Superoxide Dismutase

Superoxide dismutase (SOD) is an antioxidant enzyme that catalyzes the dismutation of superoxide radicals into hydrogen peroxide and molecular oxygen. 

SOD exists in three main isoforms: SOD1, SOD2, and SOD3, each playing distinct roles in cellular protection against oxidative stress. 

SOD1, found in the cytoplasm, uses copper and zinc as cofactors to scavenge superoxide radicals and maintain redox balance. 

SOD2, located in the mitochondria, relies on manganese to neutralize superoxide radicals generated during mitochondrial respiration, thereby protecting mitochondrial DNA and proteins. 

SOD3, an extracellular enzyme, also utilizes copper and zinc to protect against oxidative damage in the extracellular matrix and plasma. 

Each isoform's specific function and cellular location highlight the critical role of SODs in maintaining cellular health and mitigating oxidative stress-related diseases.

What is SOD?: SOD Isoforms and Their Functions

Superoxide dismutase (SOD) is an essential antioxidant enzyme that catalyzes the dismutation of superoxide radicals into hydrogen peroxide and molecular oxygen, playing a crucial role in protecting cells from oxidative stress. 

Superoxide dismutase exists in multiple isoforms, each with distinct cellular locations and metal cofactors. These isoforms play specific roles in protecting different cellular compartments from oxidative stress.

SOD1 (Cu/Zn SOD)

SOD1, also known as copper/zinc superoxide dismutase, is the cytosolic isoform found primarily in the cytoplasm of cells. It is a homodimeric enzyme that requires both copper for its catalytic activity and zinc for enzyme stability. [11., 20.] 

SOD1 is responsible for scavenging superoxide radicals generated during normal cellular metabolism and plays a crucial role in maintaining redox homeostasis in the cytosol.

SOD1 gene is located on chromosome 21q22. Various transcription factors such as NF-κB, AP-1, Sp1, AP-2, and C/EBP regulate its expression. [11.] 

Single amino acid mutations in SOD1 are linked to ALS. [20.] 

SOD2 (Mn SOD)

SOD2, or manganese superoxide dismutase, is the mitochondrial isoform that resides in the matrix of mitochondria. This isoenzyme requires manganese as a cofactor. [11., 20.] 

SOD2 is particularly important for neutralizing superoxide radicals produced as byproducts of the mitochondrial electron transport chain, thereby protecting mitochondrial DNA and proteins from oxidative damage and hyperoxic conditions.

SOD2 gene is located on chromosome 6q25.3. 

It is essential for survival in aerobic organisms, plays a role in various diseases including cancer, neurodegeneration, and cardiomyopathy. [11.] Knocking out SOD2 in mice results in lethal cardiomyopathy. [20.]

SOD3 (SOD3)

SOD3, also known as extracellular superoxide dismutase (SOD3), is the isoform found in the extracellular space, including plasma, lymph, and various tissues. Like SOD1, it requires copper (Cu2+) for catalytic activity and zinc (Zn2+) for stability. [11.] 

It plays a crucial role in scavenging superoxide radicals in the extracellular environment, protecting cells from oxidative stress induced by extracellular sources of reactive oxygen species.

SOD3 gene is located on chromosome 4. [11.] 

Mutations in SOD3 are associated with various conditions: for example, variants like the R213G mutation are associated with increased plasma levels of SOD3 and various cardiovascular and pulmonary diseases. [11., 20.] 

SOD in Health and Disease

Amyotrophic Lateral Sclerosis [3., 15.] 

ALS is a fatal degenerative disease affecting motor neurons in the cortex, brainstem, and spinal cord, leading to progressive muscle atrophy and death, typically within five years. 

Approximately 10% of ALS cases are inherited (familial ALS or FALS) with autosomal dominant traits. Both familial and sporadic ALS are clinically similar.

Research has linked FALS to a genetic defect on chromosome 21q, specifically to the SOD1 gene, which encodes the enzyme Cu/Zn superoxide dismutase (SOD1). 

Various missense mutations in the SOD1 gene have been found in both familial and sporadic ALS cases, affecting the protein's structure and function, leading to the disease.

Mutations often result in protein misfolding and aggregation, which is believed to be a key factor in ALS progression. Some mutations increase the aggregation propensity of SOD1.

The mutations influence the age of onset, disease progression, and survival time.

The toxicity in ALS is linked to the gain of toxic function rather than the loss of normal SOD1 function. Mutant SOD1 proteins form aggregates that disrupt cellular functions.

