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Evaluation of the carcinogenic potential of clofibrate in the p53+/- mouse.

Abstract
This study was conducted as part of International Life Sciences Institute (ILSI) program to evaluate the carcinogenic potential of clofibrate, a nongenotoxic, peroxisome proliferator-activated receptor (PPAR) alpha agonist, following oral administration to p53+/- heterozygous mice for a minimum of 26 weeks. p-Cresidine, a urinary bladder carcinogen, was given orally at 400 mg/kg/day as a positive control. Initial clofibrate doses were 50, 250, and 400 mg/kg/day for males and 50, 200, and 500 mg/kg/day for females. Due to unexpected mortality during the first week of dosing, clofibrate doses were lowered to 25, 75, and 100 mg/kg/day for males and 25, 75, and 125 mg/kg/day for females. Clinical signs and mortality were greater in p53+/- than wild-type (WT) mice. With the exception of liver weights, no marked differences in any other parameters either between the sexes or between WT and p53+/- mice were noted. Moderate increases in liver weights noted in WT males given 100 mg/kg/day clofibrate were not associated with any microscopic changes. No neoplastic response was observed in p53+/- mice after 6 months of exposure to clofibrate at doses up to 100 mg/kg/day for males and 125 mg/kg/day for females. Transitional-cell hyperplasia and carcinoma of the urinary bladder were noted in both sexes given p-cresidine, demonstrating that the p53+/- mouse responded to a known mouse carcinogen as expected. Clofibrate produced non-neoplastic findings in the adrenals, pancreas, and prostate, whereas p-cresidine affected the kidney, liver, pancreas, and spleen.
AuthorsCarla E Torrey, James A Campbell, Debie J Hoivik, Richard T Miller, Jane S Allen, Peter C Mann, Krzysztof Selinger, Douglas Rickert, Paul M Savina, Michael J Santostefano
JournalInternational journal of toxicology (Int J Toxicol) 2005 Sep-Oct Vol. 24 Issue 5 Pg. 289-99 ISSN: 1091-5818 [Print] United States
PMID16257849 (Publication Type: Journal Article)
Chemical References
  • Peroxisome Proliferators
  • Clofibrate
Topics
  • Administration, Oral
  • Adrenal Glands (pathology)
  • Animals
  • Carcinogenicity Tests
  • Clofibrate (administration & dosage, toxicity)
  • Dose-Response Relationship, Drug
  • Female
  • Genes, p53
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Pancreas (pathology)
  • Peroxisome Proliferators (administration & dosage, toxicity)
  • Prostate (pathology)
  • Risk Assessment
  • Time Factors

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