Therapeutic potential of pegylated hemin for reactive oxygen species-related diseases via induction of heme oxygenase-1: results from a rat hepatic ischemia/reperfusion injury model.
J Pharmacol Exp Ther
; 339(3): 779-89, 2011 Dec.
Article
en En
| MEDLINE
| ID: mdl-21890508
ABSTRACT
Many diseases and pathological conditions, including ischemia/reperfusion (I/R) injury, are the consequence of the actions of reactive oxygen species (ROS). Controlling ROS generation or its level may thus hold promise as a standard therapeutic modality for ROS-related diseases. Here, we assessed heme oxygenase-1 (HO-1), which is a crucial antioxidative, antiapoptotic molecule against intracellular stresses, for its therapeutic potential via its inducer, hemin. To improve the solubility and in vivo pharmacokinetics of hemin for clinical applications, we developed a micellar hemin by conjugating it with poly(ethylene glycol) (PEG) (PEG-hemin). PEG-hemin showed higher solubility in water and significantly prolonged plasma half-life than free hemin, which resulted from its micellar nature with molecular mass of 126 kDa in aqueous media. In a rat I/R model, administration of PEG-hemin significantly elevated HO-1 expression and enzymatic activity. This induction of HO-1 led to significantly improved liver function, reduced apoptosis and thiobarbituric acid reactive substances of the liver, and decreased inflammatory cytokine production. PEG-hemin administration also markedly improved hepatic blood flow. These results suggest that PEG-hemin exerted a significant cytoprotective effect against I/R injury in rat liver by inducing HO-1 and thus seems to be a potential therapeutic for ROS-related diseases, including I/R injury.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Polietilenglicoles
/
Cardiotónicos
/
Daño por Reperfusión
/
Especies Reactivas de Oxígeno
/
Hemo-Oxigenasa 1
/
Hemina
/
Hígado
/
Hepatopatías
Tipo de estudio:
Prognostic_studies
Idioma:
En
Revista:
J Pharmacol Exp Ther
Año:
2011
Tipo del documento:
Article
País de afiliación:
Japón