Mn porphyrin-based superoxide dismutase (SOD) mimic, MnIIITE-2-PyP5+, targets mouse heart mitochondria.
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>or=3 microM 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 microL/mg protein, the calculated MnIIITE-2-PyP5+ concentration is 5.1 microM, 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.
Spasojević
Ivan
I
Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA. spaso001@mc.duke.edu
Chen
Yumin
Y
Noel
Teresa J
TJ
Yu
Yiqun
Y
Cole
Marsha P
MP
Zhang
Lichun
L
Zhao
Yunfeng
Y
St Clair
Daret K
DK
Batinić-Haberle
Ines
I
D000818:Animals; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology*; D008345:Manganese / Q000378:metabolism; D008665:Metalloporphyrins / Q000494:pharmacology*; D051379:Mice; D008929:Mitochondria, Heart / Q000187:drug effects / Q000502:physiology*; D008958:Models, Molecular; D013053:Spectrophotometry; D013482:Superoxide Dismutase / Q000378:metabolism*; D015032:Zinc / Q000378:metabolism
D000975:Antioxidants; D008665:Metalloporphyrins; C431023:manganese (III) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin; D008345:Manganese; D013482:Superoxide Dismutase; D015032:Zinc