Mn porphyrin-based superoxide dismutase (SOD) mimic, Mn(III)TE-2-PyP(5+), targets mouse heart mitochondria.
The Mn(III) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin, Mn(III)TE-2-PyP(5+) (AEOL-10113) has proven effective in treating oxidative stress-induced conditions including cancer, radiation damage, diabetes, and central nervous system trauma. The ortho cationic pyridyl nitrogens of MnTE-2-PyP(5+) are essential for its high antioxidant potency. The exceptional ability of Mn(III)TE-2-PyP(5+) to dismute O(2)(.-) parallels its ability to reduce ONOO(-) and CO(3)(-). Decreasing levels of these species are considered its predominant mode of action, which may also involve redox regulation of signaling pathways. Recently, Ferrer-Sueta at al. (Free Radic. Biol. Med. 41:503-512; 2006) showed, with submitochondrial particles, that >/=3 muM Mn(III)TE-2-PyP(5+) was able to protect components of the mitochondrial electron transport chain from peroxynitrite-mediated damage. Our study complements their data in showing, for the first time that micromolar mitochondrial concentrations of Mn(III)TE-2-PyP(5+) are obtainable in vivo. For this study we have developed a new and sensitive method for Mn(III)TE-2-PyP(5+) determination in tissues. The method is based on the exchange of porphyrin Mn(2+) with Zn(2+), followed by the HPLC/fluorescence detection of Zn(II)TE-2-PyP(4+). At 4 and 7 h after a single 10 mg/kg intraperitoneal administration of Mn(III)TE-2-PyP(5+), the mice (8 in total) were anesthetized and perfused with saline. Mitochondria were then isolated by the method of Mela and Seitz (Methods Enzymol.55:39-46; 1979). We found Mn(III)TE-2-PyP(5+) localized in heart mitochondria to 2.95 ng/ mg protein. Given the average value of mitochondrial volume of 0.6 muL/ mg protein, the calculated Mn(III)TE-2-PyP(5+) concentration is 5.1 muM, which is sufficient to protect mitochondria from oxidative damage. This study establishes, for the first time, that Mn(III)TE-2-PyP(5+), a highly charged metalloporphyrin, is capable of entering mitochondria in vivo at levels sufficient to exert there its antioxidant action; such a result encourages its development as a prospective therapeutic agent.[1]References
- Mn porphyrin-based superoxide dismutase (SOD) mimic, Mn(III)TE-2-PyP(5+), targets mouse heart mitochondria. Spasojević, I., Chen, Y., Noel, T.J., Yu, Y., Cole, M.P., Zhang, L., Zhao, Y., St Clair, D.K., Batinić-Haberle, I. Free Radic. Biol. Med. (2007) [Pubmed]
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