Mn porphyrin-based superoxide dismutase (SOD) mimic, MnIIITE-2-PyP5+, targets mouse heart mitochondria.
Mn porphyrin-based superoxide dismutase (SOD) mimic, MnIIITE-2-PyP5+, targets mouse heart mitochondria.
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DOI：
10.1016/j.freeradbiomed.2007.01.019
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发表时间：
2007-04
影响因子：
7.4
通讯作者：
I. Spasojević;Yumin Chen;T. Noel;Yiqun Yu;Marsha P Cole;Lichun Zhang;Yunfeng Zhao;D. S. St. Clair;I. Batinic-Haberle
中科院分区：
文献类型：
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作者：
I. Spasojević;Yumin Chen;T. Noel;Yiqun Yu;Marsha P Cole;Lichun Zhang;Yunfeng Zhao;D. S. St. Clair;I. Batinic-Haberle
The Mn(III) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin, MnIIITE-2-PyP5+(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-PyP5+are essential for its high antioxidant potency. The exceptional ability of MnIIITE-2-PyP5+to dismute O2·−parallels its ability to reduce ONOO−and CO3−. 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 MnIIITE-2-PyP5+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 MnIIITE-2-PyP5+are obtainable in vivo. For this study we have developed a new and sensitive method for MnIIITE-2-PyP5+determination in tissues. The method is based on the exchange of porphyrin Mn2+with Zn2+, followed by the HPLC/fluorescence detection of ZnIITE-2-PyP4+. At 4 and 7 h after a single 10 mg/kg intraperitoneal administration of MnIIITE-2-PyP5+, 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 MnIIITE-2-PyP5+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 MnIIITE-2-PyP5+concentration is 5.1 μM, which is sufficient to protect mitochondria from oxidative damage. This study establishes, for the first time, that MnIIITE-2-PyP5+, 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.
