Since inactivated SOD was not protective, the anticlastogenic effect should be related to the catalytic function of the enzyme. Chromosomal breakage and rearrangement in cell cultures from patients with chronic inflammatory diseases with autoimmune reactions, such as progressive systemic sclerosis, rheumatoid arthritis, systemic lupus erythematosus, Crohn disease, ulcerative colitis, and disseminated sclerosis was prevented by SOD, indicating that superoxide radicals were involved in the clastogenic process (9). time dependent. It was most important for monocytes, compared with lymphocytes, neutrophils, and fibroblasts. The cytochrome assay showed significantly diminished O2? TX1-85-1 production by monocytes, pretreated with SOD and washed thereafter. The preferential and rapid binding of SOD to monocytes may be of importance not only for the superoxide-mediated genotoxic effects, described above, but also from a therapeutic standpoint. It can explain the observation that beneficial effects of injected SOD lasted for weeks and months despite rapid clearance of the enzyme from the blood stream according to pharmacodynamic studies. DNA, exposed to a xanthineCxanthine oxidase system, was prevented partially with SOD alone and completely with a combination of SOD and catalase. They concluded that O2? and H2O2 collaborated in the production of OH to cause strand breakage in DNA in a HaberCWeiss-type reaction. In recent years, the role of Fenton-type reactions was proposed to explain hydroxylCradical mediated DNA damage by interaction of peroxides with iron-binding sites on DNA (4). Studies done on cellular systems showed that these genotoxic effects were preventable by iron chelators and the hydroxyl scavenger dimethyl sulfoxide, but not by SOD (5, 6). In contrast to this, our laboratory drew attention to indirect action mechanisms, in which O2? appeared to play a primary role, since the damage was regularly prevented by SOD alone, while catalase was not or irregularly protective (7, 8). Since inactivated SOD was not protective, the anticlastogenic effect should be related to the catalytic function of the enzyme. Chromosomal breakage and rearrangement in cell cultures from patients with chronic inflammatory diseases with autoimmune reactions, such as progressive systemic sclerosis, rheumatoid arthritis, systemic lupus erythematosus, Crohn disease, ulcerative colitis, and disseminated sclerosis was prevented by SOD, indicating that superoxide radicals were involved Rabbit Polyclonal to MSHR in the clastogenic process (9). Also, the chromosomal instability and the increase in sister chromatid exchanges in cell cultures from Bloom syndrome patients could be reduced to control values by addition of SOD (150 units/ml) to the medium (10). The strongest argument for the implication of superoxide in these clastogenic effects was the observation that exposure of blood cultures to a xanthine oxidase reaction, photoreduction of flavins or a phorbol 12-myristate 13-acetate (PMA)-stimulated respiratory burst resulted in chromosomal breakage and sister chromatid exchanges.This could be consistently prevented by addition of SOD (30C150 units/ml), while catalase was irregularly protective (11C13). Because it did not seem likely that extracellularly produced O2? would reach the nucleus without being scavenged by the intracellular SOD abundantly available in the cytosol, we proposed the formation of secondary clastogenic substances as an explanation. The reports of radiation biologists (14, 15) that the chromosome damage observed in irradiated persons is accompanied by transferable clastogenic plasma factors prompted us to look for such clastogenic factors (CF) in the plasma of patients with the above-mentioned diseases accompanied by spontaneous chromosome damage. These studies showed that CF are indeed regularly present in the plasma and in supernatants of patients TX1-85-1 cell cultures (8, 10, 16). Transferable clastogenic materials of low molecular weight were also isolated from supernatants of the above mentioned systems, in which chromosome damage was produced by generation of superoxide from TX1-85-1 various sources. Formation of CF was regularly prevented, when the cells were cultivated in presence of SOD. The clastogenic effects of preformed CF, after transfer into other cell cultures, were also prevented by SOD, indicating that superoxide was involved not only in the formation of these clastogenic plasma components, but also in.
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