The Role of Peroxisome Proliferator Activated Receptor α in Peroxisome Proliferation, Physiological Homeostasis, and Chemical Carcinogenesis

  • Feank J. Gonzalez
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 422)


Peroxisomes are single membrane-bound organelles, found in all cells, that contain a variety of enzymes involved in a number of metabolic processes1. The most well characterized reactions carried out by peroxisomes are those involved in fatty acid I3-oxidation. The peroxisomal β-oxidation system metabolizes very long chain and long chain fatty acids and cannot metabolize short chain fatty acids (<6 units) whereas the mitochondrial system most efficiently oxidizes long, medium and short chain fatty acids down to two carbon units. The peroxisomal acyl-CoA oxidase enzyme generates H2O2 while the corresponding mitochondrial enzymes lead to production of NADH. Since plants lack mitochondria, peroxisomes are solely responsible for their fatty acid β-oxidation. The production of H2O2 by peroxisomal acyl-CoA oxidase has been used as a cytological marker for the organelle through staining with diaminobenzidine and historically accounts for the name “peroxisomes”1. Peroxisome proliferation can result in an excess of H2O2 that can potentially result in toxicity as discussed below. Under usual circumstances H2O2 is decomposed to molecular oxygen and water by catalase and glutathione peroxidase.


Peroxisome Proliferators Liver Fatty Acid Binding Protein Peroxisomal Enzyme Hypolipidemic Drug Peroxisomal Fatty Acid 
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  1. 1.
    Reddy, J.K. and Mannaerts, G.P. Peroxisomal lipid metabolism. Annu. Rev. Nutr., 14: 343–370, 1994.Google Scholar
  2. 2.
    Wanders, R.J., Schutgens, R.B., and Barth, P.G. Peroxisomal disorders: a review. J. Neuropathol. Exp. Neurol., 54: 726–739, 1995.CrossRefGoogle Scholar
  3. 3.
    Wanders, R.J., Barth, P.O., Schutgens, R.B., and Tager, J.M. Clinical and biochemical characteristics of peroxisomal disorders: an update. Eur. J. Pediatr., 153: S44 - S48, 1994.CrossRefGoogle Scholar
  4. 4.
    Reddy, J.K., Goel, S.K., Nemali, M.R., Canino, J.J., Laffler, T.G., Reddy, M.K., Sperbeck, S.J., Osumi, T., Hashimoto, T., and Lalwani, N.D. Transcription regulation of peroxisomal fatty acyl-CoA oxidase and enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase in rat liver by peroxisome proliferators. Proc. Natl. Acad. Sci. USA., 83: 1747–1751, 1986.CrossRefGoogle Scholar
  5. 5.
    Kimura, S., Hardwick, J.P., Kozak, C.A., and Gonzalez, F.J. The rat clofibrate-inducible CYP4A subfamily. I1. cDNA sequence of IVA3, mapping of the Cyp4a locus to mouse chromosome 4, and coordinate and tissue-specific regulation of the CYP4A genes. DNA, 8: 517–525, 1989.CrossRefGoogle Scholar
  6. 6.
    Kimura, S., Hanioka, N., Matsunaga, E., and Gonzalez, F.J. The rat clofibrate-inducible CYP4A gene subfamily. I. Complete intron and exon sequence of the CYP4A 1 and CYP4A2 genes, unique exon organization, and identification of a conserved 19-bp upstream element. DNA, 8: 503–516, 1989.CrossRefGoogle Scholar
  7. 7.
    Issemann, I., Prince, R.A., Tugwood, J.D., and Green, S. The peroxisome proliferator-activated receptor:retinoid X receptor heterodimer is activated by fatty acids and fibrate hypolipidaemic drugs. J. Mol. Endocrinol., 11: 37–47, 1993.CrossRefGoogle Scholar
  8. 8.
    Green, S. PPAR: a mediator of peroxisome proliferator action. Mutat. Res., 333: 101–109, 1995.CrossRefGoogle Scholar
  9. 9.
    Gottlicher, M., Widmark, E., Li, Q., and Gustafsson, J.A. Fatty acids activate a chimera of the clofibric acid-activated receptor and the glucocorticoid receptor. Proc. Natl. Acad. Sci. USA., 89: 4653–4657, 1992.CrossRefGoogle Scholar
  10. 10.
    Dreyer, C., Krey, G., Keller, H., Givel, F., Helftenbein, G., and Wahli, W. Control of the peroxisomal beta-oxidation pathway by a novel family of nuclear hormone receptors. Cell, 68: 879–887, 1992.CrossRefGoogle Scholar
  11. 11.
