Recombinant human superoxide dismutases: production and potential therapeutical uses.
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.
Gorecki
M
M
Bio-Technology General, Rehovot.
Beck
Y
Y
Hartman
J R
JR
Fischer
M
M
Weiss
L
L
Tochner
Z
Z
Slavin
S
S
Nimrod
A
A
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D001483:Base Sequence; D002351:Carrageenan / Q000633:toxicity; D003300:Copper; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D004926:Escherichia coli / Q000235:genetics; D005609:Free Radicals; D006801:Humans; D008345:Manganese; D051379:Mice; D008969:Molecular Sequence Data; D011833:Radiation Injuries, Experimental / Q000188:drug therapy; D011837:Radiation-Protective Agents / Q000627:therapeutic use; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000302:isolation & purification / Q000493:pharmacokinetics / Q000627:therapeutic use; D013482:Superoxide Dismutase / Q000235:genetics* / Q000302:isolation & purification / Q000493:pharmacokinetics / Q000627:therapeutic use; D015032:Zinc
D000894:Anti-Inflammatory Agents, Non-Steroidal; D005609:Free Radicals; D011837:Radiation-Protective Agents; D011993:Recombinant Fusion Proteins; D008345:Manganese; D003300:Copper; D002351:Carrageenan; D013482:Superoxide Dismutase; D015032:Zinc