peroxisome proliferators


Summary: A class of nongenotoxic CARCINOGENS that induce the production of hepatic PEROXISOMES and induce hepatic neoplasms after long-term administration.

Top Publications

  1. Cosulich S, James N, Roberts R. Role of MAP kinase signalling pathways in the mode of action of peroxisome proliferators. Carcinogenesis. 2000;21:579-84 pubmed
    b>Peroxisome proliferators (PPs) are a class of non-genotoxic chemicals that cause rodent liver enlargement and hepatocarcinogenesis...
  2. Fan L, Coley J, Miller R, Cattley R, Corton J. Opposing mechanisms of NADPH-cytochrome P450 oxidoreductase regulation by peroxisome proliferators. Biochem Pharmacol. 2003;65:949-59 pubmed
    b>Peroxisome proliferators (PPs) regulate a battery of rodent P450 genes, including CYP2B, CYP2C, and CYP4A family members...
  3. Penna F, Bonelli G, Baccino F, Costelli P. Cytotoxic properties of clofibrate and other peroxisome proliferators: relevance to cancer progression. Curr Med Chem. 2010;17:309-20 pubmed
    The biological activity of peroxisome proliferators (PPs) is mediated by a class of receptors, known as PPARs (PP-Activated Receptor), belonging to the nuclear receptor superfamily...
  4. Tharappel J, Nalca A, Owens A, Ghabrial L, Konz E, Glauert H, et al. Cell proliferation and apoptosis are altered in mice deficient in the NF-kappaB p50 subunit after treatment with the peroxisome proliferator ciprofibrate. Toxicol Sci. 2003;75:300-8 pubmed
    ..These data indicate that NF-kappaB contributes to the proliferative and apoptotic changes that occur in the liver in response to ciprofibrate. ..
  5. Parzefall W, Berger W, Kainzbauer E, Teufelhofer O, Schulte Hermann R, Thurman R. Peroxisome proliferators do not increase DNA synthesis in purified rat hepatocytes. Carcinogenesis. 2001;22:519-23 pubmed
    ..Kupffer cells are a major source of TNFalpha in the liver and have recently been shown to be activated by peroxisome proliferators, the possibility exists that the effect of peroxisome proliferators on DNA synthesis in parenchymal cells ..
  6. O Brien M, Spear B, Glauert H. Role of oxidative stress in peroxisome proliferator-mediated carcinogenesis. Crit Rev Toxicol. 2005;35:61-88 pubmed, the evidence about the role of oxidative stress in the induction of hepatocellular carcinomas by peroxisome proliferators is examined...
  7. Reddy J. Peroxisome proliferators and peroxisome proliferator-activated receptor alpha: biotic and xenobiotic sensing. Am J Pathol. 2004;164:2305-21 pubmed
  8. Tien E, Gray J, Peters J, Vanden Heuvel J. Comprehensive gene expression analysis of peroxisome proliferator-treated immortalized hepatocytes: identification of peroxisome proliferator-activated receptor alpha-dependent growth regulatory genes. Cancer Res. 2003;63:5767-80 pubmed
    Chemicals known as peroxisome proliferators (PPs) are the subject of intense study because of their ability to cause hepatocellular carcinoma in laboratory rodents...
  9. O Brien M, Twaroski T, Cunningham M, Glauert H, Spear B. Effects of peroxisome proliferators on antioxidant enzymes and antioxidant vitamins in rats and hamsters. Toxicol Sci. 2001;60:271-8 pubmed
    b>Peroxisome proliferators (PPs) cause hepatomegaly, peroxisome proliferation, and hepatocarcinogenesis in rats and mice, whereas hamsters are less responsive to PPs...

More Information


  1. Roberts R, James N, Hasmall S, Holden P, Lambe K, Macdonald N, et al. Apoptosis and proliferation in nongenotoxic carcinogenesis: species differences and role of PPARalpha. Toxicol Lett. 2000;112-113:49-57 pubmed
    b>Peroxisome proliferators (PPs) are nongenotoxic rodent hepatocarcinogens that cause liver enlargement and hepatocarcinogenesis associated with peroxisome proliferation, induction of hepatocyte DNA synthesis and suppression of apoptosis...