    Zhu, Y., Alvares, K., Huang, Q., Rao, M.S., and Reddy, J.K. Cloning of a new member of the peroxisome proliferator-activated receptor gene family from mouse liver. J. Biol. Chem., 268: 26817–26820, 1993.Google Scholar
  12. 12.
    Zhu, Y., Qi, C., Korenberg, J.R., Chen, X.N., Noya, D., Rao, M.S., and Reddy, J.K. Structural organization of mouse peroxisome proliferator-activated receptor gamma (mPPAR gamma) gene: alternative promoter use and different splicing yield two mPPAR gamma isoforms. Proc. Natl. Acad. Sci. USA., 92: 7921–7925, 1995.CrossRefGoogle Scholar
  13. 13.
    Tontonoz, P., Hu, E., Graves, R.A., Budavari, A.l., and Spiegelman, B.M. mPPAR gamma 2: tissue-specific regulator of an adipocyte enhancer. Genes. Dev., 8: 1224–1234, 1994.CrossRefGoogle Scholar
  14. 14.
    Chen, F., Law, S.W., and O’Malley, B.W. Identification of two mPPAR related receptors and evidence for the existence of five subfamily members. Biochem. Biophys. Res. Commun., 196: 671–677, 1993.Google Scholar
  15. 15.
    Kliewer, S.A., Forman, B.M., Blumberg, B., Ong, E.S., Borgmeyer, U., Mangelsdorf, D.J., Umesono, K., and Evans, R.M. Differential expression and activation of a family of murine peroxisome proliferator-activated receptors. Proc. Natl. Acad. Sci. USA., 91: 7355–7359, 1994.CrossRefGoogle Scholar
  16. 16.
    Jow, L. and Mukherjee, R. The human peroxisome proliferator-activated receptor (PPAR) subtype NUCI represses the activation of hPPAR alpha and thyroid hormone receptors. J. Biol. Chem., 270: 3836–3840, 1995.CrossRefGoogle Scholar
  17. 17.
    Amri, E.Z., Bonino, F., Ailhaud, G., Abumrad, N.A., and Grimaldi, P.A. Cloning of a protein that mediates transcriptional effects of fatty acids in preadipocytes. Homology to peroxisome proliferator-activated receptors. J. Biol. Chem., 270: 2367–2371, 1995.CrossRefGoogle Scholar
  18. 18.
    Lemberger, T., Staels, B., Saladin, R., Desvergne, B., Auwerx, J., and Wahli, W. Regulation of the peroxisome proliferator-activated receptor alpha gene by glucocorticoids. J. Biol. Chem., 269: 24527–24530, 1994.Google Scholar
  19. 19.
    Braissant, O., Foufelle, F., Scotto, C., Dauca, M., and Wahli, W. Differential expression of peroxisome proliferator-activated receptors (PPARs): tissue distribution of PPAR-alpha, -beta, and -gamma in the adult rat. Endocrinology, 137: 354–366, 1996.CrossRefGoogle Scholar
  20. 20.
    Tontonoz, P., Hu, E., and Spiegelman, B.M. Stimulation of adipogenesis in fibroblasts by PPAR gamma 2, a lipid-activated transcription factor [published erratum appears in Cell 1995 Mar 24;80(6):following 957]. Cell, 79: 1147–1156, 1994.CrossRefGoogle Scholar
  21. 21.
    Tontonoz, P., Hu, E., and Spiegelman, B.M. Regulation of adipocyte gene expression and differentiation by peroxisome proliferator activated receptor gamma. Curr. Opin. Genet. Dev., 5: 571–576, 1995.CrossRefGoogle Scholar
  22. 22.
    Lehmann, J.M., Moore, L.B., Smith-Oliver, T.A., Wilkison, W.O., Willson, T.M., and Kliewer, S.A. An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma). J. Biol. Chem., 270: 12953–12956, 1995.CrossRefGoogle Scholar
  23. 23.
    Goecke-Flora, C.M., Wyman, J.F., Jarnot, B.M., and Reo, N.V. Effect of the peroxisome proliferator perfluoro-n-decanoic acid on glucose transport in the isolated perfused rat liver. Chem. Res. Toxicol., 8: 77–81, 1995.CrossRefGoogle Scholar
  24. 24.
    Sher, T., Yi, H.F., McBride, O.W., and Gonzalez, F.J. cDNA cloning, chromosomal mapping, and functional characterization of the human peroxisome proliferator activated receptor. Biochemistry, 32: 5598–5604, 1993.Google Scholar
  25. 25.
    Muerhoff, A.S., Griffin, K.J., and Johnson, E.F. The peroxisome proliferator-activated receptor mediates the induction of CYP4A6, a cytochrome P450 fatty acid omega-hydroxylase, by clofibric acid. J. Biol. Chem., 267: 19051–19053, 1992.Google Scholar
  26. 26.
