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Time-course of cadmium-induced acute hepatotoxicity in the rat liver: the role of apoptosis

  • Organ Toxicity and Mechanisms
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Abstract

Exposure to toxic metals and pollutants is a major environmental problem. Cadmium is a metal causing acute hepatic injury but the mechanism of this phenomenon is poorly understood. In the present study, we investigated the mechanism and time-course of cadmium-induced liver injury in rats, with emphasis being placed on apoptosis in parenchymal and nonparenchymal liver cells. Cadmium (3.5 mg/kg body weight) was injected intraperitoneally and the rats were killed 0, 9, 12, 16, 24, 48 and 60 h later. The extent of liver injury was evaluated for necrosis, apoptosis, peliosis, mitoses and inflammatory infiltration in hematoxylin–eosin-stained liver sections, and by assaying serum enzyme activities. The number of cells that died via apoptosis was quantified by TUNEL assay. The identification of nonparenchymal liver cells and activated Kupffer cells was performed histochemically. Liver regeneration was evaluated by assaying the activity of liver thymidine kinase and by the rate of 3H-thymidine incorporation into DNA. Both cadmium-induced necrotic cell death and parenchymal cell apoptosis showed a biphasic elevation at 12 and 48 h and peaked at 48 and 12 h, respectively. Nonparenchymal cell apoptosis peaked at 48 h. Peliosis hepatis, another characteristic form of liver injury, was first observed at 16 h and, at all time points, closely correlated with the apoptotic index of nonparenchymal liver cells, where the lesion was also maximial at 48 h. Kupffer cell activation and neutrophil infiltration were minimal for all time points examined. Based on thymidine kinase activity, liver regeneration was found to discern a classic biphasic peak pattern at 12 and 48 h. It was very interesting to observe that cadmium-induced liver injury did not involve inflammation at any time point. Apoptosis seems to be a major mechanism for the removal of damaged cells, and constitutes the major type of cell death in nonparenchymal liver cells. Apoptosis of nonparenchymal cells is the basis of the pathogenesis of peliosis hepatis. The first peaks of necrosis and parenchymal cell apoptosis seem to evolve as a result of direct cadmium effects whereas the latter ones result from ischemia.

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Authors and Affiliations

  1. Department of Experimental Pharmacology, Medical School, Athens University, 75 Mikras Asias St., 115 27, Athens, Greece

    Konstantinos N. Tzirogiannis, Georgios I. Panoutsopoulos, Rosa I. Hereti, Katerina N. Alexandropoulou, Aristidis C. Basayannis & Michael G. Mykoniatis

  2. Histopathology Laboratory, Sismanoglion G.D. Hospital, Sismanogliou 1, Marousi, Attiki 151 27, Greece

    Maria D. Demonakou

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  1. Konstantinos N. Tzirogiannis
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  2. Georgios I. Panoutsopoulos
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  3. Maria D. Demonakou
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  4. Rosa I. Hereti
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  5. Katerina N. Alexandropoulou
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  6. Aristidis C. Basayannis
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  7. Michael G. Mykoniatis
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Correspondence to Michael G. Mykoniatis.

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Tzirogiannis, K.N., Panoutsopoulos, G.I., Demonakou, M.D. et al. Time-course of cadmium-induced acute hepatotoxicity in the rat liver: the role of apoptosis. Arch Toxicol 77, 694–701 (2003). https://doi.org/10.1007/s00204-003-0499-y

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