  2. Savas U, Hsu M, Johnson E. Differential regulation of human CYP4A genes by peroxisome proliferators and dexamethasone. Arch Biochem Biophys. 2003;409:212-20 pubmed
    ..The results indicate that CYP4A11 expression can be induced by glucocorticoids and peroxisome proliferators.
  3. Gonzalez F, Shah Y. PPARalpha: mechanism of species differences and hepatocarcinogenesis of peroxisome proliferators. Toxicology. 2008;246:2-8 pubmed
    ..These agents cause liver cancers when chronically administered to rats and mice. Peroxisome proliferators include the widely prescribed lipid and cholesterol lowering fibrate drugs...
  4. Ammerschlaeger M, Beigel J, Klein K, Mueller S. Characterization of the species-specificity of peroxisome proliferators in rat and human hepatocytes. Toxicol Sci. 2004;78:229-40 pubmed
    ..Analysis of peroxisomal marker enzyme activities confirmed that peroxisome proliferators induced acyl-CoA oxidase (ACOX) and to a lesser extent catalase in rat hepatocytes, but not in human ..
  5. Dufour J, Vo M, Bhattacharya N, Okita J, Okita R, Kim K. Peroxisome proliferators disrupt retinoic acid receptor alpha signaling in the testis. Biol Reprod. 2003;68:1215-24 pubmed
    b>Peroxisome proliferators include a diverse group of chemicals, some of which have been demonstrated to be testicular toxicants...
  6. Cheung C, Akiyama T, Ward J, Nicol C, Feigenbaum L, Vinson C, et al. Diminished hepatocellular proliferation in mice humanized for the nuclear receptor peroxisome proliferator-activated receptor alpha. Cancer Res. 2004;64:3849-54 pubmed
    ..The PPARalpha-humanized mice should serve as models for use in drug development and human risk assessment and to determine the mechanism of hepatocarcinogenesis of peroxisome proliferators.
  7. Schachtrup C, Emmler T, Bleck B, Sandqvist A, Spener F. Functional analysis of peroxisome-proliferator-responsive element motifs in genes of fatty acid-binding proteins. Biochem J. 2004;382:239-45 pubmed
    ..These results demonstrate that only PPREs of L- and A-FABP promoters are functional, and that binding of PPAR/RXR heterodimers to a PPRE in vitro does not necessarily predict transactivation. ..
  8. Wolfrum C, Borchers T, Sacchettini J, Spener F. Binding of fatty acids and peroxisome proliferators to orthologous fatty acid binding proteins from human, murine, and bovine liver. Biochemistry. 2000;39:1469-74 pubmed
    ..fatty acid binding protein (L-FABP) has been proposed to be involved in the transport of fatty acids and peroxisome proliferators from the cytosol into the nucleus for interaction with the peroxisome proliferator-activated receptors (..
  9. Roberts R. Peroxisome proliferators: mechanisms of adverse effects in rodents and molecular basis for species differences. Arch Toxicol. 1999;73:413-8 pubmed
    b>Peroxisome proliferators (PPs), such as diethylhexylphthalate (DEHP), constitute a diverse class of chemicals with many therapeutic, industrial and environmental applications...
  10. Yang Q, Xie Y, Alexson S, Nelson B, Depierre J. Involvement of the peroxisome proliferator-activated receptor alpha in the immunomodulation caused by peroxisome proliferators in mice. Biochem Pharmacol. 2002;63:1893-900 pubmed
    b>Peroxisome proliferators (PPs) are a large class of structurally diverse chemicals, which includes drugs designed to improve the metabolic abnormalities linking hypertriglyceridemia to diabetes, hyperglycemia, insulin-resistance and ..
  11. Raney A, Kline E, Tang H, McLachlan A. Transcription and replication of a natural hepatitis B virus nucleocapsid promoter variant is regulated in vivo by peroxisome proliferators. Virology. 2001;289:239-51 pubmed
    ..The nucleocapsid promoter mutation does not prevent peroxisome proliferators from increasing viral transcription and replication in the liver of these variant HBV transgenic mice...
  12. Xie Y, Yang Q, Nelson B, Depierre J. Characterization of the adipose tissue atrophy induced by peroxisome proliferators in mice. Lipids. 2002;37:139-46 pubmed
    In the present study, we characterized the effects of peroxisome proliferators (PP) on adipose tissue in mice...