    Brandes, R., Kaikaus, R.M., Lysenko, N., Ockner, R.K., and Bass, N.M. Induction of fatty acid binding protein by peroxisome proliferators in primary hepatocyte cultures and its relationship to the induction of peroxisomal beta-oxidation. Biochim. Biophys. Acta, 1034: 53–61, 1990.CrossRefGoogle Scholar
  27. 27.
    Gulick, T., Cresci, S., Caira, T., Moore, D.D., and Kelly, D.P. The peroxisome proliferator-activated receptor regulates mitochondrial fatty acid oxidative enzyme gene expression. Proc. Natl. Acad. Sci. USA., 91: 11012–11016, 1994.Google Scholar
  28. 28.
    Rodriguez, J.C., Gil-Gomez, G., Hegardt, F.G., and Haro, D. Peroxisome proliferator-activated receptor mediates induction of the mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase gene by fatty acids. J. Biol. Chem., 269: 18767–18772, 1994.Google Scholar
  29. 29.
    Castelein, H., Gulick, T., Declercq, P.E., Mannaerts, G.P., Moore, D.D., and Baes, M.I. The peroxisome proliferator activated receptor regulates malic enzyme gene expression. J. Biol. Chem., 269: 26754–26758, 1994.Google Scholar
  30. 30.
    Kaikaus, R.M., Chan, W.K., Lysenko, N., Ray, R., Ortiz de Montellano, P.R., and Bass, N.M. Induction of peroxisomal fatty acid beta-oxidation and liver fatty acid-binding protein by peroxisome proliferators. Mediation via the cytochrome P-450IVAI omega-hydroxylase pathway. J. Biol. Chem., 268: 9593–9603, 1993.Google Scholar
  31. 31.
    Demoz, A., Vaagenes, H., Aarsaether, N., Hvattum, E., Skorve, J., Gottlicher, M., Lillehaug, J.R., Gibson, G.G., Gustafsson, J.A., and Hood, S. Coordinate induction of hepatic fatty acyl-CoA oxidase and P4504A 1 in rat after activation of the peroxisome proliferator-activated receptor (PPAR) by sulphur-substituted fatty acid analogues. Xenobiotica., 24: 943–956, 1994.CrossRefGoogle Scholar
  32. 32.
    Berge, R.K., Aarsland, A., Kryvi, H., Bremer, J., and Aarsaether, N. Alkylthioacetic acid (3-thia fatty acids) -a new group of non-beta-oxidizable, peroxisome-inducing fatty acid analogues. 1. A study on the structural requirements for proliferation of peroxisomes and mitochondria in rat liver. Biochim. Biophys. Acta, 1004: 345–356, 1989.Google Scholar
  33. 33.
    Kaikaus, R.M., Sui, Z., Lysenko, N., Wu, N.Y., Ortiz de Montellano, P.R., Ockner, R.K., and Bass, N.M. Regulation of pathways of extramitochondrial fatty acid oxidation and liver fatty acid-binding protein by long-chain monocarboxylic fatty acids in hepatocytes. Effect of inhibition of camitine palmitoyltransferase I. J. Biol. Chem., 268: 26866–26871, 1993.Google Scholar
  34. 34.
    Aldridge, T.C., Tugwood, J.D., and Green, S. Identification and characterization of DNA elements implicated in the regulation of CYP4A 1 transcription. Biochem. J., 306: 473–479, 1995.Google Scholar
  35. 35.
    Kliewer, S.A., Umesono, K., Noonan, D.J., Heyman, R.A., and Evans, R.M. Convergence of 9-cis retinoic acid and peroxisome proliferator signalling pathways through heterodimer formation of their receptors. Nature, 358: 771–774, 1992.CrossRefGoogle Scholar
  36. 36.
    Gearing, K.L., Gottlicher, M., Teboul, M., Widmark, E., and Gustafsson, J.A. Interaction of the peroxisome-proliferator-activated receptor and retinoid X receptor. Proc. Natl. Acad. Sci. USA., 90: 1440–1444, 1993.CrossRefGoogle Scholar
  37. 37.
    Huan, B., Kosovsky, M.J., and Siddiqui, A. Retinoid X receptor alpha transactivates the hepatitis B virus enhancer 1 element by forming a heterodimeric complex with the peroxisome proliferator-activated receptor. J. Virol., 69: 547–551, 1995.Google Scholar
  38. 38.
    Bogazzi, F., Hudson, L.D., and Nikodem, V.M. A novel heterodimerization partner for thyroid hormone receptor. Peroxisome proliferator-activated receptor. J. Biol. Chem. 269: 11683–11686, 1994.Google Scholar
  39. 39.
