RESUMO
Protective strategies to minimize the hematological toxicity in connection with bone marrow transplantation (BMT) have been successful, but toxicity to the gastrointestinal tract prevents further dose escalation and therefore limits the application of the treatment. As it is known that chemotherapy leads to disruption of the intestinal barrier and morphological changes of mitochondria in enterocytes, this study was conducted in order to investigate intestinal energy metabolism and permeability after intensive cytotoxic therapy in rats. Intestinal damage was produced by intraperitoneal administration of the cytostatic etoposide. Intestinal permeability was assessed by a [51Cr]EDTA absorption test and intestinal purine nucleotide content by a high-performance liquid chromatography (HPLC) technique. Four hours after the administration of etoposide, and the next 48 hr, there was a significant increase in the intestinal permeability (P < 0.05) and a significant reduction of the purine nucleotide content in the intestinal epithelial cells (P < 0.01) as compared to control animals. This early disturbance in enterocyte energy metabolism may be a key event in the development of the intestinal damage, induced by chemotherapy, and an explanation for the early disruption of the intestinal barrier demonstrable before morphological changes are evident.
Assuntos
Antineoplásicos/efeitos adversos , Modelos Animais de Doenças , Etoposídeo/efeitos adversos , Enteropatias/induzido quimicamente , Enteropatias/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Nucleotídeos de Purina/análise , Nucleotídeos de Purina/metabolismo , Animais , Antineoplásicos/administração & dosagem , Permeabilidade Capilar/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Avaliação Pré-Clínica de Medicamentos , Metabolismo Energético/efeitos dos fármacos , Enterócitos/efeitos dos fármacos , Enterócitos/metabolismo , Etoposídeo/administração & dosagem , Injeções Intraperitoneais , Mucosa Intestinal/química , Contagem de Leucócitos , Masculino , Ratos , Ratos Endogâmicos Lew , Fatores de TempoRESUMO
The gastric mucosal microcirculation and purine nucleotide metabolism were studied in rats after hemorrhagic shock and retransfusion. The mucosal surface density of perfused vessels (SDPV) and the mucosal levels of ATP, ADP, AMP, IMP, hypoxanthine and uric acid were measured following 15 min of hemorrhagic shock and 10 and 30 min after retransfusion, and the effects of pretreatment with allopurinol or ascorbate were studied. During shock there was a dephosphorylation of nucleotides and a decline in the SDPV. Retransfusion led to an additional reduction in the SDPV, but a complete restoration of preshock nucleotide levels 30 min after retransfusion. Allopurinol accelerated early rephosphorylation of nucleotides without effects upon SDPV while ascorbate completely preserved the mucosal level of energy-rich nucleotides 15 min after hemorrhagic shock and increased SDPV during early reperfusion. The results showed that there was a renewal of energy stores in gastric mucosa after hemorrhagic shock and retransfusion although parts of the vascular bed were not reperfused. The mucosal energy depletion after 15 min of hemorrhagic shock and part of the mucosal vessel injury after retransfusion were prevented by pretreatment with ascorbate.
Assuntos
Alopurinol/uso terapêutico , Ácido Ascórbico/uso terapêutico , Mucosa Gástrica/irrigação sanguínea , Mucosa Gástrica/metabolismo , Traumatismo por Reperfusão/prevenção & controle , Choque Hemorrágico/tratamento farmacológico , Animais , Transfusão de Sangue Autóloga , Masculino , Microcirculação , Nucleotídeos de Purina/análise , Nucleotídeos de Purina/metabolismo , Ratos , Ratos Sprague-DawleyAssuntos
3',5'-AMP Cíclico Fosfodiesterases/análise , Nucleotídeos Cíclicos/análise , 3',5'-AMP Cíclico Fosfodiesterases/isolamento & purificação , 3',5'-AMP Cíclico Fosfodiesterases/metabolismo , Óxido de Alumínio , Linhagem Celular , Cromatografia/métodos , Humanos , Leucemia Promielocítica Aguda , Inibidores de Fosfodiesterase/farmacologia , Nucleotídeos de Purina/análise , Purinas/análise , Nucleotídeos de Pirimidina/análise , Pirimidinas/análise , Pirrolidinonas/farmacologia , Ribonucleosídeos/análise , Rolipram , Células Tumorais CultivadasRESUMO
In order to investigate the mechanisms of the anticarcinogenic effect of Chinese tea on the development of esophageal tumors in rats induced by N-nitrosomethylbenzylamine, the alkylation of DNA in various organs was studied in rats treated with 2 varieties of Chinese tea, i.e. Fujian Oolong tea and Jasmine tea. Male Wistar rats were given a single i.v. injection of N-nitroso-[methyl-14C]-benzylamine (2.5 mg/kg body wt) after having been provided tea in drinking water and by gavage for 2-3 weeks. Control rats were provided with tap water. Three to four hours after administration of the N-nitroso compound, the methylation of purine bases in the DNA isolated from various organs was measured by high performance liquid chromatography and liquid scintillation counting. In the tea-drinking rats, there was an appreciable reduction of O6-methylguanine formation in the esophageal DNA as well as the ratio of O6-methylguanine to N7-methylguanine, as compared to the control rats. No O6-methylguanine was detected in lung or liver DNA.