  13. Rusyn I, Rose M, Bojes H, Thurman R. Novel role of oxidants in the molecular mechanism of action of peroxisome proliferators. Antioxid Redox Signal. 2000;2:607-21 pubmed
    b>Peroxisome proliferators are nongenotoxic rodent carcinogens that act as tumor promoters by increasing cell proliferation; however, their precise mechanism of action is not well understood...
  14. Li X, Baumgart E, Dong G, Morrell J, Jimenez Sanchez G, Valle D, et al. PEX11alpha is required for peroxisome proliferation in response to 4-phenylbutyrate but is dispensable for peroxisome proliferator-activated receptor alpha-mediated peroxisome proliferation. Mol Cell Biol. 2002;22:8226-40 pubmed
    ..Finally, we report the identification of a third mammalian PEX11 gene, PEX11gamma, and show that it too encodes a peroxisomal protein. ..
  15. Kennedy G, Butenhoff J, Olsen G, O Connor J, Seacat A, Perkins R, et al. The toxicology of perfluorooctanoate. Crit Rev Toxicol. 2004;34:351-84 pubmed
    ..Epidemiological investigations and medical surveillance of occupationally exposed workers have not found consistent associations between PFOA exposure and adverse health effects. ..
  16. Donelson E, Chen L, Zhang X, Goswami P, Song B, Hardwick J. Genomic structure and regulation of the rat hepatic CYP4F1 gene by peroxisome proliferators. Arch Biochem Biophys. 2008;472:1-16 pubmed publisher
    ..start sites, and characterized a strong core promoter region, -760/116, induced by retinoic acids and peroxisome proliferators in rat hepatoma McA-RH7777 cells...
  17. Tsai M, Chen H, Tseng M, Chang R. Cloning of peroxisome proliferators activated receptors in the cobia (Rachycentron canadum) and their expression at different life-cycle stages under cage aquaculture. Gene. 2008;425:69-78 pubmed publisher
    ..These results showed that PPARgamma and alpha played a pivotal role in the control of lipid metabolic and storage functions in the liver, muscle and visceral fat depot of the cobia. ..
  18. Glauert H, Eyigor A, Tharappel J, Cooper S, Lee E, Spear B. Inhibition of hepatocarcinogenesis by the deletion of the p50 subunit of NF-kappaB in mice administered the peroxisome proliferator Wy-14,643. Toxicol Sci. 2006;90:331-6 pubmed
    ..We previously showed that peroxisome proliferators increase NF-kappaB DNA binding activity in rats, mice, and hepatoma cell lines, and that mice deficient ..
  19. Suga T. Hepatocarcinogenesis by peroxisome proliferators. J Toxicol Sci. 2004;29:1-12 pubmed
    ..Furthermore, since many of hypolipidemic peroxisome proliferators induce hepatocellular carcinomas in both rats and mice, the relationship between peroxisome proliferation ..
  20. Ripp S, Falkner K, Pendleton M, Tamasi V, Prough R. Regulation of CYP2C11 by dehydroepiandrosterone and peroxisome proliferators: identification of the negative regulatory region of the gene. Mol Pharmacol. 2003;64:113-22 pubmed
    Treatment of rats with peroxisome proliferators is known to affect gene expression, including suppression of CYP2C11...
  21. Scatena R, Bottoni P, Vincenzoni F, Messana I, Martorana G, Nocca G, et al. Bezafibrate induces a mitochondrial derangement in human cell lines: a PPAR-independent mechanism for a peroxisome proliferator. Chem Res Toxicol. 2003;16:1440-7 pubmed
    Bezafibrate is a hypolipidemic drug that belongs to the group of peroxisome proliferators because it binds to peroxisome proliferator-activated receptors type alpha (PPARs)...
  22. Gazouli M, Yao Z, Boujrad N, Corton J, Culty M, Papadopoulos V. Effect of peroxisome proliferators on Leydig cell peripheral-type benzodiazepine receptor gene expression, hormone-stimulated cholesterol transport, and steroidogenesis: role of the peroxisome proliferator-activator receptor alpha. Endocrinology. 2002;143:2571-83 pubmed
    In this study, we hypothesized that many of the reported effects of phthalate esters and other peroxisome proliferators (PPs) in the testis are mediated by members of the PP- activated receptor (PPAR) family of transcription factors ..
