RESUMO
Paracetamol, in toxic doses, is associated with extensive liver damage. This represents one of the common causes of morbidity and mortality in drug poisoning cases. This study was undertaken to investigate the possible potentiation of the hepatoprotective action of N-acetylcysteine (NAC) by cimetidine (CMD), an inhibitor of hepatic microsomal oxidative enzymes. The effects of NAC, cimetidine and the two in combination, administered 2 h post-paracetamol dose, on mortality, plasma glutamic oxaloacetic (GOT) and glutamic pyruvic (GPT) transaminase activities and hepatic reduced glutathione (GSH) levels were investigated in mice 24 h after treatment with a single oral dose of paracetamol (400 mg/kg). Both NAC and cimetidine caused a partial improvement of survival rate, plasma GOT and GPT activities. In addition, they prevented the depletion of hepatic GSH contents. However, concomitant administration of NAC and cimetidine produced a 100% survival rate and a marked reduction in plasma GOT and GPT activities to within the normal range, while significantly raising hepatic GSH concentrations to values close to those measured in saline-treated control animals. It is therefore concluded that cimetidine and N-acetylcysteine may have an additive hepatoprotective action in the treatment of paracetamol overdose.
Assuntos
Acetaminofen/toxicidade , Acetilcisteína/farmacologia , Analgésicos não Narcóticos/toxicidade , Cimetidina/farmacologia , Sequestradores de Radicais Livres/farmacologia , Antagonistas dos Receptores H2 da Histamina/farmacologia , Fígado/efeitos dos fármacos , Acetaminofen/administração & dosagem , Acetilcisteína/administração & dosagem , Acetilcisteína/uso terapêutico , Administração Oral , Alanina Transaminase/sangue , Analgésicos não Narcóticos/administração & dosagem , Animais , Aspartato Aminotransferases/sangue , Cimetidina/administração & dosagem , Cimetidina/uso terapêutico , Sequestradores de Radicais Livres/administração & dosagem , Sequestradores de Radicais Livres/uso terapêutico , Glutationa/metabolismo , Antagonistas dos Receptores H2 da Histamina/administração & dosagem , Antagonistas dos Receptores H2 da Histamina/uso terapêutico , Fígado/enzimologia , Fígado/patologia , Hepatopatias/mortalidade , Hepatopatias/patologia , Hepatopatias/prevenção & controle , Masculino , Camundongos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , Necrose , Taxa de SobrevidaRESUMO
Dihydrotachysterol3, a reduced (or hydrogenated) analog of vitamin D3 in which the A ring has been rotate through 180 degrees , is, after hepatic 25-hydroxylation, converted in vivo to a dihydroxylated metabolite, termed peak H, which is at present unidentified but with good affinity for the vitamin D receptor. Although peak H is made in relatively large amounts in vivo, it has not yet been possible to synthesize it in vitro. Mass spectrometric evidence suggests that peak H is 25-hydroxylated and the presumption that it is a metabolite of 25-hydroxydihydrotachysterol3 was confirmed by the demonstration that radiolabeled peak H was formed in vivo in the rat after injection of 25-hydroxy-[10,19-3H]dihydrotachysterol3, produced from [10,19-3H]dihydrotachysterol3 in a hepatic cell model. The metabolism of 25-hydroxy-[10,19-3H]dihydrotachysterol3 was also studied in a rat osteosarcoma cell UMR-106, a known target cell for vitamin D, using high (11 microM) and low (10 nM) substrate concentrations. Metabolic products were isolated by lipid extraction, purified by high-performance liquid chromatography, and characterized by direct-probe mass spectrometry and gas chromatography/mass spectrometry. The formation of peak H from 25-hydroxydihydrotachysterol3 could not be demonstrated in UMR-106 cells. However, 25-hydroxydihydrotachysterol3 was metabolized to at least seven side-chain modified metabolites, each of which was extensively characterized and tentatively identified. It is concluded that the vitamin D enzyme system present in UMR-106 cells is able to metabolize dihydrotachysterol3 very efficiently to a series of metabolites but is incapable of producing peak H.
Assuntos
Osso e Ossos/metabolismo , Di-Hidrotaquisterol/metabolismo , Animais , Carcinoma Hepatocelular/metabolismo , Cromatografia Líquida de Alta Pressão , Humanos , Hidroxilação , Fígado/metabolismo , Neoplasias Hepáticas/metabolismo , Masculino , Espectrometria de Massas , Osteossarcoma/metabolismo , Ratos , Ratos Wistar , Células Tumorais CultivadasRESUMO
Guanidination and amidination of bovine serum albumin, yeast enolase and yeast alcohol dehydrogenase were accompanied by increases in thermal stability at lower extents of modification. Decreases in thermal stability result from greater modification. These results support suggestions that surface guanidino groups (arginyl groups) are an important factor in thermal stability of proteins.
Assuntos
Álcool Desidrogenase , Arginina , Temperatura Alta , Fosfopiruvato Hidratase , Soroalbumina Bovina , Amidas , Fenômenos Químicos , Química , Estabilidade de Medicamentos , Guanidina , Guanidinas , Imidoésteres , Compostos de Metilureia , Saccharomyces cerevisiae/enzimologiaRESUMO
The potential role of sodium sulphate in possible enhancement of the hepatoprotective action of N-acetylcysteine (NAC) in paracetamol (PCM) overdose was examined. The effects of sodium sulphate (200 mg/kg) in combination with NAC (400 mg/kg) administered intraperitoneally 2 h post-PCM dose, on mortality rate and plasma activities of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were investigated in mice 24 h after receiving a single oral dose of 400 mg/kg PCM. In addition, the effect on the mortality rate of PCM-treated animals of co-administering 400 mg/kg sodium sulphate with NAC (200 or 400 mg/kg) was also studied. NAC alone caused a marked reduction in the mortality rate of PCM-treated mice and a sharp drop in their plasma AST and ALT activities to near normal values. However, no additional reduction in plasma levels of AST and ALT was observed when sodium sulphate was co-administered with NAC. Similarly, sodium sulphate (200 mg/kg) administered alone to PCM-treated mice had no effect on the high mortality rate or the elevation in plasma AST and ALT activities observed in these animals. Furthermore, increasing the dose of sodium sulphate to 400 mg/kg did not influence the mortality rate. It is therefore concluded that sodium sulphate neither protects against paracetamol-induced hepatotoxicity nor enhances the hepatoprotective action of N-acetylcysteine.