Evaluation of the Carcinogenic Potential of Clofibrate in the p53+/− Mouse

Torrey, Carla E.; Campbell, James A.; Hoivik, Debie J.; Miller, Richard T.; Allen, Jane S.; Mann, Peter C.; Selinger, Krzysztof; Rickert, Douglas E.; Savina, Paul M.; Santostefano, Michael J.

doi:10.1080/10915810500210237

Cited by 7 publications

(17 citation statements)

References 31 publications

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“…We observed that the 5 months survival of p47 phox -null and wild type C57BL/6J mice on the WY-14,643 diet was below 40% with pronounced temporal increases in serum ALT levels. Similarly, several long-term dietary feeding studies with peroxisome proliferators in rodents reported higher attrition rates (Peters et al, 1997;Torrey et al, 2005;Ward et al, 1998). This indicates that 0.1% (wt/wt) WY-14,643 is higher than a maximal tolerated dose in mice and the data in this study should be interpreted with caution.…”

Section: Resultssupporting

confidence: 56%

“…The similarities in WY-14,643-induced liver injury across strains and the disparate survival of C57BL/6J versus SV129 mice suggest that strain variations in response to WY-14,643 may not be a result of liver toxicity alone. Several studies reported significant weight loss in rodents given peroxisome proliferators chronically (Hurtt et al, 1997;Peters et al, 1997;Torrey et al, 2005;Ward et al, 1998). Excessive energy metabolism resulting in a significant reduction in fat stores is thought to be the primary contributing factor to this effect of PPARa agonists.…”

Section: Resultsmentioning

confidence: 99%

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WY-14,643–Induced Cell Proliferation and Oxidative Stress in Mouse Liver are Independent of NADPH Oxidase

Woods¹,

Burns²,

Bradford³

et al. 2007

Toxicological Sciences

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Long-term exposure of rodents to peroxisome proliferators leads to increases in peroxisomes, hepatocellular proliferation, oxidative damage, suppressed apoptosis, and ultimately results in the development of hepatic adenomas and carcinomas. Peroxisome proliferators-activated receptor (PPAR)alpha was shown to be required for these pleiotropic responses; however, Kupffer cells, resident liver macrophages, were also identified as playing a role in peroxisome proliferators-induced effects, independently of PPARalpha. Previous studies showed that oxidants from NADPH (nicotinamide adenine dinucleotide phosphate, reduced) oxidase mediate acute effects of peroxisome proliferators in rodent liver. To determine if Kupffer cell oxidants are also involved in chronic effects, NADPH oxidase-deficient (p47(phox)-null) mice were fed 4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio acetic acid (WY-14,643)-containing diet (0.1% wt/wt) for 1 week, 5 weeks, or 5 months along with Pparalpha-null and wild type mice. As expected, no change in liver size, cell replication rates, or other phenotypic effects of peroxisome proliferators were observed in Pparalpha-null mice. Through 5 months of treatment, the p47(phox)-null and wild type mice exhibited peroxisome proliferators-induced adverse liver effects, along with increased oxidative DNA damage and increased cell proliferation, a response that is potentially mediated through nuclear factor kappa B (NFkB). Suppressed apoptosis caused by WY-14,643 was dependent on both NADPH oxidase and PPARalpha. Collectively, these findings suggest that involvement of Kupffer cells in WY-14,643-induced parenchymal cell proliferation and oxidative stress in rodent liver is an acute phenomenon that is not relevant to long-term exposure, but they are still involved in chronic apoptotic responses. These results provide new insight for understanding the mode of hepatocarcinogenic action of peroxisome proliferators.

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Section: Resultssupporting

confidence: 56%

Section: Resultsmentioning

confidence: 99%

WY-14,643–Induced Cell Proliferation and Oxidative Stress in Mouse Liver are Independent of NADPH Oxidase

Woods¹,

Burns²,

Bradford³

et al. 2007

Toxicological Sciences

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“…C max of clofibric acid, the metabolite of the parent compound, did not increase proportionally with dose (Table 2). This nonlinear kinetics observed in this study was different from other alternative carcinogenicity models treated with clofibrate (Torrey et al 2005a) and may be related to structural differences rodent PPAR α receptor and/or tissue/species-specific coactivators/corepressors (Cheung et al 2004). There was no significant difference between transgenic and nontransgenic rasH2 mice.…”

Section: Resultscontrasting

confidence: 85%

“…Recent data from our laboratory indicate that clofibrate produced papillomas in Tg.AC mice after dermal application (Torrey et al 2005b) but is noncarcinogenic in p53 +/– mice after 6 months of exposure (Torrey et al 2005a) or in neonatal mice up to 1 year after treatment on litter days 9 and 16 (Nesfield et al 2005) or in Tg.AC after 6 months of oral exposure (Torrey et al 2005c). These data suggest that clofibrate was tumorgenic in most animal models that detect nongenotoxic carcinogens.…”