  23. Rusyn I, Kadiiska M, Dikalova A, Kono H, Yin M, Tsuchiya K, et al. Phthalates rapidly increase production of reactive oxygen species in vivo: role of Kupffer cells. Mol Pharmacol. 2001;59:744-50 pubmed
    The role of oxidants in the mechanism of tumor promotion by peroxisome proliferators remains controversial...
  24. Holden P, Hasmall S, James N, West D, Brindle R, Gonzalez F, et al. Tumour necrosis factor alpha (TNFalpha): role in suppression of apoptosis by the peroxisome proliferator nafenopin. Cell Mol Biol (Noisy-le-grand). 2000;46:29-39 pubmed
  25. Chevalier S, Macdonald N, Roberts R. Induction of DNA replication by peroxisome proliferators is independent of both tumour necrosis factor (alpha) priming and EGF-receptor tyrosine kinase activity. J Cell Sci. 1999;112 ( Pt 24):4785-91 pubmed
    b>Peroxisome proliferators (PPs) cause hepatocyte proliferation and tumorigenesis in rodent liver. PPs induce hepatocyte DNA synthesis although the mechanism is unclear...
  26. Upham B, Deocampo N, Wurl B, Trosko J. Inhibition of gap junctional intercellular communication by perfluorinated fatty acids is dependent on the chain length of the fluorinated tail. Int J Cancer. 1998;78:491-5 pubmed
    ..fatty acids (PFFAs), such as perfluorooctanoic acid (PFOA) and perfluorodecanoic acid (PFDA), are known peroxisome proliferators and hepatocarcinogens...
  27. Meade E, McIntyre T, Zimmerman G, Prescott S. Peroxisome proliferators enhance cyclooxygenase-2 expression in epithelial cells. J Biol Chem. 1999;274:8328-34 pubmed
    ..These compounds are members of a heterogeneous group of compounds known as peroxisome proliferators, and the prototypical peroxisome proliferator, WY-14, 643, also enhanced COX-2 expression...
  28. Inestrosa N, Carvajal F, Zolezzi J, Tapia Rojas C, Serrano F, Karmelic D, et al. Peroxisome proliferators reduce spatial memory impairment, synaptic failure, and neurodegeneration in brains of a double transgenic mice model of Alzheimer's disease. J Alzheimers Dis. 2013;33:941-59 pubmed publisher
    ..proliferation is attained through different mechanisms by a set of structurally diverse molecules called peroxisome proliferators. In the present work, a double transgenic mouse model of AD that co-expresses a mutant human amyloid-? ..
  29. Tamura K, Ono A, Miyagishima T, Nagao T, Urushidani T. Profiling of gene expression in rat liver and rat primary cultured hepatocytes treated with peroxisome proliferators. J Toxicol Sci. 2006;31:471-90 pubmed
  30. Guo D, Sarkar J, Suino Powell K, Xu Y, Matsumoto K, Jia Y, et al. Induction of nuclear translocation of constitutive androstane receptor by peroxisome proliferator-activated receptor alpha synthetic ligands in mouse liver. J Biol Chem. 2007;282:36766-76 pubmed
    b>Peroxisome proliferators activate nuclear receptor peroxisome proliferator-activated receptor alpha (PPARalpha) and enhance the transcription of several genes in liver...
  31. Fidaleo M. Human health risk assessment for peroxisome proliferators: more than 30 years of research. Exp Toxicol Pathol. 2009;61:215-21 pubmed publisher
    ..widely used in human care for their hypolipidemic effects, belong to a larger class of chemicals called peroxisome proliferators (PPs)...
  32. Giometti C, Liang X, Tollaksen S, Wall D, Lubman D, Subbarao V, et al. Mouse liver selenium-binding protein decreased in abundance by peroxisome proliferators. Electrophoresis. 2000;21:2162-9 pubmed
    ..tryptic digests of two liver proteins showing dramatic decreases in abundance in response to numerous peroxisome proliferators were used to search sequence databases...