    Ladias, J.A. and Karathanasis, S.K. Regulation of the apolipoprotein Al gene by ARP-I, a novel member of the steroid receptor superfamily. Science, 251: 561–565, 1991.CrossRefGoogle Scholar
  40. 40.
    Ladias, J.A., Hadzopoulou-Cladaras, M., Kardassis, D., Cardot, P., Cheng, J., Zannis, V., and Cladaras, C. Transcriptional regulation of human apolipoprotein genes ApoB, ApoCIII, and ApoAII by members of the steroid hormone receptor superfamily HNF-4, ARP-1, EAR-2, and EAR-3. J. Biol. Chem., 267: 15849–15860, 1992.Google Scholar
  41. 41.
    Palmer, C.N., Hsu, M.H., Muerhoff, A.S., Griffin, K.J., and Johnson, E.F. Interaction of the peroxisome proliferator-activated receptor alpha with the retinoid X receptor alpha unmasks a cryptic peroxisome proliferator response element that overlaps an ARP-I-binding site in the CYP4A6 promoter. J. Biol. Chem., 269: 18083–18089, 1994.Google Scholar
  42. 42.
    Winrow, C.J., Marcus, S.L., Miyata, K.S., Zhang, B., Capone, J.P., and Rachubinski, R.A. Transactivation of the peroxisome proliferator-activated receptor is differentially modulated by hepatocyte nuclear factor-4. Gene Expr., 4: 53–62, 1994.Google Scholar
  43. 43.
    Carter, M.E., Gulick, T., Raisher, B.D., Caira, T., Ladias, J.A., Moore, D.D., and Kelly, D.P. Hepatocyte nuclear factor-4 activates medium chain acyl-CoA dehydrogenase gene transcription by interacting with a complex regulatory element. J. Biol. Chem., 268: 13805–13810, 1993.Google Scholar
  44. 44.
    Hertz, R., Bishara-Shieban, J., and Bar-Tana, J. Mode of action of peroxisome proliferators as bypolipidemic drugs. Suppression of apolipoprotein C-III. J. Biol. Chem., 270: 13470–13475, 1995.CrossRefGoogle Scholar
  45. 45.
    Staels, B., Van Tol, A., Andreu, T., and Auwerx, J. Fibrates influence the expression of genes involved in lipoprotein metabolism in a tissue-selective manner in the rat. Arterioscler. Thromb., 12: 286–294, 1992.CrossRefGoogle Scholar
  46. 46.
    Berthou, L., Saladin, R., Yaqoob, R, Calder, P., Fruchart, J.C., Denefle, P., Auwerx, J., and Staels, B. Regulation of rat liver apolipoprotein A-I, apolipoprotein A-II, and acyl-CoA oxidase gene expression by fibrates and dietary faty acids. Eur. J. Biochem., 232: 179–187, 1985.CrossRefGoogle Scholar
  47. 47.
    Staels, B., Van Tol, A., Skretting, G., and Auwerx, J. Lecithin:cholesterol acyltransferase gene expression is regulated in a tissue-selective manner by fibrates. J. Lipid. Res., 33: 727–735, 1992.Google Scholar
  48. 48.
    Bovard-Houppermans, S., Ochoa, A., Fruchart, J.C., and Zakin, M.M. Fenofibric acid modulates the human apolipoprotein A-IV gene expression in HepG2 cells. Biochem. Biophys. Res. Commun., 198: 764–769, 1994.Google Scholar
  49. 49.
    Schmidt, A., Endo, N., Rutledge, S.J., Vogel, R., Shinar, D., and Rodan, G.A. Identification of a new member of the steroid hormone receptor superfamily that is activated by a peroxisome proliferator and fatty acids. Mol. Endocrinol., 6: 1634–1641, 1992.CrossRefGoogle Scholar
  50. 50.
    Mellies, M.J., Stein, E.A, Khoury, R, Lamkin, G., and Glueck, C.J. Effects of fenofibrate on lipids, lipoproteins and apolipoproteins in 33 subjects with primary hypercholesterolaemia. Atherosclerosis 78: 167–182, 1989.CrossRefGoogle Scholar
  51. 51.
    Vu-Dac, N., Schoonjans, K., Laine, B., Fruchart, J.C., Auwerx, J., and Staels, B. Negative regulation of the human apolipoprotein A-I promoter by fibrates can be attenuated by the interaction of the peroxisome proliferator-activated receptor with its response element. J. Biol. Chem., 269: 31012–31018, 1994.Google Scholar
  52. 52.
    Reddy, J.K., Azamoff, D.L., and Hignite, C.E. Hypolipidaemic hepatic peroxisome proliferators form a novel class of chemical carcinogens. Nature, 283: 397–398, 1980.CrossRefGoogle Scholar
  53. 53.
