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SOD

Common Name(s): Cu/Zn SOD, Fe SOD, Metalloprotein, Mn Sod, Orgotein, Palosein

Clinical Overview

Use

Superoxide dismutase (SOD) enzymes are found in all living cells in several common forms. These enzymes have been used for anti-inflammatory effects (in osteoarthritis, rheumatoid arthritis, and idiopathic pulmonary fibrosis), but limited clinical trials are available to support use. Clinical trials evaluating the use of SOD in cancer, cardiovascular disease, and other conditions in which antioxidant status plays a role, are also lacking. No evidence exists regarding long-term use of SOD.

Dosing

Oral supplementation is limited by the enzyme’s inactivation by gastric acid; however, newer formulations may overcome this limitation.

Daily intravenous (IV) administration of 40 or 80 mg of lecithinized SOD over 28 days was compared with placebo in idiopathic pulmonary fibrosis.

Weekly administration of an intra-articular injection of SOD 8 to 32 mg has been studied.

A 500 mg dosage of plant-derived oral SOD (commercial product) taken once daily over 6 weeks was used in one clinical study.

Contraindications

Contraindications have not been identified.

Pregnancy/Lactation

Avoid use. Information regarding safety and efficacy in pregnancy and lactation is lacking.

Interactions

None well documented.

Adverse Reactions

Information from large clinical studies is lacking; however, adverse effects appear to be limited. Pain and irritation at injection sites have been reported.

Toxicology

SOD is regarded as nontoxic, based on data from earlier studies. Data on newer formulations are lacking.

Source

SOD was initially biochemically extracted from the serum and liver of animals, as well as from plant sources; however, this process was inefficient.1 Induction of oxidative stress in microbes has been the mainstay of SOD production; however, a method in which recombinant Cu/Zn SOD is produced in Escherichia coli and bound to lecithin has been developed.2, 3 Commercial preparations previously relied on bovine-derived SOD (orgotein and palosein), with patents also filed for yeast- and marine-derived SOD.1

History

In 1967, geneticist George J. Brewer described the protein indophenol oxidase, which was later identified as superoxide dismutase, in his work analyzing starch gels.4 The enzymatic activity of SOD was first described in 1968 by biochemists Irwin Fridovich and Joe M. McCord.5 In Germany, SOD (as orgotein) has long been used in general medicine as an anti-inflammatory agent.6

Chemistry

SOD has 3 recognized forms in humans and other mammals. SOD1 and SOD2 (intracellular) contain copper and zinc, and SOD2 (found in mitochondria) relies on manganese for reactivity. The enzymatic forms found in plants also have an iron form.1, 5

SOD enzymes catalyze the conversion of superoxide, a reactive oxygen species (ROS) produced during aerobic respiration, to oxygen and hydrogen peroxide.5

Uses and Pharmacology

The role of SOD as a dietary supplement is examined in this monograph; for information on SOD deficiency states, see standard medical references.1

Anti-inflammatory effects

The use of SOD as an anti-inflammatory agent has been postulated because increased production of ROS is recognized to cause tissue damage associated with inflammation.7, 8, 9

Associated effects of decreased peroxynitrite production, decreased influx of neutrophils, and release of proinflammatory cytokines have been discussed.7

Animal data

Anti-inflammatory effects of SOD have been demonstrated in animal models.7, 9 Parenteral SOD has been used in the treatment of soft tissue inflammation in horses and dogs; however, in a study comparing exercise with oral SOD supplementation, biomarkers of inflammation were unaffected by SOD.10 In a study of oral SOD in horses undergoing a 60-day training regimen, creatine kinase activity, a marker of hemolysis, was steady in the SOD group compared with an increase in the placebo group.11

Clinical data

Limited, older clinical trials with intra-articular, bovine-derived SOD were conducted in patients with osteoarthritis.7 Superiority to placebo at 3 months has been demonstrated,12, 13 and a single trial evaluated the effectiveness of intramuscular bovine SOD in rheumatoid arthritis.14

In a double-blind, randomized, multicenter study in idiopathic pulmonary fibrosis (N = 55), daily IV administration of 40 or 80 mg of lecithinized SOD was compared with placebo over 28 days. Forced vital capacity did not improve in the treated arm; however, lactate dehydrogenase and surfactant protein-A makers were improved.15

Oral supplementation with plant-derived SOD improved SOD activity and reduced C-reactive protein in a study of 19 athletes. However, no effect on oxidative damage from exhaustive exercise was demonstrated.16

Cancer

Animal data

The relationship between ROS and cancer has been studied extensively, and the role of SOD expression in cancer cells has been evaluated, with most attention given to mitochondrial manganese SOD3.17, 18, 19 Animal model studies of supplemental SOD are limited.18

