Trends in Pharmacological Sciences
ReviewMetalloporphyrin class of therapeutic catalytic antioxidants
Section snippets
Catalytic antioxidants
SOD and catalase are metalloproteins that employ efficient dismutation reactions in their mechanisms to detoxify ROS. A dismutation reaction involves a series of one- or two-electron transfers where the electrons are accepted from one O2− or H2O2 and then donated to another (18, 19) (Eqns 3, 4, Fig. 1). These efficient reactions do not require reducing equivalents and thus do not require energy from the cell to operate. The overexpression of these enzymes in cell culture and in whole animals
Development of SOD mimetics
Most catalytic SOD mimetics are designed with a redox-active metal centre that catalyses the dismutation reaction with O2− in a manner similar to the active site metals of the mammalian (Cu or Mn) SODs. An ideal SOD mimetic should be stable, with high specificity for interaction with O2− and with a high rate constant; it should also be non-toxic, much like the native SODs. Additionally, their size and charge can be exploited for targeting crucial cellular sites of oxidative stress.
It has been
Antioxidant properties of metalloporphyrins
Metalloporphyrins have been shown to possess at least four distinct antioxidant properties (Table 1, Table 2)32, 33, 34, 35, 36, 37, 38, 39, 40. These include scavenging O2−, H2O2, ONOO− and lipid peroxyl radicals. The manganese moiety of the SOD mimetics functions in the dismutation reaction with O2− by alternate reduction and oxidation changing in its valence between Mn(III) and Mn(II), much like native SODs (Fig. 2). The catalase activity of metalloporphyrins could be attributed to their
SOD-null Escherichia coli
Mutant E. coli lacking MnSOD (SodA) or FeSOD (SodB), or both, provide a simple and elegant model for exploring the function of synthetic SODs. The sodAsodB-null strain of E. coli is indistinguishable from its SOD competent parental strain under anaerobic conditions, but under aerobic conditions it shows oxygen-dependent nutritional auxotrophies, retarded growth, hypersensitivity to O2− generating agents (such as paraquat) and increased mutagenesis42. The O2− dependent auxotrophies in sodAsodB
Acute lung injury
Paraquat is a herbicide that increases intracellular O2− levels by redox cycling with cellular diaphorases. Systemic administration of paraquat produces lung injury by selectively accumulating in it and elevating O2− concentrations while depleting cellular NADPH (Ref. 61). Acute paraquat poisoning produces a chemical-induced interstitial pneumonia with injury occurring primarily to capillary endothelial cells and type I pneumocytes62. The metalloporphyrin, MnTBAP, can attenuate
Limitations of metalloporphyrins
Although MnTBAP has proven to be a very effective compound in a wide range of oxidative stress paradigms, we have found that its potency and efficacy can be quite variable. This could be due to varying degrees of porphyrin modification that occurs during its metallation reaction in dimethyl formamide that greatly modulates the activity of the compound in SOD assays and in oxidative stress models. Another general limitation of metalloporphyrins is their poor blood–brain permeability that
Implications for human disease
The postulated role of ROS, as common mediators of tissue damage in diseases of diverse aetiologies, emphasizes the wide range of possible therapeutic applications of metalloporphyrins. Pathologies most likely to benefit from metalloporphyrin therapy include conditions in which a clear role for O2− and its metabolites has been established (Table 3). Inflammation, an important etiological factor that accompanies diseases involving multiple organs, comprises a major therapeutic area for
Acknowledgements
We are grateful to Drs Irwin Fridovich and James D. Crapo for guiding our research and their helpful suggestions on this manuscript.
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