Peroxisome Proliferators and Receptor-Mediated Hepatic Carcinogenesis

The peroxisome proliferators represent an important group of hepatic carcinogens in rodents that act via the nuclear receptor PPARα. The primary role of PPARα in mediating this response had led to the further characterization of potential events downstream that likely enable the carcinogenic response, including increased peroxisomal fatty acid beta oxidation and the modulation of hepatocellular replication and death, either generally or in preneoplastic lesions. A cooperative role of Kupffer cell activation has been proposed to function in the modulation of hepatocellular proliferation in rodent liver by peroxisome proliferators, but data that confirm or refute this proposal are mixed. Presently there is no evidence that links the Kupffer cell activation by peroxisome proliferators directly to the development of liver tumors. There are marked species differences in susceptibility to peroxisomal proliferation, and active investigation concerning the molecular basis of these differences continues.

[1]  H. Lobeck,et al.  Influence of fenofibrate on cellular and subcellular liver structure in hyperlipidemic patients. , 1983, Atherosclerosis.

[2]  J. Peschon,et al.  Initiation of liver growth by tumor necrosis factor: deficient liver regeneration in mice lacking type I tumor necrosis factor receptor. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[3]  J. Peters,et al.  Role of PPAR alpha in the mechanism of action of the nongenotoxic carcinogen and peroxisome proliferator Wy-14,643. , 1997, Carcinogenesis.

[4]  Garet P Lahvis,et al.  Resistance to 2,3,7,8-Tetrachlorodibenzo-p-dioxin Toxicity and Abnormal Liver Development in Mice Carrying a Mutation in the Nuclear Localization Sequence of the Aryl Hydrocarbon Receptor* , 2003, The Journal of Biological Chemistry.

[5]  J M Ward,et al.  Receptor and Nonreceptor-Mediated Organ-Specific Toxicity of Di(2-ethylhexyl)phthalate (DEHP) in Peroxisome Proliferator-Activated Receptorα-Null Mice , 1998, Toxicologic pathology.

[6]  S. Tomlinson,et al.  Species differences in peroxisome proliferation; mechanisms and relevance. , 2000, Mutation research.

[7]  N. Fausto.  Liver regeneration. , 2000, Journal of hepatology.

[8]  R. J. Price,et al.  Species differences in hepatic peroxisome proliferation, cell replication and transforming growth factor-beta1 gene expression in the rat, Syrian hamster and guinea pig. , 2000, Mutation research.

[9]  H. K. Bojes,et al.  Antibodies to tumor necrosis factor alpha prevent increases in cell replication in liver due to the potent peroxisome proliferator, WY-14,643. , 1997, Carcinogenesis.

[10]  J. Jansson,et al.  Normal pharmacologically-induced, but decreased regenerative liver growth in interleukin-6-deficient (IL-6(-/-)) mice. , 2000, Journal of hepatology.

[11]  J. Deluca,et al.  Tumor necrosis factor alpha is not required for WY14,643-induced cell proliferation. , 2001, Carcinogenesis.

[12]  Robinson,et al.  Do peroxisome proliferating compounds pose a hepatocarcinogenic hazard to humans? , 1998, Regulatory toxicology and pharmacology : RTP.

[13]  M. Katoh,et al.  Subchronic toxicity of Di(2-ethylhexyl)phthalate in common marmosets: lack of hepatic peroxisome proliferation, testicular atrophy, or pancreatic acinar cell hyperplasia. , 1998, Toxicological sciences : an official journal of the Society of Toxicology.

[14]  I. Rusyn,et al.  Oxidants from nicotinamide adenine dinucleotide phosphate oxidase are involved in triggering cell proliferation in the liver due to peroxisome proliferators. , 2000, Cancer research.

[15]  G. Ciliberto,et al.  In vivo hepatocyte proliferation is inducible through a TNF and IL-6-independent pathway , 1998, Oncogene.

[16]  T. Pineau,et al.  Targeted disruption of the alpha isoform of the peroxisome proliferator-activated receptor gene in mice results in abolishment of the pleiotropic effects of peroxisome proliferators , 1995, Molecular and cellular biology.

[17]  P Fenner-Crisp,et al.  Do peroxisome proliferating compounds pose a hepatocarcinogenic hazard to humans? , 1998, Regulatory toxicology and pharmacology : RTP.

[18]  S. Han,et al.  PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS , 2006 .

