The Liver

  • Chirukandath Gopinath
  • Vasanthi Mowat


Importance of hepatotoxicity in toxicity studies is briefly discussed. Various induced lesions occurring in the liver of experimental animals, such as degeneration, necrosis, inclusions, pigmentation, hypertrophy, hyperplasia, and tumours, are illustrated, and their relative importance is discussed. Significance of adaptive responses is also discussed.


Bile Duct Kupffer Cell Fatty Change Hepatocellular Adenoma Hydropic Degeneration 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Cullen JM. Mechanistic classification of liver injury. Toxicol Pathol. 2005;33:6–8.PubMedCrossRefGoogle Scholar
  2. 2.
    Boobis AR, Cohen SM, Doerrer NG, Galloway SM, Haley PJ, Hard GC, et al. A data-based assessment of alternative strategies for identification of potential human cancer hazards 2. Toxicol Pathol. 2009;37:714–32.PubMedCrossRefGoogle Scholar
  3. 3.
    Carmichael N, Bausen M, Boobis AR, Cohen SM, Embry M, Fruijtier-Polloth C, et al. Using mode of action information to improve regulatory decision-making: an ECETOC/ILSI RF/HESI workshop overview 1. Crit Rev Toxicol. 2011;41:175–86.PubMedCrossRefGoogle Scholar
  4. 4.
    Hall AP, Elcombe CR, Foster JR, Harada T, Kaufmann W, Knippel A, et al. Liver hypertrophy: a review of adaptive (adverse and non-adverse) changes—conclusions from the 3rd International ESTP Expert Workshop. Toxicol Pathol. 2012;40:971–94.PubMedCrossRefGoogle Scholar
  5. 5.
    Holsapple MP, Pitot HC, Cohen SM, Boobis AR, Klaunig JE, Pastoor T, et al. Mode of action in relevance of rodent liver tumors to human cancer risk 7. Toxicol Sci. 2006;89:51–6.PubMedCrossRefGoogle Scholar
  6. 6.
    Dambach DM, Andrews BA, Moulin F. New technologies and screening strategies for hepatotoxicity: use of in vitro models. Toxicol Pathol. 2005;33:17–26.PubMedCrossRefGoogle Scholar
  7. 7.
    Harada T, Maronpot RR, Morris RW, Stitzel KA, Boorman GA. Morphological and stereological characterization of hepatic foci of cellular alteration in control Fischer 344 rats. Toxicol Pathol. 1989;17:579–93.PubMedGoogle Scholar
  8. 8.
    Zimmerman HJ, Ishak KG. Hepatotoxic injury due to drugs and toxins. In: MacSween RN, Antony PP, Scheur PJ, editors. Pathology of the liver. London: Churchill Livingstone; 1979. p. 335.Google Scholar
  9. 9.
    Plaa GL. Toxic responses of the liver. In: Doull H, Klasse CD, Amdur MO, editors. Casarett and Doull’s toxicology. London: Macmillan; 1980. p. 206.Google Scholar
  10. 10.
    Zimmerman HJ. Chemical injury and its detection. In: Plaa GL, Hewitt WRP, editors. Toxicology of the liver. New York: Raven; 1982.Google Scholar
  11. 11.
    Jollow DJ, Mitchell JR, Zampaglione N, Gillette JR. Bromobenzene-induced liver necrosis. Protective role of glutathione and evidence for 3,4-bromobenzene oxide as the hepatotoxic metabolite. Pharmacology. 1974;11:151–69.PubMedCrossRefGoogle Scholar
  12. 12.
    Foster JR. Spontaneous and drug-induced hepatic pathology of the laboratory beagle dog, the cynomolgus macaque and the marmoset. Toxicol Pathol. 2005;33:63–74.PubMedCrossRefGoogle Scholar
  13. 13.
    Gopinath C, Ford JH. The role of microsomal hydroxylases in the modification of chloroform hepatotoxicity in rats. Br J Exp Pathol. 1975;56:412–22.PubMedCentralPubMedGoogle Scholar
  14. 14.
    Richard JD, Parker JS, Lobenhofer EK, Burka LT, Blackshear PE, Vallant MK, et al. Transcriptional profiling of the left and median liver lobes of male F344/N rats following exposure to acetaminophen. Toxicol Pathol. 2005;33:111–7.CrossRefGoogle Scholar
  15. 15.
    Malarkey DE, Johnson K, Ryan L, Boorman G, Maronpot RR. New insights into functional aspects of liver morphology. Toxicol Pathol. 2005;33:27–34.PubMedCrossRefGoogle Scholar
  16. 16.
