RT Journal Article
SR Electronic
T1 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
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 779
OP 789
DO 10.1124/jpet.111.185348
VO 339
IS 3
A1 Fang, Jun
A1 Qin, Haibo
A1 Seki, Takahiro
A1 Nakamura, Hideaki
A1 Tsukigawa, Kenji
A1 Shin, Takashi
A1 Maeda, Hiroshi
YR 2011
UL http://jpet.aspetjournals.org/content/339/3/779.abstract
AB 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.