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