Protective Effects of Superoxide Dismutase Related to Its Preferential Binding to Monocytes

Abstract

Superoxide dismutase (SOD) was used as a drug under the trade name Palosein before the enzymatic nature of this metallo-protein and the importance of superoxide release by inflammatory cells were recognized. The beneficial effects observed in joint disease of horses may have determined the choice of rheumatid arthritis and osteoarthritis as the first human diseases to be treated with this antioxidant enzyme. The first pilot study with bovine Cu—Zn SOD was published by Lund-Olesen and Menander (1974), and the promising results were confirmed in the following by several placebo-controlled double-blind clinical trials in patients with osteoarthritis (Flohé, 1988). However, improvement was not observed for all clinical and laboratory parameters chosen for the study. Intraarticular injection appeared to be more efficient than systemic treatment. Many other diseases were treated with SOD, including ischemia-reperfusion injury, organ transplantation, side effects of radiation and chemotherapy. For a large number of pathologies, however, the reports remained anecdotical. The general acceptance of SOD as a drug was retarded for various reasons, among which the results of pharmacodynamic studies were probably the most important. Because of the rapid clearance of the enzyme through the kidney, the clinical observations of therapeutic effects were doubted. Efforts were made to increase its maintainance in the circulation by binding the enzyme to various macromolecules, in particular polyethylene glycol. There was also considerable discussion with respect to the dosage. The first clinical trials in rheumatic disease were based on the doses found to beefficient in animal models of inflammation and varied between 2-16 mg daily. These models of inflammation had shown a bell-shaped dose response curve, higher doses being less effective than lower doses (Baret et al., 1984; Michelson et al., 1986; Vaille et al., 1990). Similar observations were reported later for SOD application after reperfusion of ischemic organs, where very high doses had been applied by bolus injection (Omar and McCord, 1990). The concept that SOD acts therapeutically according to its documented catalytic function on superoxide anion radicals released into the extracellular space was also doubtful, since there was no correlation between antiinflammatory activity and the level of circulating exogenous SOD (Baret et al., 1984). It was suggested that the anti-inflammatory action of exogenous SOD is due to attachment of the enzyme to the cell membrane (Michelson et al., 1986). This notion was supported by observations from our laboratory, demonstrating prevention of perinuclear halo formation in UVA-exposed fibroblast cultures by pretreatment with exogenous SOD, even after rinsing of the cells and resuspension in fresh, SOD-free medium before irradiation (Emerit et al., 1981). Recent observations of anticlastogenic effects in SOD-pretreated and washed lymphocyte cultures yielded similar results, which stimulated the investigations reported here.