    Margos L, Butler WH. Effect of phenobarbitone and starvation on hepatotoxicity in rats exposed to carbon disulfide. Br J Ind Med. 1972;29:95–8.Google Scholar
  17. 17.
    Rouiller C. Experimental toxic injury of the liver. In: Rouiller C, editor. The liver, vol. 2. New York: Academic; 1964. p. 335.CrossRefGoogle Scholar
  18. 18.
    Butler WH. Experimental liver injury. In: MacSween RN, Antony PP, Scheur PJ, editors. Pathology of the liver. London: Churchill Livingstone; 1979. p. 55.Google Scholar
  19. 19.
    Gopinath C, Prentice DE, Street AE, Crook D. Serum bile acid concentration in some experimental liver lesions of rat. Toxicology. 1980;15:113–27.PubMedCrossRefGoogle Scholar
  20. 20.
    Thorpe E, Gopinath C, Jones RS, Ford EJ. The effect of chloroform on the liver and the activity of serum enzymes in the horse. J Pathol. 1969;97:241–51.PubMedCrossRefGoogle Scholar
  21. 21.
    Bursch W, Lauer B, Timmermann-Trosiener I, Barthel G, Schuppler J, Schulte-Hermann R. Controlled death (apoptosis) of normal and putative preneoplastic cells in rat liver following withdrawal of tumor promoters. Carcinogenesis. 1984;5:453–8.PubMedCrossRefGoogle Scholar
  22. 22.
    Kerr JF. Shrinkage necrosis: a distinct mode of cellular death. J Pathol. 1971;105:13–20.PubMedCrossRefGoogle Scholar
  23. 23.
    Scampini G, Nava A, Newman AJ, Della TP, Mazue G. Multinucleated hepatocytes induced by rifabutin in rats. Toxicol Pathol. 1993;21:369–76.PubMedCrossRefGoogle Scholar
  24. 24.
    Jones G, Butler WH. A morphological study of the liver lesion induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin in rats. J Pathol. 1974;112:93–7.PubMedCrossRefGoogle Scholar
  25. 25.
    Denk H, Franke WW, Eckerstorfer R, Schmid E, Kerjaschki D. Formation and involution of Mallory bodies (“alcoholic hyalin”) in murine and human liver revealed by immunofluorescence microscopy with antibodies to prekeratin. Proc Natl Acad Sci U S A. 1979;76:4112–6.PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Ishmael J, Gopinath C, Howell JM. Experimental chronic copper toxicity in sheep. Histological and histochemical changes during the development of the lesions in the liver. Res Vet Sci. 1971;12:358–66.PubMedGoogle Scholar
  27. 27.
    Haywood S. The effect of excess dietary copper on the liver and kidney of the male rat. J Comp Pathol. 1980;90:217–32.PubMedCrossRefGoogle Scholar
  28. 28.
    Elrick MM, Kramer JA, Alden CL, Blomme EAG, Bunch RT, Cabonce MA, et al. Differential display in rat livers treated for 13 weeks with phenobarbital implicates a role for metabolic and oxidative stress in nongenotoxic carcinogenicity. Toxicol Pathol. 2005;33:118–26.PubMedCrossRefGoogle Scholar
  29. 29.
    Williams GM, Iatropoulos MJ. Alteration of liver cell function and proliferation: differentiation between adaptation and toxicity. Toxicol Pathol. 2002;30:41–53.PubMedCrossRefGoogle Scholar
  30. 30.
    Pruimboom-Brees IM, Brees DJJE, Shen AC, Keener M, Francone O, Amacher DE, et al. Using laser scanning cytometry to measure PPAR-mediated peroxisome proliferation and beta oxidation. Toxicol Pathol. 2005;33:86–91.PubMedCrossRefGoogle Scholar
  31. 31.
    Maronpot RR, Yoshizawa K, Nyska A, Harada T, Flake G, Mueller G, et al. Hepatic enzyme induction: histopathology. Toxicol Pathol. 2010;38:776–95.PubMedCrossRefGoogle Scholar
  32. 32.
    Thoolen B, Maronpot RR, Harada T, Nyska A, Rousseaux C, Nolte T, et al. Proliferative and nonproliferative lesions of the rat and mouse hepatobiliary system. Toxicol Pathol. 2010;38:5S–81.PubMedCrossRefGoogle Scholar
  33. 33.
    Harada T, Maronpot RR, Morris RW, Boorman GA. Observations on altered hepatocellular foci in National Toxicology Program two-year carcinogenicity studies in rats. Toxicol Pathol. 1989;17:690–706.PubMedGoogle Scholar
  34. 34.
