Authors: Ali SS; Hardt JI; Quick KL; Kim-Han JS; Erlanger BF; Huang TT; Epstein CJ; Dugan LL
Abstract: Superoxide, a potentially toxic by-product of cellular metabolism, may contribute to tissue injury in many types of human disease. Here we show that a tris-malonic acid derivative of the fullerene C60 molecule (C3) is capable of removing the biologically important superoxide radical with a rate constant (k(C3)) of 2 x 10(6) mol(-1) s(-1), approximately 100-fold slower than the superoxide dismutases (SOD), a family of enzymes responsible for endogenous dismutation of superoxide. This rate constant is within the range of values reported for several manganese-containing SOD mimetic compounds. The reaction between C3 and superoxide was not via stoichiometric "scavenging," as expected, but through catalytic dismutation of superoxide, indicated by lack of structural modifications to C3, regeneration of oxygen, production of hydrogen peroxide, and absence of EPR-active (paramagnetic) products, all consistent with a catalytic mechanism. A model is proposed in which electron-deficient regions on the C60 sphere work in concert with malonyl groups attached to C3 to electrostatically guide and stabilize superoxide, promoting dismutation. We also found that C3 treatment of Sod2(-/-) mice, which lack expression of mitochondrial manganese superoxide dismutase (MnSOD), increased their life span by 300%. These data, coupled with evidence that C3 localizes to mitochondria, suggest that C3 functionally replaces MnSOD, acting as a biologically effective SOD mimetic.
Keywords: Animals; Antioxidants/chemical synthesis/chemistry/*pharmacology; Brain/cytology; Catalysis; Cells, Cultured/metabolism; Drug Design; Drug Evaluation, Preclinical; Free Radical Scavengers/chemical synthesis/chemistry/*pharmacology; Fullerenes/chemistry/*pharmacology; Hydrogen Peroxide/metabolism; Kinetics; Longevity/drug effects; Mice; Mice, Congenic; Mice, Inbred DBA; Mice, Knockout; Mitochondria/drug effects/enzymology; Models, Chemical; Models, Molecular; Molecular Mimicry; Molecular Structure; Neurons/metabolism/ultrastructure; Oxygen/metabolism; Recombinant Proteins/analysis; Static Electricity; Structure-Activity Relationship; Subcellular Fractions/chemistry; Superoxide Dismutase/deficiency/genetics/*metabolism; Superoxides/*metabolism|
Journal: Free radical biology & medicine Volume: 37 Issue: 8 Pages: 1191-202 Date: Sept. 29, 2004 PMID: 15451059 |
Ali SS, Hardt JI, Quick KL, Kim-Han JS, Erlanger BF, Huang TT, Epstein CJ, Dugan LL (2004) A biologically effective fullerene (C60) derivative with superoxide dismutase mimetic properties. Free radical biology & medicine 37: 1191-202.
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