Species differences in hepatic peroxisome proliferation, cell replication and transforming growth factor-β1 gene expression in the rat, Syrian hamster and guinea pig

Lake, Brian G.; Rumsby, Paul C.; Price, Roger J.; Cunninghame, Morag E.

doi:10.1016/s0027-5107(99)00238-9

Cited by 34 publications

(19 citation statements)

References 47 publications

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“…Lake et al (2000) compared the changes in relative liver weight and S-phase hepatocytes (by continuous BrdU labeling) among rats, Syrian hamsters, and guinea pigs following treatment with methyl clofenapate, ciprofibrate, and WY-14,643. Daily oral doses of these compounds for 6 days resulted in increased relative liver weight and frequency of S-phase hepatocytes in rats (only methyl clofenapate evaluated), but not in guinea pigs.…”

Section: Cell Proliferation Induced Bymentioning

confidence: 99%

Regulation of cell proliferation and cell death by peroxisome proliferators

Cattley

2003

Microscopy Res & Technique

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Peroxisome proliferators cause increases in liver mass in rodents, linked to changes in cell proliferation and cell death of hepatocytes. These effects are reversible upon cessation of treatment. The underlying mechanism of the response in rodent liver is complex, but clearly dependent on activation of the nuclear receptor PPARalpha. Other signaling pathways have been implicated in this response, but evidence is mixed. Differing sensitivity among various species to effects of peroxisome proliferators has been associated with differences in PPARalpha expression and function. Changes in cell proliferation and cell death in neoplastic hepatocytes also have been found in liver tumors caused by long-term treatment with peroxisome proliferators.

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Section: Cell Proliferation Induced Bymentioning

confidence: 99%

Regulation of cell proliferation and cell death by peroxisome proliferators

Cattley

2003

Microscopy Res & Technique

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“…Although the biochemical and physiologic effects associated with hepatic peroxisome proliferation are thought to play a role in the hepatic toxicity and carcinogenicity in sensitive species of rodents, the mechanism of peroxisome proliferator-induced tumorigenesis and the nature of its species-selectivity are not understood [20–22]. The results of a limited number of published studies suggest that gemfibrozil is not mutagenic [12, 23].…”

Section: Introductionmentioning

confidence: 99%

Effects of the PPARαAgonist and Widely Used Antihyperlipidemic Drug Gemfibrozil on Hepatic Toxicity and Lipid Metabolism

et al. 2010

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Gemfibrozil is a widely prescribed hypolipidemic agent in humans and a peroxisome proliferator and liver carcinogen in rats. Three-month feed studies of gemfibrozil were conducted by the National Toxicology Program (NTP) in male Harlan Sprague-Dawley rats, B6C3F1 mice, and Syrian hamsters, primarily to examine mechanisms of hepatocarcinogenicity. There was morphologic evidence of peroxisome proliferation in rats and mice. Increased hepatocyte proliferation was observed in rats, primarily at the earliest time point. Increases in peroxisomal enzyme activities were greatest in rats, intermediate in mice, and least in hamsters. These studies demonstrate that rats are most responsive while hamsters are least responsive. These events are causally related to hepatotoxicity and hepatocarcinogenicity of gemfibrozil in rodents via peroxisome proliferator activated receptor-α (PPARα) activation; however, there is widespread evidence that activation of PPARα in humans results in expression of genes involved in lipid metabolism, but not in hepatocellular proliferation.

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“…Although the dosages chosen were in the range or even lower than those used by other authors (I-200 mg/kg b.wt./day)[see e.g. 15,19,20,23,26,54], especially after chronic treatment and with the higher dosage a toxic alteration ofthe hepatocytes mainly around the central veins was evident, but also a compensatory regeneration, as mirrored by an increased number of mitotic figures. Liver tissue concentrations of lipid peroxidation products, however, were not increased due to fibrate treatment.…”

Section: Discussionmentioning

confidence: 93%

“…The potency of a compound to produce peroxisome proliferation in general correlates with its potency as a rodent hepatocarcinogen [17]. In other species as well as in man, however, such a marked peroxisome proliferation does not occur and also a carcinogenic effect of the fibrates has not been demonstrated so far [18][19][20][21][22][23][24][25]. After treatment of rats with fibrates, in addition, a hypertrophy of both rough and smooth endoplasmic reticulum with concomitant hepatomegaly and increased amounts and activities of cytochrome P450 (CYP) 4A, but also of CYP2B and CYP2El can be observed [see e.g.…”

Section: Introductionmentioning

confidence: 99%

Single and chronic administration of ciprofibrate or of ciprofibrate-glycinate in male Fischer 344 rats: Comparison of the effects on morphological and biochemical parameters in liver and blood

Lupp

Karge

Danz

et al. 2005

European Journal of Drug Metabolism and Pharmacokinetics

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Fibrates lead to a reduction of serum triglycerides and cholesterol in hyperlipidemic patients. Their therapeutic use, however, can be associated with adverse effects like gastrointestinal disorders, myalgia, myositis and hepatotoxicity. Large doses can even cause hepatocellular carcinoma in rodents. Additionally, interactions with the biotransformation of other compounds at the cytochrome P450 (CYP) system have been observed. Thus, the discovery of new derivatives with less of these side effects is of great interest. In the present study a single (10 mg/kg body weight) or a 4-week (1 or 10 mg/kg body weight daily) oral administration of ciprofibrate or of the newly synthesized ciprofibrate-glycinate was investigated in adult male Fischer 344 rats. Serum lipid concentrations were distinctly decreased after single but only slightly after chronic administration of the two fibrates, whereas liver parameters revealed a slight concentration and time dependent hepatotoxicity. Histologically, a hypertrophy, an eosinophilia, a reduced glycogen content and also an apoptosis of the hepatocytes was observed. Effects were more pronounced after chronic treatment and after application of the higher dosage. All CYP enzymes investigated were induced in a time and concentration dependent manner. Resulting CYP mediated monooxygenase and oxidase activities showed a dependency both on enzyme induction and hepatotoxic effects. With no parameter investigated major differences were seen between ciprofibrate and ciprofibrate-glycinate. Thus, the present investigations revealed no noticeable advantages of ciprofibrate-glycinate over its parent compound ciprofibrate.

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Species differences in hepatic peroxisome proliferation, cell replication and transforming growth factor-β1 gene expression in the rat, Syrian hamster and guinea pig

Cited by 34 publications

References 47 publications

Regulation of cell proliferation and cell death by peroxisome proliferators

Regulation of cell proliferation and cell death by peroxisome proliferators

Effects of the PPARαAgonist and Widely Used Antihyperlipidemic Drug Gemfibrozil on Hepatic Toxicity and Lipid Metabolism

Single and chronic administration of ciprofibrate or of ciprofibrate-glycinate in male Fischer 344 rats: Comparison of the effects on morphological and biochemical parameters in liver and blood

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