Abstract
The Mn(III) meso-tetrakis( N-ethylpyridinium-2-yl)porphyrin, Mn IIITE-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 IIITE-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 μM Mn IIITE-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 IIITE-2-PyP 5+ are obtainable in vivo. For this study we have developed a new and sensitive method for Mn IIITE-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 IITE-2-PyP 4+. At 4 and 7 h after a single 10 mg/kg intraperitoneal administration of Mn IIITE-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 IIITE-2-PyP 5+ localized in heart mitochondria to 2.95 ng/mg protein. Given the average value of mitochondrial volume of 0.6 μL/mg protein, the calculated Mn IIITE-2-PyP 5+ concentration is 5.1 μM, which is sufficient to protect mitochondria from oxidative damage. This study establishes, for the first time, that Mn IIITE-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.
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