[19]  E. Furth,et al.  Liver Failure and Defective Hepatocyte Regeneration in Interleukin-6-Deficient Mice , 1996, Science.

[20]  R. Roberts,et al.  The peroxisome proliferator (PP) response element upstream of the human acyl CoA oxidase gene is inactive among a sample human population: significance for species differences in response to PPs. , 1999, Carcinogenesis.

[21]  K. Griffin,et al.  Peroxisome proliferator activated receptor-alpha expression in human liver. , 1998, Molecular pharmacology.

[22]  J. Corton,et al.  Hepatocellular proliferation in response to a peroxisome proliferator does not require TNFalpha signaling. , 2001, Carcinogenesis.

[23]  D. Germolec,et al.  Kupffer cells are causally responsible for the mitogenic effect of peroxisome proliferators. , 1997, Carcinogenesis.

[24]  J. F. Douglas,et al.  The carcinogenicity of dietary di(2-ethylhexyl) phthalate (DEHP) in Fischer 344 rats and B6C3F1 mice. , 1982, Journal of toxicology and environmental health.

[25]  I. Issemann,et al.  The mouse peroxisome proliferator activated receptor recognizes a response element in the 5′ flanking sequence of the rat acyl CoA oxidase gene. , 1992, The EMBO journal.

[26]  T Ichida,et al.  Induction of hepatic peroxisome proliferation in mice by lactofen, a diphenyl ether herbicide. , 1988, Toxicology and applied pharmacology.

[27]  W. Wahli,et al.  Peroxisome proliferator-activated receptors: insight into multiple cellular functions. , 2000, Mutation research.

[28]  R. Cattley,et al.  Relationship of oxidative damage to the hepatocarcinogenicity of the peroxisome proliferators di(2-ethylhexyl)phthalate and Wy-14,643. , 1989, Carcinogenesis.

[29]  W. Wahli,et al.  Peroxisome Proliferator Activated Receptors , 2005 .

[30]  I. Issemann,et al.  Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators , 1990, Nature.

[31]  N. Macdonald,et al.  Species differences in sequence and activity of the peroxisome proliferator response element (PPRE) within the acyl CoA oxidase gene promoter. , 1999, Toxicology letters.

[32]  L. Greenbaum,et al.  Transcriptional regulatory signals define cytokine-dependent and -independent pathways in liver regeneration. , 1999, Seminars in liver disease.

[33]  R. Cattley,et al.  Relationship of hepatic peroxisome proliferation and replicative DNA synthesis to the hepatocarcinogenicity of the peroxisome proliferators di(2-ethylhexyl)phthalate and [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio]acetic acid (Wy-14,643) in rats. , 1988, Cancer research.

[34]  R. J. Price,et al.  Comparison of the hepatic effects of nafenopin and WY-14,643 on peroxisome proliferation and cell replication in the rat and Syrian hamster. , 1993, Environmental health perspectives.

[35]  R. Cattley.  Regulation of cell proliferation and cell death by peroxisome proliferators , 2003, Microscopy research and technique.

[36]  J. Corton,et al.  Apoptosis, mitosis and cyclophilin-40 expression in regressing peroxisome proliferator-induced adenomas. , 2000, Carcinogenesis.

[37]  S Kettle,et al.  Mechanistically-based Human Hazard Assessment of Peroxisome Proliferator-induced Hepatocarcinogenesis , 1994, Human & experimental toxicology.

[38]  R. Roberts.  Evidence for Cross Talk between PPARα and p38 MAP Kinase , 2002 .

[39]  A. Diehl,et al.  Cytokine regulation of liver injury and repair , 2000, Immunological reviews.

[40]  T. Orton,et al.  Cytochrome P-450 induction by clofibrate. Purification and properties of a hepatic cytochrome P-450 relatively specific for the 12- and 11-hydroxylation of dodecanoic acid (lauric acid). , 1982, The Biochemical journal.

[41]  H. K. Bojes,et al.  Peroxisome proliferators activate Kupffer cells in vivo. , 1996, Cancer research.

[42]  R. Hess,et al.  NATURE OF THE HEPATOMEGALIC EFFECT PRODUCED BY ETHYL-CHLOROPHENOXY-ISOBUTYRATE IN THE RAT , 1965, Nature.

[43]  J. Deluca,et al.  Tumor necrosis factor α is not required for WY14,643-induced cell proliferation , 2001 .

[44]  J. Ashby,et al.  The genetic toxicity of the peroxisome proliferator class of rodent hepatocarcinogen. , 2000, Mutation research.

