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. 1991 Jun;93:205–209. doi: 10.1289/ehp.9193205

An overview of peroxisome proliferator-induced hepatocarcinogenesis.

M S Rao 1, J K Reddy 1
PMCID: PMC1568067  PMID: 1685443

Abstract

Peroxisome proliferators are hepatocarcinogens in rats and mice. Chronic administration of these compounds results in the development of altered areas and neoplastic nodules followed by hepatocellular carcinomas. All three types of hepatic lesions do not express gamma-glutamyltranspeptidase, glutathione 8-transferase-P, and alpha-fetoprotein and are resistant to iron accumulation after overload. The mechanism by which nongenotoxic peroxisome proliferators induce hepatic tumors is not well understood. It has been proposed that with continuous administration of peroxisome proliferators, liver cells are subjected to persistent oxidative stress resulting from marked proliferation of peroxisomes and a differential increase in the levels of H2O2 producing (20- to 30-fold) and degrading (2-fold) enzymes. Free oxygen radicals lead to DNA damage (both directly and through lipid peroxidation) and thus may cause initiation and promotion of the carcinogenic process.

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Selected References

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  1. Ames B. N., Magaw R., Gold L. S. Ranking possible carcinogenic hazards. Science. 1987 Apr 17;236(4799):271–280. doi: 10.1126/science.3563506. [DOI] [PubMed] [Google Scholar]
  2. Butterworth B. E., Loury D. J., Smith-Oliver T., Cattley R. C. The potential role of chemically induced hyperplasia in the carcinogenic activity of the hypolipidemic carcinogens. Toxicol Ind Health. 1987 Jun;3(2):129–149. doi: 10.1177/074823378700300210. [DOI] [PubMed] [Google Scholar]
  3. Ciriolo M. R., Mavelli I., Rotilio G., Borzatta V., Cristofari M., Stanzani L. Decrease of superoxide dismutase and glutathione peroxidase in liver of rats treated with hypolipidemic drugs. FEBS Lett. 1982 Aug 2;144(2):264–268. doi: 10.1016/0014-5793(82)80651-0. [DOI] [PubMed] [Google Scholar]
  4. Clayson D. B. International Commission for Protection Against Environmental Mutagens and Carcinogens. ICPEMC publication No. 17. Can a mechanistic rationale be provided for non-genotoxic carcinogens identified in rodent bioassays? Mutat Res. 1989 Jul;221(1):53–67. doi: 10.1016/0165-1110(89)90045-6. [DOI] [PubMed] [Google Scholar]
  5. Cohen A. J., Grasso P. Review of the hepatic response to hypolipidaemic drugs in rodents and assessment of its toxicological significance to man. Food Cosmet Toxicol. 1981 Oct;19(5):585–605. doi: 10.1016/0015-6264(81)90509-5. [DOI] [PubMed] [Google Scholar]
  6. Columbano A., Ledda-Columbano G. M., Lee G., Rajalakshmi S., Sarma D. S. Inability of mitogen-induced liver hyperplasia to support the induction of enzyme-altered islands induced by liver carcinogens. Cancer Res. 1987 Nov 1;47(21):5557–5559. [PubMed] [Google Scholar]
  7. DRUCKREY H., SCHILDBACH A., SCHMAEHL D., PREUSSMANN R., IVANKOVIC S. QUANTITATIVE ANALYSE DER CARCINOGENEN WIRKUNG VON DIAETHYLNITROSAMIN. Arzneimittelforschung. 1963 Oct;13:841–851. [PubMed] [Google Scholar]
  8. Elcombe C. R., Rose M. S., Pratt I. S. Biochemical, histological, and ultrastructural changes in rat and mouse liver following the administration of trichloroethylene: possible relevance to species differences in hepatocarcinogenicity. Toxicol Appl Pharmacol. 1985 Jul;79(3):365–376. doi: 10.1016/0041-008x(85)90135-8. [DOI] [PubMed] [Google Scholar]
  9. Elliott B. M., Dodd N. J., Elcombe C. R. Increased hydroxyl radical production in liver peroxisomal fractions from rats treated with peroxisome proliferators. Carcinogenesis. 1986 May;7(5):795–799. doi: 10.1093/carcin/7.5.795. [DOI] [PubMed] [Google Scholar]