    Reddy, J.K., Scarpelli, D.G., Subbarao, V., and Lalwani, N.D. Chemical carcinogens without mutagenic activity: peroxisome proliferators as a prototype. Toxicol. Pathol., 11: 172–180, 1983.CrossRefGoogle Scholar
  54. 54.
    Reddy, J.K. and Lalwani, N.D. Carcinogenesis by hepatic peroxisome proliferators: evaluation of the risk of hypolipidemic drugs and industrial plasticizers to humans. Crit. Rev. Toxicol., 12: 1–58, 1993.CrossRefGoogle Scholar
  55. 55.
    Reddy, J.K. and Rao, M.S. Peroxisome proliferators and cancer: mechanisms and implications. Trends. Pharmacol. Sci., 7: 631–636, 1996.Google Scholar
  56. 56.
    Rao, M.S., Kokkinakis, D.M., Subbarao, V., and Reddy, J.K. Peroxisome proliferator-induced hepatocarcinogenesis: levels of activating and detoxifying enzymes in hepatocellular carcinomas induced by ciprofibrate. Carcinogenesis, 8: 19–23, 1987.CrossRefGoogle Scholar
  57. 57.
    Warren, J.R., Simmon, V.F., and Reddy, J.K. Properties of hypolipidemic peroxisome proliferators in the lymphocyte [31I]thymidine and Salmonella mutagenesis assays. Cancer Res., 40: 36–41, 1980.Google Scholar
  58. 58.
    Glauert, H.P. Reddy, J.K., Kennan, W.S., Sattler, G.L., Rao, V.S., and Pitot, H.C. Effect of hypolipidemic peroxisome proliferators on unscheduled DNA synthesis in cultured hepatocytes and on mutagenesis in Salmonella. Cancer Lett., 24: 147–156, 1984.Google Scholar
  59. 59.
    Yoshikawa, K., Tanaka, A., Yamaha, T., and Kurata, H. Mutagenicity study of nine monoalkyl phthalates and a dialkyl phthalate using Salmonella typhimurium and Escherichia coli. Food. Chem. Toxicol., 21: 221–223, 1983.CrossRefGoogle Scholar
  60. 60.
    Agarwal, D.K., Lawrence, W.H., Nunez, L.J., and Autian, J. Mutagenicity evaluation of phthalic acid esters and metabolites in Salmonella typhimurium cultures. J. Toxicol. Environ. Health, 16: 61–69, 1985.CrossRefGoogle Scholar
  61. 61.
    Cattley, R.C., Smith-Oliver, T., Butterworth, B.E., and Popp, J.A. Failure of the peroxisome proliferator WY-14,643 to induce unscheduled DNA synthesis in rat hepatocytes following in vivo treatment. Carcinogenesis, 9: 1179–1183. 1988.CrossRefGoogle Scholar
  62. 62.
    Williams, G.M., Maruyama, H., and Tanaka. T. Lack of rapid initiating, promoting or sequential syncarcinogenic effects of di(2-ethylhexyl)phthalate in rat liver carcinogenesis. Carcinogenesis, 8: 875–880, 1987.CrossRefGoogle Scholar
  63. 63.
    Cattley, R.C., Marsman, D.S., and Popp, J.A. Failure of the peroxisome proliferator WY-14,643 to initiate growth-selectable foci in rat liver. Toxicology., 56: 1–7, 1989.CrossRefGoogle Scholar
  64. 64.
    Conway, J.G., Tomaszewski, K.E., Olson, M.J., Cattley, R.C., Marsman, D.S., and Popp, J.A. Relationship of oxidative damage to the hepatocarcinogenicity of the peroxisome proliferators di(2-ethylhexyl)phthalate and Wy-14,643. Carcinogenesis, 10: 513–519, 1989.CrossRefGoogle Scholar
  65. 65.
    Marsman, D.S., Goldsworthy, T.L., and Popp, J.A. Contrasting hepatocytic peroxisome proliferation, lipofuscin accumulation and cell turnover for the hepatocarcinogens Wy-14,643 and clofibric acid. Carcinogenesis, 13: 1011–1017, 1992.CrossRefGoogle Scholar
  66. 66.
    Kasai, H. Okada, Y., Nishimura, S., Rao, M.S., and Reddy, J.K. Formation of 8-hydroxydeoxyguanosine in liver DNA of rats following long-term exposure to a peroxisome proliferator. Cancer Res., 49: 2603–2605, 1989.Google Scholar
  67. 67.