In vitro/in vivo data

A study of recombinant manganese SOD (rMnSOD) for pediatric acute lymphoblastic leukemia found increased apoptotic death in leukemic cells, with no effect on healthy lymphocytes at low and moderate concentrations.20

Clinical data

In a study evaluating the relationship between serum SOD levels and risk of cancer mortality, elevated serum SOD levels were associated with an increased risk of death from all cancers combined; this result may indicate an increased response to stress.21 Clinical studies of supplemental SOD in cancer treatment are limited. SOD has been evaluated in limited studies for its protective effects against irradiation-induced toxicities, with some reduction in late toxicity noted in one study of patients receiving pelvic radiation.9, 22

A lecithinized human recombinant SOD was not protective against the cardiotoxic effects of anthracycline treatment in breast cancer patients.23

Antiangiogenic properties of an inhibitor of Cu/Zn SOD have been evaluated in 47 patients with prostate cancer.24

Other uses

Antioxidant effects, such as in reperfusion injury, have been studied in rodents.25

No evidence exists regarding long-term use of SOD.

Dermatological applications have been evaluated, and a role for SOD3 supplementation has been theorized.26, 27 In a small clinical study of vitiligo (N = 25), topical application of a combination preparation containing catalase and SOD was similarly effective as compared with a topical corticosteroid.28

Limited clinical studies report equivocal results in psychometric scale measures and depression for oral administration of gliadin-SOD supplements compared with placebo.29, 30

Post hoc analysis of data in a subgroup of newborns suggested a reduction in the risk of retinopathy of prematurity with intratracheal administration of recombinant human Cu/Zn SOD.31

Combination preparations of alpha-lipoic acid and SOD are available and have been studied in diabetic neuropathy and chronic neck pain; however, attributing the observed effects to either of the compounds alone was not possible.32, 33

A rodent study reported benefit for angiotensin II–dependent hypertension using a nanozyme (nanomedicine-based delivery system) CuZnSOD; however, significance of results is limited due to limitations of the intracerebroventricular route of administration.34

Pretreatment with rMnSOD greatly reduced contrast-induced nephropathy in rats, including both intratubular cysts and tubular necrosis.35

Dosing

Orally administered SOD alone (including that occurring naturally in food) is rapidly degraded by gastric acids when ingested, even if enteric coated.36, 37 Methods such as liposomal encapsulation and coating with wheat-derived gliadin attempt to overcome poor oral bioavailability.25

Daily IV administration of 40 or 80 mg of lecithinized SOD over 28 days was compared with placebo in idiopathic pulmonary fibrosis.15

Weekly administration of an intra-articular injection of SOD 8 to 32 mg has been studied.12, 13

A 500 mg dosage of plant-derived oral SOD (commercial product) taken once daily over 6 weeks was used in one clinical study.16

Pharmacokinetic studies of a recombinant-derived SOD have evaluated IV doses of up to 160 mg and report a mean terminal half-life of 25 hours (standard deviation [SD] = 4 hours) for an 80 mg dose and 31 hours (SD = 15 hours) for a single 160 mg dose.2, 3

Pregnancy / Lactation

Avoid use. Information regarding safety and efficacy in pregnancy and lactation is lacking.

Interactions

None well documented.

Adverse Reactions

Information from large clinical studies is lacking; however, adverse effects appear to be limited.25 Pain and irritation at injection sites have been reported.7, 8

Toxicology

SOD is regarded as nontoxic, based on data from earlier studies. Data on newer formulations are lacking.38 The safety of SOD has been investigated in numerous animal models using doses up to 40,000 times the average human clinical dose of 0.1 mg/kg/day. Abnormalities were noted rarely following acute or long-term parenteral administration in mice, rats, dogs, and monkeys. SOD did not induce embryonic or teratogenic changes in rats or rabbits.39 The minimal lethal dose in animals was greater than 40,000 times the anticipated human clinical dose.40