  10. Fitzgerald J. E., Sanyer J. L., Schardein J. L., Lake R. S., McGuire E. J., de la Iglesia F. A. Carcinogen bioassay and mutagenicity studies with the hypolipidemic agent gemfibrozil. J Natl Cancer Inst. 1981 Nov;67(5):1105–1116. [PubMed] [Google Scholar]
  11. Glauert H. P., Beer D., Rao M. S., Schwarz M., Xu Y. D., Goldsworthy T. L., Coloma J., Pitot H. C. Induction of altered hepatic foci in rats by the administration of hypolipidemic peroxisome proliferators alone or following a single dose of diethylnitrosamine. Cancer Res. 1986 Sep;46(9):4601–4606. [PubMed] [Google Scholar]
  12. Gold L. S., Sawyer C. B., Magaw R., Backman G. M., de Veciana M., Levinson R., Hooper N. K., Havender W. R., Bernstein L., Peto R. A carcinogenic potency database of the standardized results of animal bioassays. Environ Health Perspect. 1984 Dec;58:9–319. doi: 10.1289/ehp.84589. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Gray R. H., de la Iglesia F. A. Quantitative microscopy comparison of peroxisome proliferation by the lipid-regulating agent gemfibrozil in several species. Hepatology. 1984 May-Jun;4(3):520–530. doi: 10.1002/hep.1840040328. [DOI] [PubMed] [Google Scholar]
  14. Kasai H., Okada Y., Nishimura S., Rao M. S., Reddy J. K. Formation of 8-hydroxydeoxyguanosine in liver DNA of rats following long-term exposure to a peroxisome proliferator. Cancer Res. 1989 May 15;49(10):2603–2605. [PubMed] [Google Scholar]
  15. Kluwe W. M., Huff J. E., Matthews H. B., Irwin R., Haseman J. K. Comparative chronic toxicities and carcinogenic potentials of 2-ethylhexyl-containing compounds in rats and mice. Carcinogenesis. 1985 Nov;6(11):1577–1583. doi: 10.1093/carcin/6.11.1577. [DOI] [PubMed] [Google Scholar]
  16. Lake B. G., Gray T. J., Gangolli S. D. Hepatic effects of phthalate esters and related compounds--in vivo and in vitro correlations. Environ Health Perspect. 1986 Aug;67:283–290. doi: 10.1289/ehp.8667283. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Lalwani N. D., Alvares K., Reddy M. K., Reddy M. N., Parikh I., Reddy J. K. Peroxisome proliferator-binding protein: identification and partial characterization of nafenopin-, clofibric acid-, and ciprofibrate-binding proteins from rat liver. Proc Natl Acad Sci U S A. 1987 Aug;84(15):5242–5246. doi: 10.1073/pnas.84.15.5242. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Lalwani N. D., Reddy M. K., Qureshi S. A., Sirtori C. R., Abiko Y., Reddy J. K. Evaluation of selected hypolipidemic agents for the induction of peroxisomal enzymes and peroxisome proliferation in the rat liver. Hum Toxicol. 1983 Jan;2(1):27–48. doi: 10.1177/096032718300200103. [DOI] [PubMed] [Google Scholar]
  19. Lijinsky W., Reuber M. D., Blackwell B. N. Liver tumors induced in rats by oral administration of the antihistaminic methapyrilene hydrochloride. Science. 1980 Aug 15;209(4458):817–819. doi: 10.1126/science.7403848. [DOI] [PubMed] [Google Scholar]
  20. Loeb L. A. Endogenous carcinogenesis: molecular oncology into the twenty-first century--presidential address. Cancer Res. 1989 Oct 15;49(20):5489–5496. [PubMed] [Google Scholar]
  21. Machlin L. J., Bendich A. Free radical tissue damage: protective role of antioxidant nutrients. FASEB J. 1987 Dec;1(6):441–445. [PubMed] [Google Scholar]
  22. Marsman D. S., Cattley R. C., Conway J. G., 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. 1988 Dec 1;48(23):6739–6744. [PubMed] [Google Scholar]
  23. Menghini R. Genotoxicity of active oxygen species in mammalian cells. Mutat Res. 1988 May;195(3):215–230. [PubMed] [Google Scholar]
  24. Miller E. C. Some current perspectives on chemical carcinogenesis in humans and experimental animals: Presidential Address. Cancer Res. 1978 Jun;38(6):1479–1496. [PubMed] [Google Scholar]
