PT  - JOURNAL ARTICLE
AU  - Jun Fang
AU  - Haibo Qin
AU  - Takahiro Seki
AU  - Hideaki Nakamura
AU  - Kenji Tsukigawa
AU  - Takashi Shin
AU  - Hiroshi Maeda
TI  - 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
AID  - 10.1124/jpet.111.185348
DP  - 2011 Dec 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 779--789
VI  - 339
IP  - 3
4099  - http://jpet.aspetjournals.org/content/339/3/779.short
4100  - http://jpet.aspetjournals.org/content/339/3/779.full
SO  - J Pharmacol Exp Ther2011 Dec 01; 339
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.