References

1. Bafana A, Dutt S, Kumar S, Ahuja PS. Superoxide dismutase: an industrial perspective. Crit Rev Biotechnol. 2011;31(1):65-76.20919818
2. Broeyer FJ, van Aken BE, Suzuki J, et al. The pharmacokinetics and effects of a long-acting preparation of superoxide dismutase (PC-SOD) in man. Br J Clin Pharmacol. 2008;65(1):22-29.17610527
3. Suzuki J, Broeyer F, Cohen A, Takebe M, Burggraaf J, Mizushima Y. Pharmacokinetics of PC-SOD, a lecithinized recombinant superoxide dismutase, after single- and multiple-dose administration to healthy Japanese and Caucasian volunteers. J Clin Pharmacol. 2008;48(2):184-192.18089770
4. Brewer GJ. Achromatic regions of tetrazolium stained starch gels: inherited electrophoretic variation. Am J Hum Genet. 1967;19(5):674-680.4292999
5. McCord JM, Fridovich I. Superoxide dismutase. An enzymic function for erythrocuprein (hemocuprein). J Biol Chem. 1969;244(22):6049-6055.5389100
6. Huskisson E, Scott J. Orgotein in osteoarthritis of the knee joint. Eur J Rheumatol Inflamm. 1981;4(2):212-218.7044788
7. Afonso V, Champy R, Mitrovic D, Collin P, Lomri A. Reactive oxygen species and superoxide dismutases: role in joint diseases. Joint Bone Spine. 2007;74(4):324-329.17590367
8. Uthman I, Raynauld JP, Haraoui B. Intra-articular therapy in osteoarthritis. Postgrad Med J. 2003;79(934):449-453.12954956
9. Carillon J, Rouanet JM, Cristol JP, Brion R. Superoxide dismutase administration, a potential therapy against oxidative stress related diseases: several routes of supplementation and proposal of an original mechanism of action. Pharm Res. 2013;30(11):2718-2728.23793992
10. Lamprecht ED, Williams CA. Biomarkers of antioxidant status, inflammation, and cartilage metabolism are affected by acute intense exercise but not superoxide dismutase supplementation in horses. Oxid Med Cell Longev. 2012;2012:920932.22919442
11. Notin C, Vallon L, Desbordes F, Leleu C. Oral supplementation with superoxide dismutase in Standardbred trotters in training: a double-blind placebo-controlled study. Equine Vet J Suppl. 2010;42(suppl 38):375-381.21059033
12. McIlwain H, Silverfield JC, Cheatum DE, et al. Intra-articular orgotein in osteoarthritis of the knee: a placebo-controlled efficacy, safety, and dosage comparison. Am J Med. 1989;87(3):295-300.2773967
13. Goebel KM, Storck U, Neurath F. Intrasynovial orgotein therapy in rheumatoid arthritis. Lancet. 1981;1(8228):10151017.6112411
14. Walravens M, Dequeker J. Comparison of gold and orgotein treatment in rheumatoid arthritis. Curr Ther Res Clin Exp. 1976;20(1):62-69.821707
15. Kamio K, Azuma A, Ohta K, et al. Double-blind controlled trial of lecithinized superoxide dismutase in patients with idiopathic interstitial pneumonia - short term evaluation of safety and tolerability. BMC Pulm Med. 2014;14:86.24886036
16. Skarpanska-Stejnborn A, Pilaczynska-Szczesniak L, Basta P, Deskur-Smielecka E, Woitas-Slubowska D, Adach Z. Effects of oral supplementation with plant superoxide dismutase extract on selected redox parameters and an inflammatory marker in a 2,000-m rowing-ergometer test. Int J Sport Nutr Exerc Metab. 2011;21(2):124-134.21558574
17. Dhar SK, St Clair DK. Manganese superoxide dismutase regulation and cancer. Free Radic Biol Med. 2012;52(11-12):2209-2222.22561706
18. Robbins D, Zhao Y. Manganese superoxide dismutase in cancer prevention. Antioxid Redox Signal. 2014;20(10):1628-1645.23706068
19. Holley AK, Dhar SK, Xu Y, St Clair DK. Manganese superoxide dismutase: beyond life and death. Amino Acids. 2012;42(1):139-158.20454814
20. Pica A, Di Santi A, D'Angelo V, et al. Effect of rMnSOD on survival signaling in pediatric high risk T-cell acute lymphoblastic leukaemia. J Cell Physiol. 2015;230(5):1086-1093.25294747
21. Pham TM, Fujino Y, Nakachi K, et al; JACC Study Group. Relationship between serum levels of superoxide dismutase activity and subsequent risk of cancer mortality: Findings from a nested case-control study within the Japan Collaborative Cohort Study. Asian Pac J Cancer Prev. 2009;10(suppl):69-73.20553085
22. Esco R, Valencia J, Coronel P, Carceller JA, Gimeno M, Bascón N. Efficacy of orgotein in prevention of late side effects of pelvic irradiation: a randomized study. Int J Radiat Oncol Biol Phys. 2004;60(4):1211-1219.15519794
23. Broeyer FJ, Osanto S, Suzuki J, et al. Evaluation of lecithinized human recombinant super oxide dismutase as cardioprotectant in anthracycline-treated breast cancer patients. Brit J Clin Pharmacol. 2014;78(5):950-960.24844787
24. Lin J, Zahurak M, Beer TM, et al. A non-comparative randomized phase II study of 2 doses of ATN-224, a copper/zinc superoxide dismutase inhibitor, in patients with biochemically recurrent hormone-naive prostate cancer. Urol Oncol. 2013;31(5):581-588.21816640