    Takagi, A., Sai, K., Umemura, T., Hasegawa, R., and Kurokawa, Y. Relationship between hepatic peroxisome proliferation and 8-hydroxydeoxyguanosine formation in liver DNA of rats following long-term exposure to three peroxisome proliferators; di(2-ethylhexyl) phthalate, aluminium clofibrate and simfibrate. Cancer Lett., 53: 33–38, 1990.CrossRefGoogle Scholar
  68. 68.
    Hegi, M.E., Ulrich, D., Sagelsdorff, R, Richter, C., and Lutz, W.K. No measurable increase in thymidine glycol or 8-hydroxydeoxyguanosine in liver DNA of rats treated with nafenopin or choline-devoid lowmethionine diet. Mutat. Res., 238: 325–329, 1990.CrossRefGoogle Scholar
  69. 69.
    Cattley, R.C. and Glover, S.E. Elevated 8-hydroxydeoxyguanosine in hepatic DNA of rats following exposure to peroxisome proliferators: relationship to carcinogenesis and nuclear localization. Carcinogenesis, 14: 2495–2499, 1993.CrossRefGoogle Scholar
  70. 70.
    Chu, S., Huang, Q., Alvares, K., Yeldandi, A.V., Rao, M.S., and Reddy, J.K. Transformation of mammalian cells by overexpressing H,02-generating peroxisomal fatty acyl-CoA oxidase. Proc. Natl. Acad. Sci. USA, 92: 7080–7084, 1995.CrossRefGoogle Scholar
  71. 71.
    Mikalsen, S.O., Holen, I., and Sanner, T. Morphological transformation and catalase activity of Syrian hamster embryo cells treated with hepatic peroxisome proliferators, TPA and nickel sulphate. Cell Biol. Toxicol., 6: 1–13, 1990.Google Scholar
  72. 72.
    Tsutsui, T., Watanabe, E., and Barrett, J.C. Ability of peroxisome proliferators to induce cell transformation, chromosome aberrations and peroxisome proliferation in cultured Syrian hamster embryo cells. Carcinogenesis, 14: 611–618, 1993.CrossRefGoogle Scholar
  73. 73.
    Cattley, R.C., Marsman, D.S., and Popp, J.A. Age-related susceptibility to the carcinogenic effect of the peroxisome proliferator WY-14,643 in rat liver. Carcinogenesis (in press), 1996.Google Scholar
  74. 74.
    Farber, E. Experimental induction of hepatocellular carcinoma as a paradigm for carcinogenesis. Clin. Physiol. Biochem., 5: 152–159, 1987.Google Scholar
  75. 75.
    Moody, D.E., Rao, M.S., and Reddy, J.K. Mitogenic effect in mouse liver induced by a hypolipidemic drug, nafenopin. Virchows Arch. B. Cell Pathol., 23: 291–296, 1977.Google Scholar
  76. 76.
    Marsman, D.S., Cattley, R.C., Conway, J.G., and Popp, J.A. 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. Cancer Res., 48: 6739–6744, 1988.Google Scholar
  77. 77.
    Reddy, J.K., Reddy, M.K., Usman, M.I., Lalwani, N.D., and Rao, M.S. Comparison of hepatic peroxisome proliferative effect and its implication for hepatocarcinogenicity of phthalate esters, di(2-ethylhexyl) phthalate, and di(2-ethylhexyl) adipate with a hypolipidemic drug. Environ. Health Perspect., 65: 3I7–327, 1986.Google Scholar
  78. 78.
    Tomaszewski, K.E., Agarwal, D.K., and Melnick, R.L. In vitro steady-state levels of hydrogen peroxide after exposure of male F344 rats and female B6C3F I mice to hepatic peroxisome proliferators. Carcinogenesis, 7: 1871–1876, 1986.Google Scholar
  79. 79.
    Barrett, J.C. Mechanisms for species differences in receptor-mediated carcinogenesis. Mutat. Res., 333: 189–202, 1995.CrossRefGoogle Scholar
  80. 80.
    Bayly, A.C., Roberts, R.A., and Dive, C. Suppression of liver cell apoptosis in vitro by the non-genotoxic hepatocarcinogen and peroxisome proliferator nafenopin. J. Cell Biol., 125: 197–203, 1994.CrossRefGoogle Scholar
  81. 81.
    Roberts, R.A., Soames, A.R., Gill, J.H., James, N.H., and Wheeldon, E.B. Non-genotoxic hepatocarcinogens stimulate DNA synthesis and their withdrawal induces apoptosis, but in different hepatocyte populations. Carcinogenesis, 16: 1693–1698, 1995.CrossRefGoogle Scholar
  82. 82.
    James, N.H. and Roberts, R.A. The peroxisome proliferator class of non-genotoxic hepatocarcinogens synergize with epidermal growth factor to promote clonal expansion of initiated rat hepatocytes. Carcinogenesis, 15: 2687–2694, 1994.CrossRefGoogle Scholar
  83. 83.
