Abstract
Iatrogenic Hepatitis: Intrinsic and Idiosyncratic Toxicity. Substances capable of producing liver damage and, more specifically, hepatocyte damage are known as hepatotoxins. They are classified (Zimmerman and Ishak, 1995, Castell et al., 1992) according to whether they exert their effects in all individuals, in a dose-dependent and hence predictable manner (intrinsic hepatotoxins), or in certain individuals, occasionally after several contacts, in a non-dose dependent and therefore unpredictable way (idiosyncratic hepatotoxins). These substances can act directly on cells (active hepatotoxins), or become toxic after biotransformation (latent hepatotoxins). Idiosyncratic hepatotoxicity is the consequence, either of an unusual metabolism of the drug by susceptible individuals which produce too large amounts of toxic metabolites (metabolic idiosincrasy), or is due to an immune-mediated attack to sensitised hepatocytes (drug hypersensitivity).
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References
Bellomo G., Mirabelli F., Richelmi P. and Orrenius S. (1983). Critical role of sulfhydryl groups in the ATP-dependent Ca2+-sequestration by the plasma membrane fraction from rat liver. FEBS letters 163, 136–139.
Boelsterli U. A. (1993). Specific targets of covalent drug-protein interactions in hepatocytes and their toxicological significance in drug-induced liver injury. Drug Metabolism Reviews 25, 395–451.
Boobis A. R., Duncan J., Fawthrop J. and Davies D. S. (1989). Mechanisms of cell death. Trends in Pharmacological Sciences 10, 275–280.
Castell J.V. and Gómez-Lechón M.J. (1992). The in vitro evaluation of the potential risk of hepatotoxicity of drugs. In: In vitro alternatives to animal pharmaco-toxicology. (J. V. Castell and M. J. Gómez-Lechón, Eds), pp. 179–204. Farmaindustria, Barcelona.
Columbano A. (1995). Cell death: Current difficulties in discriminating apoptosis from necrosis in the context of pathological processes in vivo. Journal of Cellular Biochemistry 58,181–190.
Gómez-Lechón M. J., Carrasquer J., Berenguer J. and Castell J. V. (1996). Evidence of antibodies to erythromycin in serum of a patient following an episode of acute drug-induced hepatitis. Clinical and Experimental Allergy 26, 590–596.
Hargus, S. J., Amouzedeh H. R., Pumford N. R. et al. (1994). Metabolic activation and immunochemical localization of liver protein adducts on the nonsteroidal anti-inflamatory drug diclofenac. Chemical Research in Toxicology 7, 575–582.
Hinson J.A., and Roberts D.W. (1992). Role of covalent and noncovalent interactions in cell toxicity: effects on proteins. Annu. Reviews in Pharmacology and Toxicology 32, 471–510.
Homberg J. C. N., Abauf S., Helmy-Khalil M. et al., (1985). Drug induced hepatitis associated with anticytoplasmic organelle autoantibodies. Hepatology 5, 722–727.
Holtzman J. L. (1995). The role of covalent binding to microsomal proteins in the hepatotoxicity of acetaminophen. Drug Metabolism Reviews 27, 277–297.
Kretz-Rommel A. and Boelsterli U. A. (1994). Mechanism of covalent adduct formation of diclofenac in rat hepatic microsomal proteins. Retention of the glucuronic acid moiety in the sdduct. Drug Metabolism and Disposition 22, 956–961.
Loeper J. Descatoire V., Maurice M. et al. (1993). Cytochromes P-450 in human hepatocyte plasma membrane: recognition by several autoantibodies. Gastroenterology 104, 203–216.
Maria V. A. J. and Vitorino R. (1994). Lymphocyte proliferative response to drugs: Analysis of the value of a 24-well lymphocyte culture system. Toxicology in Vitro 5,1041–1044.
Nieminen A. L., Saylor A. K., Tesfai S. A., Herman B. and Lemasters J. J. (1995). Contribution of the mitochondrial permeability transition to lethal injury after exposure of hepatocytes to t-butylhydroperoxide. Biochemical Journal 307, 99–106.
Poli, G., Albano, E., and Dianzani, M.U. (1987). The role of lipid peroxidation in liver damage. Chemistry and Physics of Lipids 45,117–142.
Ponsoda X., Bort R., Jover R., Gómez-Lechón M. J. and Castell J.V. (1995). Molecular mechanisms of diclofenac hepatotoxicity: cell injury is associated to the metabolism of the drug and is preluded by a decrease in ATP levels. Toxicology in Vitro 9, 439–444.
Reed J. D. (1990). Glutathione: Toxicological implications. Ann. Rev. Pharmacological Toxicology 30, 603–631.
Robin M. A., Maratrat M., Loeper J., et al. (1995). Cytochrome P4502B follows a vesicular route to the plasma membrane in cultured rat hepatocytes. Gastroenterology 108, 1110–1123.
Ross D. (1989). Mechanistic toxicology: A radical perspective. Journal of Pharmacy and Pharmacology 41, 505–511.
Rosser B. G. and Gores G. J. (1995). Liver cell necrosis: cellular mechanisms and clinical implications. Gastroenterology 108, 252–275.
Shen W., Kamendulis L.M., Ray S.D., and Corcoran G.B. (1992). Acetaminophen-induced cytotoxicity in cultured mouse hepatocytes: effects of Ca2+-endonuclease, DNA repair, and glutathione depletion inhibitors on DNA fragmentation and cell death. Toxicology and Applied Pharmacology 112, 32–40.
Sies H. (1991). Oxidative stress: Introduction. In: Oxidative Stress. Oxidants and Antioxidants. (H. Sies, Ed), Academic Press. London.
Swartz M. N. (1995). Mitochondrial toxicity: New adverse drug effects. New England Journal of Medicine. 333, 1146–1148.
Tsutsui H., Terano Y., SAkagami C. et al. (1992). Drug-specific T cells derived from patients with drug-induced allergic hepatitis. Journal of Immunology 149, 706–716.
Van-Pelt F. N. and Kenna J. G. (1994). Formation of trifluoroacetylated protein antigens in cultured rat hepatocytes exposed to halothane in vitro. Biochemical Pharmacology 48, 461–471.
Zimmerman H. J. and Ishak K. G. (1995). General aspects od drug- induced liver diseases. Gastroenterology Clinical North America 24, 739–758.
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© 1997 Springer-Verlag Berlin Heidelberg
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Castell, J.V., Gómez-Lechón, M.J., Ponsoda, X., Bort, R. (1997). In vitro Investigation of the Molecular Mechanisms of Hepatotoxicity. In: Seiler, J.P., Vilanova, E. (eds) Applied Toxicology: Approaches Through Basic Science. Archives of Toxicology, vol 19. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-60682-3_29
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DOI: https://doi.org/10.1007/978-3-642-60682-3_29
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