Superoxide Dismutase

Description

Superoxide dismutase (SOD) is an enzyme found in humans protecting against toxic by-products of oxygen metabolism and damage from oxygen-derived free radicals.

Superoxide dismutase acts as an antioxidant to handle cytotoxic free radicals formed from oxygen. These highly reactive free radicals are: superoxide radical, hydrogen peroxide, hydroxyl radical, singlet oxygen and peroxide radical. Free radicals can originate endogenously from normal metabolic reactions or exogenously as components of tobacco smoke, air pollutants and pesticides.

Target molecules of free radicals are proteins, DNA and polyunsaturated fatty acids. Alterations in these target molecules can lead to cell death. Superoxide dismutase converts the free radical form of oxygen, superoxide anion (also known as the superoxide radical), into harmless molecular oxygen (O2) and hydrogen peroxide (H2O2). Along with another enzyme, eglutathione peroxidase, SOD constitutes the first line of defense against radical oxidants. Evidence suggests an increase in antioxidant activity is associated with higher resistance to oxidant stresses.

There are two forms of SOD in human tissue. The majority of the SOD enzyme is found in the liver and erythrocytes. Smaller quantities are found in neutrophils. One form is a protein containing two atoms each of copper and zinc and is present in the cytosol. The other form is a much larger molecule containing four atoms of manganese and is found in the mitochondria and cytosol. Therefore, significant changes in cellular concentrations of copper, manganese and zinc have the potential of altering the antioxidant activity of SOD. Cellular concentrations of these minerals can affect the efficiency and rate at which SOD traps the free radical species.

The lungs are particularly susceptible to damage from oxygen free radicals, such as the superoxide radical. Some sources of superoxide radicals include: photochemical smog, ozone, nitrogen dioxide, phosgene (mustard gas), x-irradiation, some anticancer agents (e.g. bleomycin, adriamycin), some antibacterial agents (e.g. nitrofurantoin) and herbicides (e.g. paraquat).

To protect against damage to lung cells upon exposure to the above substances, SOD and other scavenging enzymes increase production. When this is not possible, injected SOD acts as a protective agent, such as with an immature infant having respiratory distress syndrome who requires vigorous hyperoxic therapy and who is prone to the development of bronchopulmonary dysplasia (BPD).

Oxygen therapy for premature infants is one of many such examples used in medicine today. However, such therapies are recognized as potentially toxic since oxygen is supplied at concentrations greater than those in normal air. An example would be the use of hyperbaric oxygen therapy reported in the early treatment of multiple sclerosis, or in the critical care of stroke or spinal cord injury cases.

Method of Action

Mitochondrial SOD contains manganese, while cytoplasmic SOD requires zinc and copper. These antioxidants reduce peroxy radicals to phenoxyl radicals, which are stable and relatively nonreactive. This stability interrupts the chain reaction. Phenoxyl radicals may eventually be destroyed by reacting with a second peroxy radical, thereby yielding non-radical products, or being reduced to the starting phenol by a water-soluble reducing agent such as ascorbic acid (vitamin C).

SOD given as orgotein (the generic name for a drug identical to SOD) has pronounced anti-inflammatory effects in animal models. Evidence suggests extracellular SOD stabilizes the cell and organelle membranes of polymorphonuclear leukocytes and macrophages, thus protecting these cell types against lysis induced by phagocytosis. Primary attention is given to studies of localized inflammatory pathologies such as degenerative joint diseases, osteoarthritis and osteoarthrosis, radiation-induced chronic inflammation, and selected musculoskeletal diseases.

Evidence for superoxide dismutase (SOD) as a primary defense against oxygen toxicity comes from numerous in vitro and in vivo eukaryote and prokaryote studies.

Therapeutic Approaches

The bioavailability of SOD (as orgotein), by routes other than i.v., is less than 100%. Oral SOD is the least effective route of administration. A study at University of California showed SOD-supplemented mice had no difference in the activity of copper, zinc or manganese SOD in the intestine, liver, kidney or blood than controls receiving SOD supplements.

Since SOD is an enzyme, it may be completely digested (degraded) before absorption. These results should not discredit the injectable form of SOD, namely, orgotein.

