Effect of 5-HT(2) receptor blockade on cadmium-induced acute toxicity.

The protective effect of 5-HT(2) receptor blockade with ketanserin or ritanserin against cadmium liver injury was investigated. Male Wistar rats were injected intraperitoneally with a sublethal dose of cadmium (3.5 mg/kg body weight). Rats were treated with normal saline (group I), ketanserin (3 mg/kg body weight; group II), or ritanserin (3 mg/kg body weight; group III) 2 hr prior and 4 hr after cadmium administration and killed at different time points. Hematoxylin/eosin-stained liver sections were assessed for necrosis, apoptosis, peliosis, mitoses, and inflammatory infiltration. Apoptosis was also quantified by the TUNEL assay. Nonparenchymal liver cells and activated Kupffer cells were identified histochemically. Necrosis, hepatocyte apoptosis, nonparenchymal cell apoptosis, and macroscopic and microscopic peliosis were markedly reduced or minimized in ketanserin- or ritanserin-treated rats. The observed protective effect was almost identical for both ketanserin and ritanserin administration. 5-HT(2) receptor blockade exerts a protective effect against acute cadmium-induced hepatotoxicity.

The effect of hepatic stimulator substance (HSS) on liver regeneration arrest induced by 5-HT2 receptor blockade.

BACKGROUND: The restorative effect of hepatic stimulator substance (HSS) against hepatic regeneration arrest induced by 5-HT2 receptor blockade was investigated. MATERIALS AND METHODS: Male Wistar rats were subjected to 60-70% partial hepatectomy and to 5-HT2 receptor blockade at 16 h after partial hepatectomy by ketanserin administration (6 mg/kg bodyweight intraperitoneally; group I). HSS at the dose of 100 mg protein/kg bodyweight was administered at 10 or 17 h after partial hepatectomy in ketanserin-treated rats (groups II and III). The mitotic index in hematoxylin-eosin-stained liver sections, immunochemical detection of PCNA and Ki 67 nuclear antigens and the rate of [3H]-thymidine incorporation into hepatic DNA were used as indices of liver regeneration. RESULTS: Liver regeneration, as evaluated by [3H]-thymidine incorporation into hepatic DNA, mitotic index, PCNA and Ki67 nuclear antigens, peaked at 40 h in groups I, II and III of rats and no significant differences were observed between the studied groups. CONCLUSION: HSS administration is not capable of reversing the liver regeneration arrest induced by 5-HT2 receptor blockade.

Effect of hepatic stimulator substance (HSS) on cadmium-induced acute hepatotoxicity in the rat liver.

The hepatoprotective effect of HSS against cadmium-induced liver injury was investigated. Rats were intoxicated with a dose of cadmium (3.5 mg/kg b.w.). The rats were treated with normal saline (group I) or HSS (100 mg protein/kg b.w.; group II) 2 hr later and killed at different time points. Hematoxylin-eosin (HE) sections were assessed for necrosis, apoptosis, peliosis, mitoses, and inflammatory infiltration. Serum enzyme activities were assayed. Apoptosis was quantified by the Tunel technique. Thymidine kinase activity and the rate of [3H]thymidine incorporation into DNA were also assayed. Necrosis, hepatocyte apoptosis, and peliosis were minimized in HSS-treated rats (group II). Nonparenchymal cell apoptosis and liver regeneration were not quantitively altered in the HSS-treated group, though the time profile was different. HSS protects hepatocytes against cadmium-induced necrosis, apoptosis, and peliosis. Apoptosis was the major type of cell death for nonparenchymal liver cells and strongly correlated with the extent of peliosis. Interactions between hepatocytes and nonparenchymal liver cells seem to be important for the genesis of hepatic trauma in acute cadmium hepatotoxicity.

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

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.