    Lake, B.G., Evans, J.G., Gray, T.J., Korosi, S.A., and North, C.J. Comparative studies on nafenopin-induced hepatic peroxisome proliferation in the rat, Syrian hamster, guinea pig, and marmoset. Toxicol. Appl. Pharmacol., 99: 148–160, 1989.CrossRefGoogle Scholar
  84. 84.
    Reddy, J.K. and Rao, M.S. Peroxisome proliferation and hepatocarcinogenesis. 1992.Google Scholar
  85. 85.
    Varanasi, U., Chu, R., Huang, Q., Castellon, R., Yeldandi, A.V., and Reddy, J.K. Identification of a peroxisome proliferator-responsive element upstream of the human peroxisomal fatty acyl coenzyme A oxidase gene. J. Biol. Chem., 271: 2147–2155, 1996.CrossRefGoogle Scholar
  86. 86.
    Hardwick, J.P., Song, B.J., Huberman, E., and Gonzalez, F.J. Isolation, complementary DNA sequence, and regulation of rat hepatic lauric acid omega-hydroxylase (cytochrome P-450LA omega). Identification of a new cytochrome P-450 gene family. J. Biol. Chem., 262: 801–810, 1987.Google Scholar
  87. 87.
    Lee, S.S., Pineau, T., Drago, J., Lee, E.J., Owens, J.W., Kroetz, D.L., Fernandez-Salguero, P.M., Westphal, H., and Gonzalez, F.J. 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. Mol. Cell Biol., 15: 3012–3022, 1995.Google Scholar
  88. 88.
    Gonzalez, F.J., Fernandez-Salguero, P., Lee, S.S., Pineau, T., and Ward, J.M. Xenobiotic receptor knockout mice. Toxicol. Lett., 82–83: 117–121, 1995.Google Scholar
  89. 89.
    Lemberger, T. Saladin, R., Vazquez, M., Assimacopoulos, F., Staels, B., Desvergne, B., Wahli, W., and Auwerx, J. Expression of the peroxisome proliferator-activated receptor alpha gene is stimulated by stress and follows a diurnal rhythm. J. Biol. Chem., 271: 1764–1769, 1996.Google Scholar
  90. 90.
    Issemann, I. and Green, S. Cloning of novel members of the steroid hormone receptor superfamily. J. Steroid. Biochem. Mol. Biol., 40: 263–269, 1991.Google Scholar
  91. 91.
    Yamada, J., Sakuma, M., Ikeda, T., and Suga, T. Activation of dehydroepiandrosterone as a peroxisome proliferator by sulfate conjugation. Arch. Biochem. Biophys., 313: 379–381, 1994.CrossRefGoogle Scholar
  92. 92.
    Yamada, J., Sakuma, M., Ikeda, T., Fukuda, K., and Suga, T. Characteristics of dehydroepiandrosterone as a peroxisome proliferator. Biochim. Biophys. Acta, 1092: 233–243, 1991.CrossRefGoogle Scholar
  93. 93.
    Frenkel, R.A., Slaughter, C.A., Orth, K., Moomaw, C.R., Hicks, S.H., Snyder, J.M., Bennett, M., Prough, R.A., Putnam, R.S., and Milewich, L. Peroxisome proliferation and induction of peroxisomal enzymes in mouse and rat liver by dehydroepiandrosterone feeding. J. Steroid. Biochem., 35: 333–342, 1990.CrossRefGoogle Scholar
  94. 94.
    Hayashi, F., Tamura, H., Yamada, J., Kasai, H., and Suga, T. Characteristics of the hepatocarcinogenesis caused by dehydroepiandrosterone, a peroxisome proliferator, in male F-344 rats. Carcinogenesis, 15: 2215–2219, 1994.CrossRefGoogle Scholar
  95. 95.
    Shibata, M., Hasegawa, R., Imaida, K., Hagiwara, A., Ogawa, K., Hirose, M., Ito, N., and Shirai, T. Chemoprevention by dehydroepiandrosterone and indomethacin in a rat multiorgan carcinogenesis model. Cancer Res., 55: 4870–4874, 1995.Google Scholar
  96. 96.
    Gordon, G.B., Helzlsouer, K.J., and Comstock, G.W. Serum levels of dehydroepiandrosterone and its sulfate and the risk of developing bladder cancer. Cancer Res., 51: 1366–1369, 1991.Google Scholar
  97. 97.
    Waxman, D.J. Role of metabolism in the activation of dehydroepiandrosterone as a peroxisome prolifera-tor. Mol. Pharmacol., 50: 67–74, 1996.Google Scholar
  98. 98.