  33. Song He W, Nara T, Nakamura M. Delayed induction of delta-6 and delta-5 desaturases by a peroxisome proliferator. Biochem Biophys Res Commun. 2002;299:832-8 pubmed
    ..of D6D gene is activated by both sterol regulatory element binding protein-1c (SREBP-1c) and peroxisome proliferators (PP)...
  34. Ozaki K, Mahler J, Haseman J, Moomaw C, Nicolette M, Nyska A. Unique renal tubule changes induced in rats and mice by the peroxisome proliferators 2,4-dichlorophenoxyacetic acid (2,4-D) and WY-14643. Toxicol Pathol. 2001;29:440-50 pubmed
    b>Peroxisome proliferators are non-mutagenic carcinogens in the liver of rodents, acting both as initiators and promoters...
  35. Dzhekova Stojkova S, Bogdanska J, Stojkova Z. Peroxisome proliferators: their biological and toxicological effects. Clin Chem Lab Med. 2001;39:468-74 pubmed
    ..and induction of peroxisomal and extraperoxisomal fatty acid-oxidizing enzymes in rodent liver, called peroxisome proliferators. This list includes hypolipidemic drugs, analgesics, uricosuric drugs, environmental pollutants, ..
  36. Seo K, Kim K, Kim Y, Choi J, Lee K, Choi K. Comparison of oxidative stress and changes of xenobiotic metabolizing enzymes induced by phthalates in rats. Food Chem Toxicol. 2004;42:107-14 pubmed
    Phthalates are widely used as a plasticizer and cause a peroxisome proliferation. Peroxisome proliferators (PPs), such as di-2-ethylhexyl phthalate (DEHP) and clofibrate (CF) are known to have a hepatocarcinogenic potential in rodents...
  37. Anderson S, Cattley R, Corton J. Hepatic expression of acute-phase protein genes during carcinogenesis induced by peroxisome proliferators. Mol Carcinog. 1999;26:226-38 pubmed
    ..This dysregulation may indicate alterations in cytokine signaling networks regulating both APP gene expression and hepatocellular proliferation. ..
  38. Xiao S, Anderson S, Swanson C, Bahnemann R, Voss K, Stauber A, et al. Activation of peroxisome proliferator-activated receptor alpha enhances apoptosis in the mouse liver. Toxicol Sci. 2006;92:368-77 pubmed
    Chronic exposure to peroxisome proliferators (PPs) leads to increased incidence of liver tumors in rodents. Liver tumor induction is thought to require increased hepatocyte proliferation and suppression of apoptosis...
  39. Tharappel J, Cunningham M, Spear B, Glauert H. Differential activation of hepatic NF-kappaB in rats and hamsters by the peroxisome proliferators Wy-14,643, gemfibrozil, and dibutyl phthalate. Toxicol Sci. 2001;62:20-7 pubmed
    ..These species are sensitive to the hepatocarcinogenic effects of peroxisome proliferators, whereas other species such as Syrian hamsters are not...
  40. Lai D. Rodent carcinogenicity of peroxisome proliferators and issues on human relevance. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev. 2004;22:37-55 pubmed
    ..They are grouped under the generic term peroxisome proliferators (PP) because of their unique property of inducing peroxisome proliferation...
  41. Pauley C, Ledwith B, Kaplanski C. Peroxisome proliferators activate growth regulatory pathways largely via peroxisome proliferator-activated receptor alpha-independent mechanisms. Cell Signal. 2002;14:351-8 pubmed
    b>Peroxisome proliferators (PPs) induce liver tumors in rodents through an unknown mechanism requiring PP-activated receptor (PPAR) alpha...
  42. Ge R, Tao L, Kramer P, Cunningham M, Pereira M. Effect of peroxisome proliferators on the methylation and protein level of the c-myc protooncogene in B6C3F1 mice liver. J Biochem Mol Toxicol. 2002;16:41-7 pubmed
    b>Peroxisome proliferators in general are nongenotoxic mouse liver carcinogens for which DNA hypomethylation and altered gene expression are proposed mechanisms...
  43. Yamashita M. Peroxisome proliferator-activated receptor alpha-independent effects of peroxisome proliferators on cysteinyl leukotriene production in mast cells. Eur J Pharmacol. 2007;556:172-80 pubmed
    The effects of peroxisome proliferators, the ligands of a nuclear receptor peroxisome proliferator-activated receptor (PPAR) alpha, on cysteinyl leukotriene production were investigated in rodent mast cells...