[45]  J. Reddy,et al.  Hypolipidaemic hepatic peroxisome proliferators form a novel class of chemical carcinogens , 1980, Nature.

[46]  E. Ros,et al.  Fibrate treatment does not modify the expression of acyl coenzyme A oxidase in human liver , 2002, Clinical pharmacology and therapeutics.

[47]  D. Azarnoff,et al.  NAFENOPIN-INDUCED HEPATIC MICROBODY (PEROXISOME) PROLIFERATION AND CATALASE SYNTHESIS IN RATS AND MICE , 1974, The Journal of cell biology.

[48]  J. D. Frank,et al.  Studies of early hepatocellular proliferation and peroxisomal proliferation in Sprague-Dawley rats treated with tumorigenic doses of clofibrate. , 1992, Toxicology and applied pharmacology.

[49]  D. Moller,et al.  Evidence for peroxisome proliferator-activated receptor (PPAR)alpha-independent peroxisome proliferation: effects of PPARgamma/delta-specific agonists in PPARalpha-null mice. , 2000, Molecular pharmacology.

[50]  N. Fausto,et al.  Deficient liver regeneration after carbon tetrachloride injury in mice lacking type 1 but not type 2 tumor necrosis factor receptor. , 1998, The American journal of pathology.

[51]  I. Rusyn,et al.  WY-14 643 rapidly activates nuclear factor kappaB in Kupffer cells before hepatocytes. , 1998, Carcinogenesis.

[52]  R. Buchanan,et al.  Light and electron microscopy of liver in hyperlipoproteinemic patients under long-term gemfibrozil treatment. , 1982, Atherosclerosis.

[53]  Margaret S. Wu,et al.  Evidence for Peroxisome Proliferator-Activated Receptor (PPAR)α-Independent Peroxisome Proliferation: Effects of PPARγ/δ-Specific Agonists in PPARα-Null Mice , 2000 .

[54]  C Kemmer,et al.  Relationship between morphological changes and lipid-lowering action of p-chlorphenoxyisobutyric acid (CPIB) on hepatic mitochondria and peroxisomes in man. , 1983, Atherosclerosis.

[55]  J. Klaunig,et al.  Effects of di-isononyl phthalate, di-2-ethylhexyl phthalate, and clofibrate in cynomolgus monkeys. , 2000, Toxicological sciences : an official journal of the Society of Toxicology.

[56]  T. Sueyoshi,et al.  Phenobarbital induction of drug/steroid-metabolizing enzymes and nuclear receptor CAR. , 2003, Biochimica et biophysica acta.

[57]  F. Steele.  Genetic "differences". , 2002, Genomics.

[58]  J. Popp,et al.  Role of fatty acyl coenzyme A oxidase in the efflux of oxidized glutathione from perfused livers of rats treated with the peroxisome proliferator nafenopin. , 1987, Cancer research.

[59]  P. Genton,et al.  Morphometric study of human hepatic cell modifications induced by fenofibrate. , 1987, Metabolism: clinical and experimental.

[60]  B Staels,et al.  A truncated human peroxisome proliferator-activated receptor alpha splice variant with dominant negative activity. , 1999, Molecular endocrinology.

[61]  M. Serra,et al.  Predictors of morbidity and mortality after the first episode of upper gastrointestinal bleeding in liver cirrhosis. , 2000, Journal of hepatology.

[62]  T. Goldsworthy,et al.  Contrasting hepatocytic peroxisome proliferation, lipofuscin accumulation and cell turnover for the hepatocarcinogens Wy-14,643 and clofibric acid. , 1992, Carcinogenesis.

[63]  Chi-Wai Wong,et al.  Estrogen receptor-interacting protein that modulates its nongenomic activity-crosstalk with Src/Erk phosphorylation cascade , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[64]  J. Reddy,et al.  Hydrogen peroxide generation in peroxisome proliferator-induced oncogenesis. , 2000, Mutation research.

[65]  I. Issemann,et al.  The peroxisome proliferator-activated receptor:retinoid X receptor heterodimer is activated by fatty acids and fibrate hypolipidaemic drugs. , 1993, Journal of molecular endocrinology.

[66]  C. Duve,et al.  A fatty acyl-CoA oxidizing system in rat liver peroxisomes; enhancement by clofibrate, a hypolipidemic drug. , 1976, Proceedings of the National Academy of Sciences of the United States of America.