  25. Moody D. E., Reddy J. K. Morphometric analysis of the ultrastructural changes in rat liver induced by the peroxisome proliferator SaH 42-348. J Cell Biol. 1976 Dec;71(3):768–780. doi: 10.1083/jcb.71.3.768. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Nemali M. R., Usuda N., Reddy M. K., Oyasu K., Hashimoto T., Osumi T., Rao M. S., Reddy J. K. Comparison of constitutive and inducible levels of expression of peroxisomal beta-oxidation and catalase genes in liver and extrahepatic tissues of rat. Cancer Res. 1988 Sep 15;48(18):5316–5324. [PubMed] [Google Scholar]
  27. Olson M. J. DNA strand breaks induced by hydrogen peroxide in isolated rat hepatocytes. J Toxicol Environ Health. 1988;23(3):407–423. doi: 10.1080/15287398809531123. [DOI] [PubMed] [Google Scholar]
  28. Pool B. L., Schmähl D. What's new in mutagenicity and carcinogenicity--status of short-term assay systems as tools in genetic toxicology and carcinogenesis. Pathol Res Pract. 1987 Oct;182(5):704–712. [PubMed] [Google Scholar]
  29. Popp J. A., Scortichini B. H., Garvey L. K. Quantitative evaluation of hepatic foci of cellular alteration occurring spontaneously in Fischer-344 rats. Fundam Appl Toxicol. 1985 Apr;5(2):314–319. doi: 10.1016/0272-0590(85)90079-x. [DOI] [PubMed] [Google Scholar]
  30. Rao M. S., Dwivedi R. S., Subbarao V., Reddy J. K. Induction of peroxisome proliferation and hepatic tumours in C57BL/6N mice by ciprofibrate, a hypolipidaemic compound. Br J Cancer. 1988 Jul;58(1):46–51. doi: 10.1038/bjc.1988.159. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Rao M. S., Kokkinakis D. M., Subbarao V., Reddy J. K. Peroxisome proliferator-induced hepatocarcinogenesis: levels of activating and detoxifying enzymes in hepatocellular carcinomas induced by ciprofibrate. Carcinogenesis. 1987 Jan;8(1):19–23. doi: 10.1093/carcin/8.1.19. [DOI] [PubMed] [Google Scholar]
  32. Rao M. S., Lalwani N. D., Reddy J. K. Sequential histologic study of rat liver during peroxisome proliferator [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio]-acetic acid (Wy-14,643)-induced carcinogenesis. J Natl Cancer Inst. 1984 Oct;73(4):983–990. [PubMed] [Google Scholar]
  33. Rao M. S., Nemali M. R., Usuda N., Scarpelli D. G., Makino T., Pitot H. C., Reddy J. K. Lack of expression of glutathione-S-transferase P, gamma-glutamyl transpeptidase, and alpha-fetoprotein messenger RNAs in liver tumors induced by peroxisome proliferators. Cancer Res. 1988 Sep 1;48(17):4919–4925. [PubMed] [Google Scholar]
  34. Rao M. S., Reddy J. K. Peroxisome proliferation and hepatocarcinogenesis. Carcinogenesis. 1987 May;8(5):631–636. doi: 10.1093/carcin/8.5.631. [DOI] [PubMed] [Google Scholar]
  35. Rao M. S., Subbarao V., Reddy J. K. Increased resistance of peroxisome proliferator-induced hepatic lesions to iron overload in rats. Cancer Lett. 1986 Jul;32(1):33–39. doi: 10.1016/0304-3835(86)90036-4. [DOI] [PubMed] [Google Scholar]
  36. Rao M. S., Tatematsu M., Subbarao V., Ito N., Reddy J. K. Analysis of peroxisome proliferator-induced preneoplastic and neoplastic lesions of rat liver for placental form of glutathione S-transferase and gamma-glutamyltranspeptidase. Cancer Res. 1986 Oct;46(10):5287–5290. [PubMed] [Google Scholar]
  37. Reddy J. K., Azarnoff D. L., Hignite C. E. Hypolipidaemic hepatic peroxisome proliferators form a novel class of chemical carcinogens. Nature. 1980 Jan 24;283(5745):397–398. doi: 10.1038/283397a0. [DOI] [PubMed] [Google Scholar]
  38. Reddy J. K., Goel S. K., Nemali M. R., Carrino J. J., Laffler T. G., Reddy M. K., Sperbeck S. J., Osumi T., Hashimoto T., 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 U S A. 1986 Mar;83(6):1747–1751. doi: 10.1073/pnas.83.6.1747. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Reddy J. K., Krishnakantha T. P., Azarnoff D. L., Moody D. E. 1-methyl-4piperidyl-bis (P-chlorophenoxy) acetate: a new hypolipidemic peroxisome proliferator. Res Commun Chem Pathol Pharmacol. 1975 Mar;10(3):589–592. [PubMed] [Google Scholar]