25. Romao S. Therapeutic value of oral supplementation with melon superoxide dismutase and wheat gliadin combination. Nutrition. 2015;31(3):430-436.25701330
26. Kwon MJ, Kim B, Lee YS, Kim TY. Role of superoxide dismutase 3 in skin inflammation. J Dermatol Sci. 2012;67(2):81-87.22763488
27. Hellstrom WJ. Medical management of Peyronie's disease. J Androl. 2009;30(4):397-405.18974422
28. Sanclemente G, Garcia JJ, Zuleta JJ, Diehl C, Correa C, Falabella R. A double-blind, randomized trial of 0.05% betamethasone vs. topical catalase/dismutase superoxide in vitiligo. J Eur Acad Dermatol Venereol. 2008;22(11):1359-1364.18624857
29. Carillon J, Notin C, Schmitt K, Simoneau G, Lacan D. Dietary supplementation with a superoxide dismutase-melon concentrate reduces stress, physical and mental fatigue in healthy people: a randomised, double-blind, placebo-controlled trial. Nutrients. 2014;6(6):2348-2359.24949549
30. Houghton CA, Steels EL, Fassett RG, Coombes JS. Effects of a gliadin-combined plant superoxide dismutase extract on self-perceived fatigue in women aged 50-65 years. Phytomedicine. 2011;18(6):521-526.21044831
31. Parad RB, Allred EN, Rosenfeld WN, Davis JM. Reduction of retinopathy of prematurity in extremely low gestational age newborns treated with recombinant human Cu/Zn superoxide dismutase. Neonatology. 2012;102(2):139-144.22710821
32. Bertolotto F, Massone A. Combination of alpha lipoic acid and superoxide dismutase leads to physiological and symptomatic improvements in diabetic neuropathy. Drugs R D. 2012;12(1):29-34.22329607
33. Letizia Mauro G, Cataldo P, Barbera G, Sanfilippo A. α-Lipoic acid and superoxide dismutase in the management of chronic neck pain: a prospective randomized study. Drugs R D. 2014;14(1):1-7.24477618
34. Savalia K, Manickam DS, Rosenbaugh EG, et al. Neuronal uptake of nanoformulated superoxide dismutase and attenuation of antiotension II-dependent hypertension after central administration. Free Rad Biol Med. 2014;73:299-307.24924945
35. Pisani A, Sabbatini M, Riccio E, et al. Effect of a recombinant manganese superoxide dismutase on prevention of contrast-induced acute kidney injury. Clin Exp Nephrol. 2014;18(3):424-431.23807430
36. Zidenberg-Cherr S, Keen CL, Lönnerdal B, Hurley LS. Dietary superoxide dismutase does not affect tissue levels. Am J Clin Nutr. 1983;37(1):5-7.6849282
37. Giri SN, Misra HP. Fate of superoxide dismutase in mice following oral route of administration. Med Biol. 1984;62(5):285-289.6530902
38. Batinić-Haberle I, Rebouças JS, Spasojević I. Superoxide dismutase mimics: chemistry, pharmacology, and therapeutic potential. Antioxid Redox Signal. 2010;13(6):877-918.20095865
39. Carson S, Vogin EE, Huber W, Shulte TL. Safety tests of orgotein, an antiinflammatory protein. Toxicol Appl Pharmacol. 1973;26(2):184-202.4201575
40. Lund-Olesen K, Menander KB. Orgotein: a new anti-inflammatory metalloprotein drug: preliminary evaluation of clinical efficacy and safety in degenerative joint disease. Curr Ther Res Clin Exp. 1974;16(7):706-717.4210460

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This information relates to an herbal, vitamin, mineral or other dietary supplement. This product has not been reviewed by the FDA to determine whether it is safe or effective and is not subject to the quality standards and safety information collection standards that are applicable to most prescription drugs. This information should not be used to decide whether or not to take this product. This information does not endorse this product as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this product. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this product. This information is not specific medical advice and does not replace information you receive from your health care provider. You should talk with your health care provider for complete information about the risks and benefits of using this product.

This product may adversely interact with certain health and medical conditions, other prescription and over-the-counter drugs, foods, or other dietary supplements. This product may be unsafe when used before surgery or other medical procedures. It is important to fully inform your doctor about the herbal, vitamins, mineral or any other supplements you are taking before any kind of surgery or medical procedure. With the exception of certain products that are generally recognized as safe in normal quantities, including use of folic acid and prenatal vitamins during pregnancy, this product has not been sufficiently studied to determine whether it is safe to use during pregnancy or nursing or by persons younger than 2 years of age.

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