RESUMO
Arachidonic acid (AA)-induced cytotoxicity was evaluated in leukocytes: the human leukemia cell lines HL-60, Jurkat and Raji and in rat lymphocytes. Such cytotoxicity was dose- and time-dependent. At concentrations below 5 microM, AA was not toxic; at 10-400 microM, AA induced apoptosis and at concentrations beyond 400 microM, necrosis. The minimum exposure time to trigger cell death was of around 1 h, but the effect was increased by longer exposure times until 6-24 h. Apoptosis was morphologically characterized by a decrease in cell and nuclear volume, chromatin condensation and DNA fragmentation and the presence of lipid bodies, without changes in organelle integrity. Biochemically, AA-induced apoptosis was associated with internucleosomal fragmentation and caspase activation, evaluated by PARP cleavage and the use of a caspase inhibitor. Necrosis was characterized by increased cell volume, presence of loose chromatin, appearance of vacuoles, loss of membrane integrity and of the definition of organelles. The apoptotic effect of AA was studied as to oxidative-reductive imbalance and the participation of eicosanoids. Apoptotic AA treatment was accompanied by an increase in the quantity of thiobarbituric acid reactive substances (TBARS), low-level chemiluminescence and in the glutathione disulfide/reduced glutathione ratio, indicating oxidative stress. The addition of tocopherol, ascorbate, prostaglandin E2 and lipoxygenase inhibitors delayed cell death, whereas the inhibition of cyclooxygenase promoted AA-induced cell death. Cell treatment with AA was accompanied by increased cellular production of LTB4. AA, therefore, is cytotoxic at physiological and supraphysiological concentrations, causing apoptosis and necrosis. Cell treatment with apoptotic concentrations of AA involves oxidative stress and changes in eicosanoid biosynthesis.
Assuntos
Apoptose/efeitos dos fármacos , Ácido Araquidônico/toxicidade , Citotoxinas/toxicidade , Eicosanoides/biossíntese , Leucócitos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Animais , Antioxidantes/farmacologia , Apoptose/fisiologia , Ácido Araquidônico/metabolismo , Caspases/efeitos dos fármacos , Caspases/metabolismo , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Núcleo Celular/patologia , Inibidores de Ciclo-Oxigenase/farmacologia , Citotoxinas/metabolismo , Fragmentação do DNA/efeitos dos fármacos , Fragmentação do DNA/fisiologia , Relação Dose-Resposta a Droga , Esquema de Medicação , Dissulfeto de Glutationa/efeitos dos fármacos , Dissulfeto de Glutationa/metabolismo , Células HL-60 , Humanos , Células Jurkat , Leucócitos/metabolismo , Leucotrieno B4/metabolismo , Necrose , Estresse Oxidativo/fisiologia , Poli(ADP-Ribose) Polimerase-1 , Poli(ADP-Ribose) Polimerases , Proteínas/efeitos dos fármacos , Proteínas/metabolismo , Ratos , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismoRESUMO
Os autores estudaram o efeito da cimetidina na sobrevida de camundongos inoculados com o tumor de Ehrlich e concluíram que a droga aumenta a sobrevida desses animais, sugerindo ainda uma açäo imunomoduladora dessa substância
Assuntos
Animais , Masculino , Feminino , Camundongos , Carcinoma de Ehrlich/imunologia , Cimetidina/farmacologia , Carcinoma de Ehrlich/mortalidadeRESUMO
Os autores estudaram a sobrevida de camundongos inoculados com o tumor de Ehrlich e concluíram que a famotidina e a ranitidina aumentaram a sobrevida destes aimais. Os autores também descreveram que a cimetidina, famotidina e a ranitidina näo alteram a hipersensibilidade tardia do BCG