  40. Reddy J. K., Lalwai N. D. Carcinogenesis by hepatic peroxisome proliferators: evaluation of the risk of hypolipidemic drugs and industrial plasticizers to humans. Crit Rev Toxicol. 1983;12(1):1–58. doi: 10.3109/10408448309029317. [DOI] [PubMed] [Google Scholar]
  41. Reddy J. K., Rao M. S. Enhancement by Wy-14,643, a hepatic peroxisome proliferator, of diethylnitrosamine-initiated hepatic tumorigenesis in the rat. Br J Cancer. 1978 Oct;38(4):537–543. doi: 10.1038/bjc.1978.241. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Reddy J. K., Rao M. S. Oxidative DNA damage caused by persistent peroxisome proliferation: its role in hepatocarcinogenesis. Mutat Res. 1989 Sep;214(1):63–68. doi: 10.1016/0027-5107(89)90198-x. [DOI] [PubMed] [Google Scholar]
  43. Reddy J. K., Rao S., Moody D. E. Hepatocellular carcinomas in acatalasemic mice treated with nafenopin, a hypolipidemic peroxisome proliferator. Cancer Res. 1976 Apr;36(4):1211–1217. [PubMed] [Google Scholar]
  44. Reddy J. K., Reddy M. K., Usman M. I., Lalwani N. D., 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. 1986 Mar;65:317–327. doi: 10.1289/ehp.8665317. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Reddy J. K., Scarpelli D. G., Subbarao V., Lalwani N. D. Chemical carcinogens without mutagenic activity: peroxisome proliferators as a prototype. Toxicol Pathol. 1983;11(2):172–180. doi: 10.1177/019262338301100209. [DOI] [PubMed] [Google Scholar]
  46. Tamburini P. P., Masson H. A., Bains S. K., Makowski R. J., Morris B., Gibson G. G. Multiple forms of hepatic cytochrome P-450. Purification, characterisation and comparison of a novel clofibrate-induced isozyme with other major forms of cytochrome P-450. Eur J Biochem. 1984 Mar 1;139(2):235–246. doi: 10.1111/j.1432-1033.1984.tb07999.x. [DOI] [PubMed] [Google Scholar]
  47. Tomaszewski K. E., Agarwal D. K., Melnick R. L. In vitro steady-state levels of hydrogen peroxide after exposure of male F344 rats and female B6C3F1 mice to hepatic peroxisome proliferators. Carcinogenesis. 1986 Nov;7(11):1871–1876. doi: 10.1093/carcin/7.11.1871. [DOI] [PubMed] [Google Scholar]
  48. Vainio H., Linnainmaa K., Kähönen M., Nickels J., Hietanen E., Marniemi J., Peltonen P. Hypolipidemia and peroxisome proliferation induced by phenoxyacetic acid herbicides in rats. Biochem Pharmacol. 1983 Sep 15;32(18):2775–2779. doi: 10.1016/0006-2952(83)90091-6. [DOI] [PubMed] [Google Scholar]
  49. Wu H. Q., Masset-Brown J., Tweedie D. J., Milewich L., Frenkel R. A., Martin-Wixtrom C., Estabrook R. W., Prough R. A. Induction of microsomal NADPH-cytochrome P-450 reductase and cytochrome P-450IVA1 (P-450LA omega) by dehydroepiandrosterone in rats: a possible peroxisomal proliferator. Cancer Res. 1989 May 1;49(9):2337–2343. [PubMed] [Google Scholar]
  50. Yeldandi A. V., Milano M., Subbarao V., Reddy J. K., Rao M. S. Evaluation of liver cell proliferation during ciprofibrate-induced hepatocarcinogenesis. Cancer Lett. 1989 Sep 15;47(1-2):21–27. doi: 10.1016/0304-3835(89)90172-9. [DOI] [PubMed] [Google Scholar]
  51. Yeldandi A. V., Subbarao V., Rajan A., Reddy J. K., Rao M. S. gamma-Glutamyltranspeptidase-negative phenotypic property of preneoplastic and neoplastic liver lesions induced by ciprofibrate does not change following 2-acetylaminofluorene administration. Carcinogenesis. 1989 Apr;10(4):797–799. doi: 10.1093/carcin/10.4.797. [DOI] [PubMed] [Google Scholar]
  52. Yokoyama S., Sells M. A., Reddy T. V., Lombardi B. Hepatocarcinogenic and promoting action of a choline-devoid diet in the rat. Cancer Res. 1985 Jun;45(6):2834–2842. [PubMed] [Google Scholar]
  53. de Duve C. Microbodies in the living cell. Sci Am. 1983 May;248(5):74–84. doi: 10.1038/scientificamerican0583-74. [DOI] [PubMed] [Google Scholar]

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