Peroxisome proliferation in response to xenobiotics

Jw, DePierre; Ak, Sohlenius; Cai, Yuchen; Am, Eriksson; Andersson, Karin; Sundberg, Carola

doi:10.1042/bst0230425

Cited by 8 publications

(5 citation statements)

References 5 publications

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“…With both substances the well known fibrate effects on liver weights and on liver histology (hypertrophy of the hepatocytes, increased eosinophilia of the cytoplasm because of a pronounced proliferation of the peroxisomes and mitochondria) [13][14][15][16]19,26,54,55] were reproduced also in the present investigation. Additionally, after fibrate treatment a remarkable increase was observed with the kidney weights.…”

Section: Discussionsupporting

confidence: 68%

“…Large doses can even cause hepatocellular carcinoma in rodents [9,10].The toxic but also the therapeutic effects of the fibrates are attributed to their action on so-called peroxisome proliferatoractivated receptors (pPARs),but also to signallingthrough other receptors or through non-receptor pathways [11][12][13].As a typical effect, after treatment of rats with fibrates a pronounced proliferation of peroxisomes in the livers can be observed [see e.g. [14][15][16]. The potency of a compound to produce peroxisome proliferation in general correlates with its potency as a rodent hepatocarcinogen [17].…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionsupporting

confidence: 68%

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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“…These include enzymes involved in the β‐oxidation of fatty acids, fatty acid elongation, and the synthesis of cholesterol, bile acids, dolicols, and ether phospholipids. PPAR‐α activation by PPs alters transcriptional regulation of most of these enzymes, resulting in decreased hepatic lipid synthesis and increased lipid oxidation and secretion 22…”

Section: Effects Of Ppar‐α Activation On Lipid Homeostasismentioning

confidence: 99%

“…Down‐regulation of apo‐C‐III protein16,17 gives rise to increased clearance of circulating lipid. In addition, in the case of the human, up‐regulation of hepatic production of the A‐I and A‐II apolipoproteins22,23 increases the plasma HDL concentration and enhances reverse cholesterol flux. Thus, although PPs exert hypolipidemic effects on both rodents and humans, different pathways are involved.…”

Section: Effects Of Ppar‐α Activation On Lipid Homeostasismentioning

confidence: 99%

The Effects of Peroxisome Proliferators on Global Lipid Homeostasis and the Possible Significance of These Effects to Other Responses to These Xenobiotics

Xie

Yang

DePierre

2002

Annals of the New York Academy of Sciences

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Peroxisome proliferators (PPs) have been shown to regulate hepatic lipid metabolism via activation of the peroxisome proliferator-activated receptor alpha (PPAR-alpha). Recent studies have revealed that PPs also exert considerable influence on certain extrahepatic tissues, including adipose tissue and lymphoid organs, in an indirect fashion. Inhibition of the proliferation of thymocytes and splenocytes and alteration of fatty acid uptake into and release from adipose tissue might be consequences of the hypolipidemic effect of PPs involving both PPARalpha-dependent and -independent pathways. Exposure to PPs reduces the cholesterol content of circulating low-density lipoprotein (LDL), which is the major supply of this steroid to most peripheral tissues. In addition, PPs increase serum levels of high-density lipoprotein (HDL), which extracts cholesterol from peripheral tissues and returns it to the liver, thereby further decreasing the cholesterol content of peripheral tissues. This net flux of cholesterol from extrahepatic tissues to the liver represents a change in global lipid homeostasis. In normal healthy young mice, this hypolipidemic effect could result in loss of cholesterol and other lipids from peripheral tissues (e.g., adipose tissue, thymus, and spleen), especially from plasma membrane caveolae, which might perturb normal cellular signaling and result in tissue atrophy. On the other hand, the increased hepatic cholesterol content in the hepatocyte plasma membrane might actually enhance signaling, playing a role in the liver hypertrophy and hepatocarcinogenecally associated with long-term PP treatment. In conclusion, it is important to consider the systemic effects of PPs, rather than to focus on the liver alone.

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“…In rat livers typically a pronounced proliferation of peroxisomes can be observed (see e.g. [23][24][25]). The effectiveness of a compound to produce peroxisome proliferation in general correlates with its potency as a hepatocarcinogen in rodents, ciprofibrate being one of the most potent substances in this respect identified so far [15,16,26].…”

Section: Introductionmentioning

confidence: 99%

Ciprofibrate, Clofibric Acid and Respective Glycinate Derivatives

Lupp

Karge

Deufel

et al. 2011

Arzneimittelforschung

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Fibrates are widely prescribed in hyperlpidemic patients to prevent atherosclerosis. Their therapeutic use, however, can be associated with adverse effects like gastrointestinal disorders, myalgia, myositis and hepatotoxicity. In rodents large doses can even cause hepatocellular carcinoma. Additionally, interactions with the biotransformation of other compounds at the cytochrome P450 (CYP) system have been observed. Thus, the discovery of new substances or derivatives with less side effects is of great interest. In the present study the influence of a four-week daily oral administration of 2 mg/kg body weight ciprofibrate (CAS 52214-84-3) or of 100 mg/kg body weight clofibric acid (CAS 882-09-7) was compared to that of the respective doses of their newly synthesized glycine conjugates in adult male lean and obese Zucker rats. Although obese rats displayed distinctly higher serum lipid concentrations, after fibrate treatment values were significantly lowered in lean animals only. Livers of obese rats were significantly enlarged, histologically showing a fine-droplet like fatty degeneration and an increase in glycogen content, but no signs of inflammation. After fibrate administration histologically a hypertrophy, an eosinophilia, a reduced glycogen content and also hepatocyteapoptosis were observed. Livers of obese rats displayed higher CYP1A1 andCYP2E1 expression, but lower immunostaining for CYP2B1 and CYP3A2. No differences between the two groups of rats were seen with respect to CYP4A1 expression. Due to fibrate treatment especially CYP2E1 and CYP4A1, but also CYP1A1, 2B1 and 3A2 were induced. Resulting CYP mediated monooxygenase activities were also elevated in most cases. In general, effects of clofibric acid and clofibric acid glycinate (CAS 4896-55-3) were less distinct than those of ciprofibrate and its glycinate (CAS 640772-36-7). With no parameterinvestigated major differences were seen between the parent fibrates and their glycine conjugates. Thus, the present investigations revealed no noticeable advantages of the glycinates over ciprofibrate or clofibric acid.

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Peroxisome proliferation in response to xenobiotics

Cited by 8 publications

References 5 publications

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

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

The Effects of Peroxisome Proliferators on Global Lipid Homeostasis and the Possible Significance of These Effects to Other Responses to These Xenobiotics

Ciprofibrate, Clofibric Acid and Respective Glycinate Derivatives

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