RESUMO
BACKGROUND: Retrorsine, a naturally occurring pyrrolizidine alkaloid, impairs liver regeneration after partial hepatectomy by mechanisms that are still unclear. AIM: The aim of the study was to clarify the influence of retrorsine on cell cycle progression in the regenerating liver lobes of rats after portal branch ligation (PBL). METHODS: Liver weight, protein and DNA contents, DNA synthesis (5'-bromodeoxyuridine (BrdU) incorporation) and cellular levels of Cyclin E, CDK-2, CDK-4 and proliferating cell nuclear antigen (PCNA) were assessed before and 24, 48, 72 and 168 h after PBL. RESULTS: Before surgery, higher levels of cyclin E, CDK-2, CDK-4 and PCNA as well as BrdU incorporation were found in the liver of retrorsine-treated rats than in untreated rats. Liver weight gain, protein and DNA synthesis as well as induction of cell cycle related proteins were all strongly impaired by retrorsine in the regenerating lobes after PBL. CONCLUSIONS: In conclusion, retrorsine impairs liver regeneration in the PBL model not only by an S or G2/M phase block, but also by a block located before the G1/S transition of the cell cycle.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Hepatopatias/tratamento farmacológico , Regeneração Hepática/efeitos dos fármacos , Veia Porta , Proteínas Proto-Oncogênicas , Alcaloides de Pirrolizidina/farmacologia , Animais , Western Blotting , Bromodesoxiuridina , Quinases relacionadas a CDC2 e CDC28/metabolismo , Ciclina E/metabolismo , Quinase 2 Dependente de Ciclina , Quinase 4 Dependente de Ciclina , Quinases Ciclina-Dependentes/metabolismo , DNA/biossíntese , Modelos Animais de Doenças , Cinética , Ligadura , Hepatopatias/patologia , Hepatopatias/fisiopatologia , Masculino , Tamanho do Órgão , Antígeno Nuclear de Célula em Proliferação/metabolismo , Ratos , Ratos Wistar , Aumento de Peso/efeitos dos fármacosRESUMO
BACKGROUND/AIMS: Fatty liver is known to be associated with increased mortality and morbidity after liver resection. The ability of fatty liver to regenerate after two-thirds partial hepatectomy was studied in three different models of steatosis in rats: obese Zucker rats, orotic acid-fed Wistar rats and Wistar rats fed a methionine-low, choline-deficient diet. METHODS: Liver regeneration was assessed 24 h after partial hepatectomy by bromodeoxyuridine incorporation (immunohistochemistry), proliferating cell nuclear antigen, cyclin E and cyclin-dependent kinase 2 protein expression (Western blot analysis) and cyclin-dependent kinase 2 activity (kinase assays using histone H1 as a substrate). RESULTS: No significant difference of proliferative response was found between orotic acid or methionine-low, choline-deficient diet-fed and control Wistar rats 24 h after partial hepatectomy. In contrast, hepatocyte proliferation in obese Zucker rats after partial hepatectomy was significantly reduced when compared with their lean controls. CONCLUSIONS: Steatosis per se does not impair liver regeneration. The reduced liver regeneration observed in obese Zucker rats may not be due to fatty infiltration itself but to other factors such as leptin receptor dysfunction.