ABSTRACT
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.
Subject(s)
Growth Substances/pharmacology , Liver Regeneration/drug effects , Liver/pathology , Peptides/pharmacology , Receptors, Serotonin, 5-HT2/metabolism , Serotonin 5-HT2 Receptor Antagonists , Animals , Biological Assay , Body Weight , Intercellular Signaling Peptides and Proteins , Ketanserin/pharmacology , Ki-67 Antigen/biosynthesis , Liver/metabolism , Male , Mitogens , Mitosis , Proliferating Cell Nuclear Antigen/metabolism , Rats , Rats, Wistar , Thymidine/metabolism , Time FactorsABSTRACT
BACKGROUND: The mechanism of cadmium-induced liver regeneration arrest in relation to hepatic stimulator substance (HSS) biological activity was investigated. MATERIALS AND METHODS: In Wistar rats subjected to 65 - 70% partial hepatectomy, saline, cadmium, cadmium and HSS were administered. The rats were also subjected to 30 - 34% partial hepatectomy. Mitotic index, immunochemistry for PCNA, 3[H]-thymidine incorporation into DNA and thymidine kinase activity were used as indices of liver regeneration. HSS biological activity was evaluated in all groups of rats using a bioassay. RESULTS: Liver regeneration and HSS activity were arrested by cadmium during the first 24 h after partial hepatectomy. Both in normal and in cadmium-treated rats, the HSS activity was increased and liver regeneration coincided. HSS activity was stable in 30 - 34% hepatectomized rats. HSS administration was able to restore liver regeneration arrest induced by cadmium. CONCLUSION: The biological activity of HSS increased at the time of G1/S transition of hepatocytes in the cell cycle and no increase was observed with asynchronous G1/S transition (30 - 34% partial hepatectomy). The suppression of HSS biological activity by cadmium seems to represent an important factor for liver regeneration arrest induced by the metal and HSS administration is able to restore liver regeneration.
Subject(s)
Cadmium/toxicity , Growth Substances/metabolism , Liver Regeneration/drug effects , Mitogens/metabolism , Peptides/metabolism , Animals , DNA/biosynthesis , DNA/drug effects , Growth Substances/pharmacology , Hepatectomy , Immunohistochemistry , Injections, Intraperitoneal , Intercellular Signaling Peptides and Proteins , Liver/drug effects , Liver/enzymology , Liver/pathology , Male , Mitogens/pharmacology , Mitotic Index , Peptides/pharmacology , Proliferating Cell Nuclear Antigen/metabolism , Rats , Rats, Wistar , Thymidine Kinase/drug effects , Thymidine Kinase/metabolismABSTRACT
Male Wistar rats were randomized to receive ethanol (2.5 ml/kg by gastric intubation every 8 hr; group I), equal volumes of isocaloric to ethanol sucrose solution (group II), or ethanol and HSS (100 mg/kg intraperitoneally 10 and 16 hr after partial hepatectomy; groups III and IV, respectively) for up to 96 hr after partial hepatectomy, with ethanol administration starting 1 hr prior to partial hepatectomy. Animals were killed at 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 60, and 96 hr after partial hepatectomy. The rate of liver regeneration was evaluated by the mitotic index in H&E-stained sections, immunochemical detection of Ki67 nuclear antigen, rate of [3H]thymidine incorporation into hepatic DNA, and liver thymidine kinase enzymatic activity. The biological activity of HSS in groups I and II rats was evaluated using a bioassay. Ethanol administration arrested liver regeneration during the first 32 hr after partial hepatectomy and suppressed HSS activity throughout the period examined. Liver regeneration progressed after 32 hr despite the low levels of HSS activity. HSS administration at 10 and 16 hr reversed liver regeneration arrest induced by ethanol. Acute ethanol administration induces cell cycle arrest during the first 32 hr after partial hepatectomy and suppression of HSS biological activity seems to contribute to this effect. HSS administration reversed the inhibitory effect of ethanol on liver regeneration and caused synchronized entrance of hepatocytes in the S phase of the cell cycle. HSS seems to participate in the network of growth factors controlling the G1/S cell cycle checkpoint.