title: 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: Laboratory of Microbiology and Oncology, Faculty of Pharmaceutical Sciences, DDS Research Institute, Sojo University, Kumamoto 860-0082, Japan.
authors: Jun
authors: J
authors: Fang
authors: Haibo
authors: H
authors: Qin
authors: Takahiro
authors: T
authors: Seki
authors: Hideaki
authors: H
authors: Nakamura
authors: Kenji
authors: K
authors: Tsukigawa
authors: Takashi
authors: T
authors: Shin
authors: Hiroshi
authors: H
authors: Maeda
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002248:Carbon Monoxide / Q000097:blood; D002316:Cardiotonic Agents / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D018932:Chemokine CCL2 / Q000097:blood; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004790:Enzyme Induction; D051547:Heme Oxygenase-1 / Q000096:biosynthesis*; D006427:Hemin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D022781:Hepatocytes / Q000187:drug effects; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008102:Liver Circulation; D008107:Liver Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D011092:Polyethylene Glycols / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D000637:Transaminases / Q000097:blood
chemical_list: D002316:Cardiotonic Agents; D018932:Chemokine CCL2; D017382:Reactive Oxygen Species; D011092:Polyethylene Glycols; D006427:Hemin; D002248:Carbon Monoxide; D051547:Heme Oxygenase-1; D000637:Transaminases; D053148:Caspase 3; D053179:Caspase 7