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.

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.

• Authors: Jun Fang, Haibo Qin, Takahiro Seki, Hideaki Nakamura, Kenji Tsukigawa, Takashi Shin, Hiroshi Maeda
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 339 Issue 3 Pg. 779-89 (Dec 2011) ISSN: 1521-0103 [Electronic] United States
• PMID: 21890508 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cardiotonic Agents
• Chemokine CCL2
• Reactive Oxygen Species
• Polyethylene Glycols
• Hemin
• Carbon Monoxide
• Heme Oxygenase-1
• Transaminases
• Caspase 3
• Caspase 7

Topics

• Animals
• Apoptosis (drug effects)
• Carbon Monoxide (blood)
• Cardiotonic Agents (pharmacology)
• Caspase 3 (metabolism)
• Caspase 7 (metabolism)
• Cell Survival (drug effects)
• Chemokine CCL2 (blood)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Drug Evaluation, Preclinical
• Enzyme Induction
• Heme Oxygenase-1 (biosynthesis)
• Hemin (analogs & derivatives, chemistry, pharmacology, therapeutic use)
• Hepatocytes (drug effects)
• Humans
• Liver (drug effects, metabolism)
• Liver Circulation
• Liver Diseases (drug therapy, metabolism, physiopathology)
• Male
• Polyethylene Glycols (chemistry, pharmacology, therapeutic use)
• Rats
• Rats, Wistar
• Reactive Oxygen Species (metabolism)
• Reperfusion Injury (drug therapy, metabolism, physiopathology)
• Transaminases (blood)