Recombinant Human Superoxide Dismutases: Production and Potential Therapeutical Uses

Abstract

In many pathological situations, tissue damage is caused by cellular generation of superoxide free radicals (O2-). These active species are generated during post-ischemic reperfusion of organs, in hyperoxic tissue, during acute and chronic inflammation and during exposure to ionizing radiation. Exogenous superoxide dismutase (SOD) was shown to significantly prevent such damage. The genes for human cytosolic Cu/ZnSOD and mitochondrial MnSOD were cloned and introduced into an E. coli expression system. The proteins were expressed in high yields and purified to homogeneity, yielding pharmaceutical-grade materials. These enzymes were used in a variety of in vivo animal models for the demonstration of their protective effects against oxidative damage. Comparative pharmacokinetic studies in rats have revealed that the half-life of Cu/ZnSOD was 6-10 min., while that of MnSOD was 5-6 hours, thus indicating that MnSOD may be superior to Cu/ZnSOD for the treatment of chronic diseases. Indeed, MnSOD was found to be effective as an anti-inflammatory agent in the rat carrageenan induced paw edema acute inflammation model. Both enzymes were also effective in ameliorating post-irradiation damage in mice exposed to whole-body or localized chest X-ray radiation.

Adenovirus-mediated overexpression of extracellular superoxide dismutase improves endothelial dysfunction in a rat model of hypertension

“…The half-lives of CuZnSOD and MnSOD have been estimated to be 6 min and 6 h, respectively, 43 whereas the half-life of ECSOD has been calculated at 20 h. 44 This is almost certainly the result of the ability of ECSOD to bind to the endothelial cell surface heparan sulphate proteoglycans. If this correlates to the half-life of SODs in the vessel wall, the combination of the longer-lasting SOD isoform with continuous protein production from gene transfer will provide a definite improvement over earlier SOD protein infusion methods and forms a promising basis for future longer-term experiments.…”

Superoxide Dismutases: Role in Redox Signaling, Vascular Function, and Diseases

“…Unlike SOD1, SOD2 does not exhibit product inhibition by H 2 O 2 (10,17). Also, SOD2 has a half-life in sera of 5-6 hr compared with 6-10 min for the SOD1 (78). The essential role of SOD2 in maintaining mitochondrial function is demonstrated by the neonatal lethality of mice with targeted disruption of the gene for SOD2.…”

Characterization of the Manganese-Containing Superoxide Dismutase and Its Gene Regulation in Stress Response of Schizosaccharomyces pombe

“…The observation that the purified Sod2p of S. pombe exists as a homodimer contrasts with other eukaryotic MnSODs, which are usually homotetramers, similar to the procaryotic enzymes which are dimers (1). Since the tertiary structure and the subunit assembly of MnSODs are known to be important for their functions (39,40), the dimeric form of the eukaryotic MnSOD presents a good example to investigate the relationship between oligomeric state and the enzymatic activity.…”