Section: Resultsmentioning

confidence: 99%

Evaluation of the Carcinogenic Potential of Clofibrate in the rasH2 Mouse

et al. 2005

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The purpose of the study was to support of the International Life Sciences Institute (ILSI) alternative carcinogenicity models initiative to evaluate the carcinogenic potential of the nongenotoxic carcinogen, clofibrate, a peroxisome proliferator-activated receptor (PPAR) alpha agonist, following oral administration to rasH2 mice. Peroxisome proliferators are one of the most widely studied of the nongenotoxic carcinogens and have diverse industrial and therapeutic uses (Gonzalez et al. J. Nat. Cancer Inst. 90: 1702-1709, 1998); however, the nongenotoxic mechanism of carcinogenicity is currently unknown. Male mice were administered doses of clofibrate at 50, 100, or 200 mg/kg/day and female mice were administered doses of 50, 150, or 250 mg/kg/day by oral gavage at 10 ml/kg for 27 weeks. In addition, rasH2 male and female mice were treated with N-nitroso-N-methylurea (NMU). Nontransgenic male and female mice were treated with 200 and 250 mg/kg/day, respectively, of clofibrate. The NMU-treated mice were given a single intraperitoneal dose of 75 mg/kg, which was followed by a 90-day observation period; all others were sacrificed after 6 months of daily dosing. Hepatocellular neoplasms were observed in clofibrate-treated rasH2 male mice after 6 months of treatment but not in nontransgenic males or females. Clofibrate treatment (250 mg/kg/day) of female rasH2 mice was associated with a slight increase in the incidence of various neoplasms (harderian gland, lungs, skin, spleen, tail, thymus, and uterus) compared with untreated transgenic mice and with similarly treated nontransgenic mice. Non-neoplastic changes were found in the liver of transgenic and nontransgenic mice of both sexes and in the kidneys of male mice. NMU produced findings are consistent with previous studies. The data suggest that the rasH2 mice are a good model for testing epigenetic carcinogens in a shorter timeframe than conventional mouse carcinogenicity bioassays.

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“…However, humans are resistant to peroxisomal proliferation and the development of liver tumors after exposure to PPARα ligands (Klaunig et al 2003). Recent data from our laboratory indicate that clofibrate is hepatocarcinogenic in rasH2 mice after 6 months of oral exposure (Nesfield et al 2005a), but noncarcinogenic in p53 + / − mice after 6 months of exposure (Torrey et al 2005a), or in neonatal mice up to 1 year after treatment on litter days 9 and 16 (Nesfield et al 2005b), and in Tg.AC after 6 months of oral exposure (Torrey et al 2005b). Recent literature suggests that structural differences between the human and rodent PPARα receptor or tissue/species-specific coactivators/corepressors may be responsible for the species-specific difference in hepatocarcinogenesis (Cheung et al 2004).…”

mentioning

confidence: 99%

Evaluation of the Carcinogenic Potential of Clofibrate in the FVB/Tg.AC Mouse After Dermal Application—Part II

et al. 2005

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This study was conducted as part of the International Life Sciences Institute (ILSI) Alternatives to Carcinogenicity Testing program and evaluated the carcinogenic potential of clofibrate, a nongenotoxic, peroxisome proliferator-activated receptor (PPAR) alpha agonist following dermal application to transgenic Tg.AC and nontransgenic FVB mice for a minimum of 26 weeks. Clofibrate doses of 12, 28, or 36 mg/200 microl/day were used. Positive controls for papilloma formation were benzene (174.8 mg/200 microl), and 12-o-tetradecanoylphorbol-13-acetate (TPA [0.00250 mg/200 microl]). Clofibrate was tolerated at doses up to 36 mg/200 microl. In Tg.AC mice, clofibrate produced a dose-related increase in the incidence of mice with cutaneous papillomas; and dose-related decreases in mean time to first tumor, mean multiplicity of tumors per mouse, and mean weeks to maximal yield, as well as numerous nonneoplastic microscopic lesions in the liver, kidney, spleen, and skin. Benzene and TPA induced both neoplastic and/or non-neoplastic proliferative lesions in Tg.AC mice. Clofibrate did not increase the incidence or multiplicity of papillomas, or any other tumors in FVB mice. These data show that the Tg.AC dermal model has increased sensitivity in detecting skin papillomas caused by the nongenotoxic rodent carcinogen, clofibrate, compared to wild type FVB mice, at systemic exposures that are 3x higher than the systemic exposure observed in humans taking clofibrate (AUC = 1100 microg.h/ml) at the recommended maximum therapeutic dose of 500 mg. In addition, this study supports the proposed concept that Tg.AC model may detect compounds with nongenotoxic carcinogenic potential in a shorter timeframe than conventional mouse carcinogenicity bioassays.

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Evaluation of the Carcinogenic Potential of Clofibrate in the p53⁺^/⁻ Mouse

Cited by 7 publications

References 31 publications

WY-14,643–Induced Cell Proliferation and Oxidative Stress in Mouse Liver are Independent of NADPH Oxidase

WY-14,643–Induced Cell Proliferation and Oxidative Stress in Mouse Liver are Independent of NADPH Oxidase

Evaluation of the Carcinogenic Potential of Clofibrate in the rasH2 Mouse

Evaluation of the Carcinogenic Potential of Clofibrate in the FVB/Tg.AC Mouse After Dermal Application—Part II

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