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.
Footnotes
This work was supported in part by the Ministry of Education, Science, Culture, Sports, and Technology of Japan [Grants-in-Aid 17016076, 20015405]; and research funds from the Faculty of Pharmaceutical Sciences at Sojo University.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.111.185348.
↵ The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
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ABBREVIATIONS:
- ROS
- reactive oxygen species
- HO
- heme oxygenase
- XO
- xanthine oxidase
- PEG
- poly(ethylene glycol)
- EPR
- enhanced permeability and retention
- I/R
- ischemia/reperfusion
- TBARS
- thiobarbituric acid reactive substance
- PCR
- polymerase chain reaction
- ZnPP
- zinc protoporphyrin
- DLS
- dynamic light scattering
- AUC
- area under the concentration versus time curve
- Hc
- hepatocytes
- GAPDH
- glyceraldehyde-3-phosphate dehydrogenase
- SMA
- styrene maleic acid
- ALT
- alanine aminotransferase
- AST
- aspartate aminotransferase
- LDH
- lactate dehydrogenase
- TUNEL
- terminal deoxynucleotidyl transferase dUTP nick-end labeling
- 8-OHdG
- 8-hydroxydeoxyguanosine
- ELISA
- enzyme-linked immunosorbent assay
- MCP-1
- monocyte chemotactic protein 1.
- Received June 23, 2011.
- Accepted September 2, 2011.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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