Evaluation of the carcinogenic potential of clofibrate in the p53+/- mouse.
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.
Torrey
Carla E
CE
GlaxoSmithKline, Safety Assessment, Research Triangle Park, North Carolina 27709, USA.
Campbell
James A
JA
Hoivik
Debie J
DJ
Miller
Richard T
RT
Allen
Jane S
JS
Mann
Peter C
PC
Selinger
Krzysztof
K
Rickert
Douglas
D
Savina
Paul M
PM
Santostefano
Michael J
MJ
D000284:Administration, Oral; D000311:Adrenal Glands / Q000473:pathology; D000818:Animals; D015197:Carcinogenicity Tests; D002994:Clofibrate / Q000008:administration & dosage / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005260:Female; D016158:Genes, p53; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010179:Pancreas / Q000473:pathology; D020025:Peroxisome Proliferators / Q000008:administration & dosage / Q000633:toxicity*; D011467:Prostate / Q000473:pathology; D018570:Risk Assessment; D013997:Time Factors
D020025:Peroxisome Proliferators; D002994:Clofibrate