thioacetamide and gadolinium-chloride

It is well known that gadolinium chloride (GD) attenuates drug-induced hepatotoxicity by selectively inactivating Kupffer cells. In the present study the effect of GD in reference to cell cycle and postnecrotic liver regeneration induced by thioacetamide (TA) in rats was studied. Two months male rats, intraveously pretreated with a single dose of GD (0.1 mmol/Kg), were intraperitoneally injected with TA (6.6 mmol/Kg). Samples of blood and liver were obtained from rats at 0, 12, 24, 48, 72 and 96 h following TA intoxication. Parameters related to liver damage were determined in blood. In order to evaluate the mechanisms involved in the post-necrotic regenerative state, the levels of cyclin D and cyclin E as well as protein p27 and Proliferating Cell Nuclear Antigen (PCNA) were determined in liver extracts because of their roles in the control of cell cycle check-points. The results showed that GD significantly reduced the extent of necrosis. Noticeable changes were detected in the levels of cyclin D1, cyclin E, p27 and PCNA when compared to those induced by thioacetamide. Thus GD pre-treatment reduced TA-induced liver injury and accelerated the postnecrotic liver regeneration. These results demonstrate that Kupffer cells are involved in TA-induced liver and also in the postnecrotic proliferative liver states.

Topics: Animals; Cell Cycle; Cell Cycle Checkpoints; Cell Proliferation; Chemical and Drug Induced Liver Injury; Cyclin D; Cyclin E; Gadolinium; Kupffer Cells; Liver; Liver Regeneration; Male; Necrosis; Proliferating Cell Nuclear Antigen; Rats; Rats, Wistar; Thioacetamide

Gadolinium chloride (GD) attenuates drug-induced hepatotoxicity by selectively inactivating Kupffer cells. The effect of GD was studied in reference to postnecrotic liver regeneration induced in rats by thioacetamide (TA). Rats, intravenously pretreated with a single dose of GD (0.1 mmol/Kg), were intraperitoneally injected with TA (6.6 mmol/Kg). Hepatocytes were isolated from rats at 0, 12, 24, 48, 72 and 96 h following TA intoxication, and samples of blood and liver were obtained. Parameters related to liver damage were determined in blood. In order to evaluate the mechanisms involved in the post-necrotic regenerative state, the time course of DNA distribution and ploidy were assayed in isolated hepatocytes. The levels of circulating cytokine TNFα was assayed in serum samples. TNFα was also determined by RT-PCR in liver extracts. The results showed that GD significantly reduced the extent of necrosis. The effect of GD induced noticeable changes in the post-necrotic regeneration, causing an increased percentage of hepatocytes in S phase of the cell cycle. Hepatocytes increased their proliferation as a result of these changes. TNFα expression and serum level were diminished in rats pretreated with GD. Thus, GD pre-treatment reduced TA-induced liver injury and accelerated postnecrotic liver regeneration. No evidence of TNFα implication in this enhancement of hepatocyte proliferation and liver regeneration was found. These results demonstrate that Kupffer cells are involved in TA-induced liver damage, as well as and also in the postnecrotic proliferative liver states.

Topics: Animals; Anti-Inflammatory Agents; Cell Proliferation; DNA; Gadolinium; Hepatocytes; Kupffer Cells; Liver; Liver Regeneration; Male; Necrosis; Ploidies; Rats; Rats, Wistar; Thioacetamide; Tumor Necrosis Factor-alpha

The ratio of ornithine carbamoyltransferase (OCT) to alanine aminotransferase (ALT) or glutamate dehydrogenase (GDH) in serum has been suggested as an indicator for the diagnosis of hepatocellular carcinoma and alcoholic liver disease, respectively. However, the mechanisms responsible for the increase in these ratios are still unclear.. Wistar rats were pretreated with lipopolysaccharide (LPS) or gadolinium chloride (GD) before being administered with thioacetamide (TAA, 200 mg/kg, ip). Serum OCT and ALT levels were compared with control values. Half-lives of the enzymes in circulation were evaluated after the intravenous injection of the purified enzymes into rats with or without the pretreatment.. The serum level of OCT at 24 h after the administration of TAA was significantly lower in the LPS-treated group, and not influenced by pretreatment with GD. The half-life of OCT was prolonged from 1.06+/-0.14 to 2.07+/-0.29 h (p<0.05) by the pretreatment with GD, but not influenced by the administration of LPS. No change was observed in the clearance of GDH or ALT among the pretreatments.. Leakage into and clearance from the circulation of OCT are influenced by whether Kupffer cells are activated or not. OCT alone or in combination with other markers may be a useful indicator for Kupffer cell activation as well as mitochondrial damage in hepatic cells.

Topics: Alanine Transaminase; Animals; Anti-Inflammatory Agents; Chemical and Drug Induced Liver Injury; Gadolinium; Glutamate Dehydrogenase; Hepatocytes; Kupffer Cells; Lipopolysaccharides; Liver; Liver Diseases; Male; Ornithine Carbamoyltransferase; Rats; Rats, Wistar; Thioacetamide

Kupffer cell function plays an important role in drug-induced liver injury. Thus, gadolinium chloride (GD), by selectively inactivating Kupffer cells, can alleviate drug-induced hepatotoxicity. The effect of GD was studied in reference to metallothionein and heat shock proteins expression in an in vivo model of liver necrosis induced by thioacetamide. Rats, pre-treated or not with GD (0.1 mmol/kg), were intraperitoneally injected with thioacetamide (6.6 mmol/kg), and samples of blood and liver were obtained at 0, 12, 24, 48, 72 and 96 hr. Parameters related to liver damage, Kupffer cell function, microsomal FAD monooxygenase activity, oxidative stress, and the expression of metallothionein and HSP70 were determined. GD significantly reduced serum myeloperoxidase activity and serum concentration of TNF alpha and IL-6, increased by thioacetamide. The extent of necrosis, the degree of oxidative stress and lipoperoxidation and microsomal FAD monooxygenase activity were significantly diminished by GD. The effect of GD induced noticeable changes in the expression of both metallothionein and HSP70, compared to those induced by thioacetamide. We conclude that GD pre-treatment reduces thioacetamide-induced liver injury and enhances the expression of metallothionein and HSP70. This effect, parallel to reduced levels of serum cytokines and myeloperoxidase activity, demonstrates that Kupffer cells are involved in thioacetamide-induced liver injury, the degree of contribution being approximately 50%.

Topics: Animals; Anti-Inflammatory Agents; Biotransformation; Chemical and Drug Induced Liver Injury; Drug Interactions; Gadolinium; Gene Expression; HSP70 Heat-Shock Proteins; Kupffer Cells; Male; Metallothionein; Microsomes, Liver; Mixed Function Oxygenases; NADP; Oxidative Stress; Rats; Rats, Wistar; Thioacetamide