related Content PubMed PubMed Citation Articles by Torrey, C. E. Articles by Santostefano, M. J. Social Bookmarking                         What's this?

Evaluation of the Carcinogenic Potential of Clofibrate in FVB/Tg.AC Mouse After Oral Administration—Part I

GlaxoSmithKline, Safety Assessment, Research Triangle Park, North Carolina, USA

Henry G. Wall

Experimental Pathology Laboratories, Research Triangle Park, North Carolina, USA

James A. Campbell
Puntipa Kwanyuen
Debie J. Hoivik
Richard T. Miller

GlaxoSmithKline, Safety Assessment, Research Triangle Park, North Carolina, USA

Jane S. Allen

Jane Allen Consulting, Inc., Raleigh, North Carolina, USA

Manuel J. Jayo

Pathology Associates Inc., Research Triangle Park, North Carolina, USA

Krzysztof Selinger

Forest Laboratories Inc., Bioanalytical and Drug Metabolism Department, Farmingdale, New York

Paul M. Savina

GlaxoSmithKline, Drug Metabolism and Pharmacokinetics, Research Triangle Park, North Carolina, USA

Michael J. Santostefano

GlaxoSmithKline, Safety Assessment, Research Triangle Park, North Carolina, USA

Correspondence: Address correspondence to Michael J. Santostefano, GlaxoSmithKline, Safety Assessment, 5 Moore Drive, Research Triangle Park, NC 27709, USA. E-mail:michael.j.santostefano{at}gsk.com

This study was conducted as part of the International Life Sciences Institute (ILSI) program to evaluate the carcinogenic potential of clofibrate, a nongenotoxic, peroxisome proliferator-activated receptor (PPAR) agonist following oral administration to Tg.AC (transgenic) and wild-type FVB (nontransgenic) mice for a minimum for 6 months. Clofibrate was well tolerated at doses up to 500 (males) and 650 (females) mg/kg/day. Oral administration of clofibrate to Tg.AC or FVB (wild-type) male and female mice for 6 months did not result in the increased formation of neoplastic lesions. Epithelial hyperplasia in the urinary bladder (Tg.AC and FVB) and prostate gland (Tg.AC only), and interstitial-cell hyperplasia in the testes (Tg.AC) were noted at 500 mg/kg/day. Non-neoplastic nonproliferative findings included hepatic hypertrophy and hematopoietic changes (myeloid hyperplasia, myelodysplasia, lymphoid depletion, and erythropoiesis) in Tg.AC and FVB mice of both sexes; reproductive (cystic degeneration and dilatation, hypospermia, spermatocele, dilated inspissated protein) and urogenital (tubular-cell hypertrophy, degenerative/regenerative nephropathy, necrosis/fibrosis) changes in Tg.AC and FVB male mice; congestion in the lung in male Tg.AC mice; gall bladder dilatation in female Tg.AC mice; and adrenal (intracellular lipofuscinosis and atrophy) and heart (eosinophillic myofibers) findings in Tg.AC mice of both sexes and in female FVB mice. The results of this study indicate that the clofibrate is not carcinogenic when administered to Tg.AC mice by oral gavage for 6 months at doses up to 500 (males) and 650 (females) mg/kg/day, which did produce liver hypertrophy.

Key Words: Carcinogenicity • Clofibrate • Dimethylvinyl Chloride • FVB • N-methyl-N'-nitrosourea • Tg.AC

International Journal of Toxicology, Vol. 24, No. 5, 313-325 (2005)
DOI: 10.1080/10915810500208264


CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				Y. M. Shah, K. Morimura, Q. Yang, T. Tanabe, M. Takagi, and F. J. Gonzalez Peroxisome Proliferator-Activated Receptor {alpha} Regulates a MicroRNA-Mediated Signaling Cascade Responsible for Hepatocellular Proliferation Mol. Cell. Biol., June 15, 2007; 27(12): 4238 - 4247. [Abstract] [Full Text] [PDF]

				M. J. Santostefano, D. J. Hoivik, and R. T. Miller Investigations of Clofibrate in Alternative Carcinogenicity Models International Journal of Toxicology, September 1, 2005; 24(5): 285 - 288. [Full Text] [PDF]

				C. E. Torrey, J. A. Campbell, D. J. Hoivik, R. T. Miller, J. S. Allen, P. C. Mann, K. Selinger, D. Rickert, P. M. Savina, and M. J. Santostefano Evaluation of the Carcinogenic Potential of Clofibrate in the p53+/- Mouse International Journal of Toxicology, September 1, 2005; 24(5): 289 - 299. [Abstract] [Full Text] [PDF]

				S. R. Nesfield, C. J. Clarke, D. J. Hoivik, R. T. Miller, J. S. Allen, K. Selinger, and M. J. Santostefano Evaluation of the Carcinogenic Potential of Clofibrate in the rasH2 Mouse International Journal of Toxicology, September 1, 2005; 24(5): 301 - 311. [Abstract] [Full Text] [PDF]

				C. E. Torrey, H. G. Wall, J. A. Campbell, P. Kwanyuen, D. J. Hoivik, R. T. Miller, J. S. Allen, M. J. Jayo, K. Selinger, and M. J. Santostefano Evaluation of the Carcinogenic Potential of Clofibrate in the FVB/Tg.AC Mouse After Dermal Application--Part II International Journal of Toxicology, September 1, 2005; 24(5): 327 - 339. [Abstract] [Full Text] [PDF]

				S. R. Nesfield, T. C. Williams, D. J. Hoivik, R. T. Miller, J. S. Allen, K. Selinger, D. Rickert, and M. J. Santostefano Evaluation of the Carcinogenic Potential of Clofibrate in the Neonatal Mouse International Journal of Toxicology, September 1, 2005; 24(5): 341 - 348. [Abstract] [Full Text] [PDF]