    Bannasch P, Moore MA, Klimek F, Zerban H. Biological markers of preneoplastic foci and neoplastic nodules in rodent liver. Toxicol Pathol. 1982;10:19–34.CrossRefGoogle Scholar
  35. 35.
    Williams GM, Watanabe K. Quantitative kinetics of development of N-2-fluorenylacetamide-induced, altered (hyperplastic) hepatocellular foci resistant to iron accumulation and of their reversion or persistence following removal of carcinogen. J Natl Cancer Inst. 1978;61:113–21.PubMedGoogle Scholar
  36. 36.
    Kushida M, Kamendulis LM, Peat TJ, Klaunig JE. Dose-related induction of hepatic preneoplastic lesions by diethylnitrosamine in C57BL/6 mice. Toxicol Pathol. 2011;39:776–86.PubMedCrossRefGoogle Scholar
  37. 37.
    Maronpot RR, Harada T, Murthy AS, Boorman GA. Documenting foci of hepatocellular alteration in two-year carcinogenicity studies: current practices of the National Toxicology Program. Toxicol Pathol. 1989;17:675–83.PubMedGoogle Scholar
  38. 38.
    Bannasch P, Bloch M, Zerban H. Spongiosis hepatis. Specific changes of the perisinusoidal liver cells induced in rats by N-nitrosomorpholine. Lab Invest. 1981;44:252–64.PubMedGoogle Scholar
  39. 39.
    Karbe E, Kerlin RL. Cystic degeneration/spongiosis hepatis in rats. Toxicol Pathol. 2002;30:216–27.PubMedCrossRefGoogle Scholar
  40. 40.
    Tatematsu M, Ho RH, Kaku T, Ekem JK, Farber E. Studies on the proliferation and fate of oval cells in the liver of rats treated with 2-acetylaminofluorene and partial hepatectomy. Am J Pathol. 1984;114:418–30.PubMedCentralPubMedGoogle Scholar
  41. 41.
    Kang JS, Morimura K, Salim EI, Wanibuchi H, Yamaguchi S, Fukushima S. Persistence of liver cirrhosis in association with proliferation of nonparenchymal cells and altered location of alpha-smooth muscle actin-positive cells. Toxicol Pathol. 2005;33:329–35.PubMedCrossRefGoogle Scholar
  42. 42.
    Low TY, Leow CK, Salto-Tellez M, Chung MC. A proteomic analysis of thioacetamide-induced hepatotoxicity and cirrhosis in rat livers. Proteomics. 2004;4:3960–74.PubMedCrossRefGoogle Scholar
  43. 43.
    Nuber R, Teutsch HF, Sasse D. Metabolic zonation in thioacetamide-induced liver cirrhosis. Histochemistry. 1980;69:277–88.PubMedCrossRefGoogle Scholar
  44. 44.
    Greaves P, Goonetilleke R, Nunn G, Topham J, Orton T. Two-year carcinogenicity study of tamoxifen in Alderley Park Wistar-derived rats. Cancer Res. 1993;53:3919–24.PubMedGoogle Scholar
  45. 45.
    Klaunig JE, Babich MA, Baetcke KP, Cook JC, Corton JC, David RM, et al. PPARalpha agonist-induced rodent tumors: modes of action and human relevance. Crit Rev Toxicol. 2003;33:655–780.PubMedCrossRefGoogle Scholar
  46. 46.
    Nelson LW, Kelly WA. Progestogen-related gross and microscopic changes in female beagles. Vet Pathol. 1976;13:143–56.PubMedGoogle Scholar
  47. 47.
    Walsh KM, Rothwell CE. Hepatic effects in beagle dogs administered atorvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, for 2 years. Toxicol Pathol. 1999;27:395–401.PubMedCrossRefGoogle Scholar
  48. 48.
    Waites CR, Dominick MA, Sanderson TP, Schilling BE. Nonclinical safety evaluation of muraglitazar, a novel PPARalpha/gamma agonist. Toxicol Sci. 2007;100:248–58.PubMedCrossRefGoogle Scholar
  49. 49.
    Gopinath C, Prentice DE, Lewis DJ. The liver. In: Atlas of experimental toxicological pathology. Boston: MTP Press Limited; 1987. p. 43–60.Google Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Chirukandath Gopinath
    • 1
  • Vasanthi Mowat
    • 2
  1. 1.Consultant in Toxicology and PathologyCambridgeshireUK
  2. 2.Huntingdon Life SciencesCambridgeshireUK

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