On the selectivity of superoxide dismutase mimetics and its importance in pharmacological studies

Abstract

The list of pathophysiological conditions associated with the overproduction of superoxide expands every day. Much of the knowledge compiled on the role of this radical in disease has been gathered using the native superoxide dismutase enzyme and, more recently, by the use of superoxide dismutase knockout models or transgenic models that overexpress the various isoforms of the enzyme. Although the native enzyme has shown promising anti‐inflammatory properties in both preclinical and clinical studies, there were drawbacks and issues associated with its use as a therapeutic agent and pharmacological tool. Based on the concept that removal of superoxide modulates the course of inflammation, synthetic, low‐molecular‐weight mimetics of the superoxide dismutase enzymes that could overcome some of the limitations associated with the use of the native enzyme have been designed. In this review, we will discuss the advances made using various superoxide dismutase mimetics that led to the proposal that superoxide (and/or the product of its interaction with nitric oxide, peroxynitrite) is an important mediator of inflammation, and to the conclusion that superoxide dismutase mimetics can be utilized as therapeutic agents in diseases of various etiologies. The importance of the selectivity of such compounds in pharmacological studies will be discussed. British Journal of Pharmacology (2003) 140, 445–460. doi:

Reduction of paraquat-induced renal cytotoxicity by manganese and copper complexes of EGTA and EHPG

“…The role of superoxide in paraquat toxicity has prompted much interest in the development of safe and effective antioxidants to negate its injurious effects [12]. Unfortunately, native SOD cannot be used effectively due to recognized problems with its short half-life, poor bioavailability, and immunogenicity [13], [14] and [15]. Furthermore, SOD can have pro-oxidant activities at higher concentrations, e.g., Cu/ZnSOD can promote the generation of hydroxyl radicals [16] and [48] and inhibit the ability of superoxide to regulate lipid peroxidation [19] and [49].…”

“…Furthermore, SOD can have pro-oxidant activities at higher concentrations, e.g., Cu/ZnSOD can promote the generation of hydroxyl radicals [16] and [48] and inhibit the ability of superoxide to regulate lipid peroxidation [19] and [49]. This has generated much interest in SODm, leading to the development of agents including macrocyclics, manganese salens, nitroxides, porphyrins, and many other catalytic antioxidants [15], [20], [50], [51], [52], [53], [54] and [55]. However, many of these have also suffered problems ranging from cytotoxicity to poor stability [23] and [56].…”

“…Unfortunately, the effectiveness of exogenously administered antioxidant enzymes such as SOD in vivo has been hindered by factors such as its poor bioavailability, low stability, or rapid hydrolysis in the blood and problems regarding its immunogenicity [13], [14] and [15]. Furthermore, SOD itself can have pro-oxidant effects at higher concentrations [16], [17], [18] and [19], for example, via the possibility that Cu 2+ derived from Cu/ZnSOD may facilitate the generation of oxidative stress in the presence of glutathione [17] or via the ability of superoxide to both initiate and terminate lipid peroxidation [19].…”

“…Furthermore, SOD itself can have pro-oxidant effects at higher concentrations [16], [17], [18] and [19], for example, via the possibility that Cu 2+ derived from Cu/ZnSOD may facilitate the generation of oxidative stress in the presence of glutathione [17] or via the ability of superoxide to both initiate and terminate lipid peroxidation [19]. Subsequently, many different types of SOD mimetics (SODm) have been synthesized [15] and [20], including manganese(III) tetrakis(4-benzoic acid) porphyrin (MnTBAP) and M40401 (a manganese-containing SODm), which have been shown to reduce paraquat-induced lung and brain injury in the mouse and rat, respectively [21] and [22]. However, SODm also suffer problems regarding bioavailability and toxicity, e.g., their poor stability in vivo and pro-oxidant activities [23] and [24].…”

Superoxide Dismutase Mimics: Chemistry, Pharmacology, and Therapeutic Potential

“…All synthetic SOD mimics can scavenge peroxynitrite or its degradation products (Table 1). It has been claimed that Mn(II) cyclic polyamine cannot do so (see later under Mn cyclic polyamines), but no experimental evidence or explanation was given to support such claims (230). MnTBAP 3À is not an SOD mimic, but is an ONOO À scavenger and could thus be used for mechanistic studies, in combination with SOD mimic, MnTE-2-PyP 5þ , to distinguish the role of those species in vivo.…”