Studies suggest many neurological and degenerative diseases and disorders, ie. Down's syndrome, Batten's syndrome and myocardial dysfunction, may be associated with free radical pathology. The highly reactive free radical molecules can cause tissue damage by reacting with polyunsaturated fatty acids in cellular membranes, nucleotides in DNA and critical sulfhydryl bonds in proteins.

This may help to explain how these free radicals contribute to cardiovascular disease, emphysema, various inflammatory diseases and cancer. Some studies are examining the possibility that restoring low levels of SOD back to normal may be beneficial in these and related conditions.

Throughout Europe, orgotein is widely used as a registered drug for the treatment of osteoarthritis, rheumatoid arthritis, tendinitis, bursitis, epicondylitis, interstitial and radiation cystitis, and the amelioration of proctitis and acute cystitis occurring during radiotherapy of abdominal malignancies.

Osteoarthritis

Like glycosaminoglycan preparations, intra-articular injections of SOD have proven to be beneficial in the treatment of osteoarthritis in humans.

Ischemia-reperfusion Injury

SOD has been shown to reduce reperfusion-induced red blood cell loss across the gastric mucosa in rats exposed to hemorrhagic shock and in cats subjected to local reduction of celiac artery pressure. SOD has been shown to reduce the formation of gross lesions after retransfusion of shed blood in the rat.

This basic tenant of antioxidant therapy was demonstrated in a review of SOD (as orgotein) and free radical pathology: delivery of an effective amount of the factor to sites of pathology requires continued intake of sufficiently high total doses to establish the concentration gradient which will produce the desired result.

Nutritional deficiencies of manganese, zinc or copper can greatly lower SOD activity, so it is important to evaluate red blood cell activity.

For example, red blood cell SOD activity has been found to be useful in evaluating the biochemical index of copper nutrition.

In a double-blind study of 17 infants recovering from malnutrition and receiving copper supplementation, there was a significant rise in plasma copper from 96 mcg/dl to 165 mcg/dl and SOD activity from 1073 to 1371units per gram of hemoglobin.

In another study it was found manganese levels correlate with SOD activity in the red blood cell. Therefore, it has been concluded the evaluation of SOD activity in the red blood cell may be a useful tool for establishing both manganese and copper adequacy.

SOD appears to be an anti-inflammatory, as demonstrated by laboratory animal studies. A review of numerous studies using orgotein (a SOD drug) has found it to be a unique anti-inflammatory drug with long-lasting effects.

Orgotein can be used in conjunction with other anti-inflammatory drugs, such as aspirin, with very low toxicity potential. Further, new research has found SOD should not be easily inactivated by hypochlorous acid (HOCI) at sites of inflammation.

This refractoriness may contribute to SOD's effectiveness as an anti-inflammatory agent while minimizing reperfusion injury.

In cases of pulmonary infection, with or without pneumonia, evidence suggests SOD levels are lower and superoxide radical levels higher. These findings suggest a decreased activity and concentration of SOD in compromised controls may be partly responsible for the depression of the host's immune system.

Toxicity Factors

SOD, in the form of the generic drug called orgotein, has been extensively studied for its safety. A comprehensive discussion of SOD's lack of toxicity has been published Huber and Saifer. That orgotein and SOD are identical has been established beyond doubt by assay. At least 80% of orgotein protein is Cu-Zn SOD. The shelf life of the single-dose vials of sterile, non-pyrogenic, lyophilized powder at 40 degrees C is in excess of five years. Studies of orgotein's safety have included acute, subacute and chronic toxicity; evaluation of hematology, biochemistry and histopathology; and reproduction and teratology studies. No toxic effects have been seen in any of the studies reported by Huber and Saifer.

Orgotein has been safely administered in humans by intravenous, intra-arterial, intra-peritoneal, intramuscular, subcutaneous, intra-articular, subconjunctival, intraocular, intrathecal, intramural, intrapulmonary and topical routes. The safety of orgotein is due in part to the fact it remains outside the cell after administration and thus does not interfere with intracellular functions.

As a nutritional supplement 100 iu is a typical dosage. Endogenous production is 5 million units a day!

Abstracts

References

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