    Ledwith, B.J., Johnson, T.E., Wagner, L.K., Pauley, C.J., Manam, S., Galloway, S.M., and Nichols, W.W. Growth regulation by peroxisome proliferators:opposing activities in early and late GI. Cancer Res., 56: 3257–3264, 1996.Google Scholar
  99. 99.
    Schulz, S. and Nyce, J.W. Inhibition of protein farnesyltransferase: a possible mechanism of tumor prevention by dehydroepiandrosterone sulfate [published erratum appears in Carcinogenesis 1995 Jan;16(1):149] [retracted by Nyce JW. In: Carcinogenesis 1995 May;16(5):1257]. Carcinogenesis, 15: 2649–2652, 1994.Google Scholar
  100. 100.
    Nyce, J.W. Inhibition of protein farnesyltransferase: a possible mechanism of tumor prevention for dehydroepiandrosterone sulfate [retraction of Schulz S, Nyce JW. In: Carcinogenesis 1994 Nov;15(11):2649–52]. Carcinogenesis, 16: 1257, 1995.Google Scholar
  101. 101.
    Peters, J.M., Zhou, Y.C., Ram, P.A., Lee, S.S.T., Gonzalez, F.J., and Waxman, D.J. Peroxisome proliferator-activated receptor alpha required for gene induction by dehydroepiandrosterone-3-beta-sulfate. Mol. Pharmacol., 50: 67–74, 1996.Google Scholar
  102. 102.
    Thibault, A., Cooper, M.R., Figg, W.D., Venzon, D.J., Sartor, A.O., Tompkins, A.C., Weinberger, M.S., Headlee, D.J., McCall, N.A., and Samid, D. A phase 1 and pharmacokinetic study of intravenous phenylacetate in patients with cancer. Cancer Res., 54: 1690–1694, 1994.Google Scholar
  103. 103.
    Samid, D., Shack, S., and Myers, C.E. Selective growth arrest and phenotypic reversion of prostate cancer cells in vitro by nontoxic pharmacological concentrations of phenylacetate. J. Clin. Invest., 91: 2288–2295, 1993.CrossRefGoogle Scholar
  104. 104.
    Samid, D., Rani, Z., Hudgins, W.R., Shack, S., Liu, L., Walbridge, S., Oldfield, E.H., and Myers, C.E. Selective activity of phenylacetate against malignant gliomas: resemblance to fetal brain damage in phenylketonuria. Cancer Res., 54: 891–895, 1994.Google Scholar
  105. 105.
    Liu, L., Shack, S., Stetler-Stevenson, W.G., Hudgins, W.R., and Samid, D. Differentiation of cultured human melanoma cells induced by the aromatic fatty acids phenylacetate and phenylbutyrate. J. Invest. Dermatol., 103: 335–340, 1994.CrossRefGoogle Scholar
  106. 106.
    Stockhammer, G., Manley, G.T., Johnson, R., Rosenblum, M.K., Samid, D., and Liebennan, F.S. Inhibition of proliferation and induction of differentiation in medulloblastoma-and astrocytoma-derived cell lines with phenylacetate. J. Neurosurg., 83: 672–681, 1995.CrossRefGoogle Scholar
  107. 107.
    Lipschutz, J.H., Samid, D., and Cunha, G.R. Phenylacetate is an inhibitor of prostatic growth and development in organ culture. J. Urol., 155: 1762–1770, 1996.CrossRefGoogle Scholar
  108. 108.
    Pineau, T., Hudgins, W.R., Liu, L., Chen, L.C., Sher, T., Gonzalez, F.J., and Samid, D. Activation of a human peroxisome proliferator-activated receptor by the antitumor agent phenylacetate and its analogs. Biochem. Pharmacol., 52: 659–667, 1996.CrossRefGoogle Scholar
  109. 109.
    Forman, B.M., Tontonoz, P., Chen, J., Brun, R.P., Spiegelman, B.M., and Evans, R.M. 15-Deoxy-delta 12, 14-prostaglandin J2 is a ligand for the adipocyte determination factor PPAR gamma. Cell, 83: 803–812, 1995.CrossRefGoogle Scholar
  110. 110.
    Yu, K., Bayona, W., Kallen, C.B., Harding, H.P., Rayera, C.P., McMahon, G., Brown, M., and Lazar, M.A. Differential activation of peroxisome proliferator-activated receptors by eicosanoids. J. Biol. Chem., 270: 23975–23983, 1995.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1997

Authors and Affiliations

  • Feank J. Gonzalez
    • 1
    • 2
  1. 1.Laboratory of Metabolism Division of Sciences National Cancer InstituteNational Institutes of HealthBethesdaUSA
  2. 2.National Institutes of HealthBethesdaUSA

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