  44. Hurst C, Waxman D. Activation of PPARalpha and PPARgamma by environmental phthalate monoesters. Toxicol Sci. 2003;74:297-308 pubmed
  45. Goll V, Viollon Abadie C, Nicod L, Richert L. Peroxisome proliferators induce apoptosis and decrease DNA synthesis in hepatoma cell lines. Hum Exp Toxicol. 2000;19:193-202 pubmed
    We examined the effects of various peroxisome proliferators (PPs) such as the hypolipidaemic agents clofibric acid (CLO), bezafibrate (BEZA), ciprofibrate (CIPRO) and nafenopin (NAFE) and the plasticizer di-(2-ethylhexyl)phthalate (DEHP) ..
  46. Hansmannel F, Clémencet M, Le Jossic Corcos C, Osumi T, Latruffe N, Nicolas Francès V. Functional characterization of a peroxisome proliferator response-element located in the intron 3 of rat peroxisomal thiolase B gene. Biochem Biophys Res Commun. 2003;311:149-55 pubmed
    Expression of the rat peroxisomal 3-ketoacyl-CoA thiolase gene B is induced by peroxisome proliferators. Although a sequence element like a peroxisome proliferator-activated receptor (PPAR)-binding site is located in the promoter region ..
  47. Cattley R. Regulation of cell proliferation and cell death by peroxisome proliferators. Microsc Res Tech. 2003;61:179-84 pubmed
    b>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...
  48. Werle Schneider G, Wölfelschneider A, von Brevern M, Scheel J, Storck T, Muller D, et al. Gene expression profiles in rat liver slices exposed to hepatocarcinogenic enzyme inducers, peroxisome proliferators, and 17alpha-ethinylestradiol. Int J Toxicol. 2006;25:379-95 pubmed
    ..included the enzyme inducers phenobarbital, alpha-hexachlorocyclohexane, and cyproterone acetate; the peroxisome proliferators WY-14,643, dehydroepiandrosterone, and ciprofibrate; and the hormone 17alpha-ethinylestradiol...
  49. Hanselman J, Vartanian M, Koester B, Gray S, Essenburg A, Rea T, et al. Expression of the mRNA encoding truncated PPAR alpha does not correlate with hepatic insensitivity to peroxisome proliferators. Mol Cell Biochem. 2001;217:91-7 pubmed
    ..To determine if a high PPAR alpha2/PPAR alpha1 mRNA ratio was associated with insensitivity to peroxisome proliferators, we treated human, rat, and rabbit hepatocytes with WY14643, a potent PPAR alpha activator, and measured ..
  50. O Brien M, Cunningham M, Spear B, Glauert H. Effects of peroxisome proliferators on glutathione and glutathione-related enzymes in rats and hamsters. Toxicol Appl Pharmacol. 2001;171:27-37 pubmed
    ..and total glutathione (GSH) in male Sprague-Dawley rats and Syrian hamsters fed two doses of three known peroxisome proliferators [dibutylphthalate (DBP), gemfibrozil, and Wy-14,643] for 6, 34, or 90 days...
  51. Yang Q, Xie Y, DePierre J. Effects of peroxisome proliferators on the thymus and spleen of mice. Clin Exp Immunol. 2000;122:219-26 pubmed
    The effects of peroxisome proliferators on the immune system of male C57B1/6 mice have been investigated. Significant atrophy of the thymus and spleen was observed in animals treated with potent peroxisome proliferators (e.g...
  52. Casas F, Domenjoud L, Rochard P, Hatier R, Rodier A, Daury L, et al. A 45 kDa protein related to PPARgamma2, induced by peroxisome proliferators, is located in the mitochondrial matrix. FEBS Lett. 2000;478:4-8 pubmed
    ..of nuclear gene expression by activating several peroxisome proliferator-activated receptors (PPARs), peroxisome proliferators influence mitochondrial activity...
  53. David R, Moore M, Cifone M, Finney D, Guest D. Chronic peroxisome proliferation and hepatomegaly associated with the hepatocellular tumorigenesis of di(2-ethylhexyl)phthalate and the effects of recovery. Toxicol Sci. 1999;50:195-205 pubmed