Alzheimer’s Disease

Alzheimer's disease (AD) is characterized by amyloid β (Aβ) deposits, cognitive impairment, and synaptic dysfunction, with oxidative stress closely linked to neurodegeneration and contributing to Aβ-induced toxicity. 

Copper/Zinc Superoxide Dismutase (SOD1), which converts superoxide radicals into less harmful molecules, plays a crucial protective role. 

Studies have shown that SOD1 deficiency accelerates Aβ oligomerization and cognitive impairment in a mouse model of AD, leading to increased oxidative stress, memory loss, and synaptic dysfunction. [12.] 

In these SOD1-deficient mice overexpressing amyloid precursor protein (APP), researchers observed accelerated Aβ oligomerization, memory impairment, increased plaque formation, neuronal inflammation, and oxidative damage markers compared to controls. [12.] 

Human studies have confirmed that SOD1 levels are significantly decreased in AD patients, while mitochondrial SOD (SOD2) and extracellular SOD (SOD3) levels remain unchanged. [12.] 

These findings suggest that enhancing SOD1 activity could be a therapeutic strategy to inhibit AD progression by reducing oxidative stress and preventing Aβ oligomerization. 

Parkinson’s Disease [4., 16.]

Parkinson’s Disease (PD) is marked by the progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta, leading to dopamine deficiency. Oxidative damage is predominantly observed in the substantia nigra region.

The pathogenesis of PD includes chronic inflammatory responses, mitochondrial dysfunction, dysregulation of the immune response, and an imbalance between the production of reactive oxygen metabolites (ROMs) and antioxidant activity.

PD patients exhibit increased levels of circulating inflammatory cytokines and oxidative stress markers, along with reduced levels of antioxidants in the blood.

Clinical studies indicate a significant reduction in plasma levels of SOD and other antioxidants in PD patients compared to healthy controls. [16.]

Increasing midbrain SOD activity enhances the resistance of dopaminergic neurons to nitric oxide (NO) cytotoxicity by suppressing the formation of peroxynitrite. [16.] 

Cancer [7., 14.]

Reactive oxygen species (ROS) are crucial for cellular signaling but must be balanced to prevent damage. Elevated ROS levels in cancer cells can drive tumor progression, making the superoxide dismutase (SOD) family vital in mitigating these effects. 

Specifically, cancer prevention or suppression is the most effective strategy to combat its high mortality rate. Reduced SOD activities during early cancer stages make them key candidates for prevention. [14.]

Oxidative stress contributes to cancer development. SODs are the first defense against superoxide radicals. Cu-ZnSOD activity decreases in breast and gastric carcinomas, and SOD2 levels are lower in breast, oral, and esophageal cancers. 

SOD3 is downregulated in lung carcinomas due to promoter hypermethylation.

SOD2 in Cancer

There are conflicting views on SOD2's role in cancer. Some suggest SOD2 is pro-oxidant, promoting H2O2 accumulation and oncogenic pathways. Others argue SOD2 protein levels increase during tumorigenesis while its activity decreases.

However, it is recognized that mitochondrial dysregulation contributes to cancer. [14.] Targeting both glycolytic and mitochondrial metabolism may be effective. Small molecules that selectively inhibit mitochondrial pathways induce apoptosis in cancer cells.

Cancer cells often rely on glycolysis (Warburg effect) for energy. SOD2 may inhibit glycolysis and support oxidative phosphorylation, thereby suppressing tumorigenesis. [14.]

Dietary SOD2 inducers including hesperidin, curcumin and ginger show potential for cancer prevention. [14.] SOD2 expression affects ROS levels, influencing cancer cell survival and response to therapies. Combining SOD-based approaches with other treatments may enhance efficacy.

SOD3 in Cancer

SOD3, located in the extracellular space, regulates ROS signaling and acts as a unique tumor suppressor. Its differential expression is significant in cancerous versus normal tissues, with low SOD3 levels linked to poor survival in cancer patients. [7.] 

SOD3 is downregulated in various cancers, including breast, lung, prostate, pancreatic, and thyroid cancers. [7.] Overexpression of SOD3 inhibits tumor growth and metastasis, highlighting its role as a tumor suppressor. 

The loss of SOD3 promotes a microenvironment conducive to cancer progression due to genetic and epigenetic mechanisms like promoter hypermethylation, microRNA regulation, and loss of heterozygosity.

Cardiovascular Disease [1., 10.]

Effects of SODs in Cardiovascular Health

SODs modulate vascular tone, gene expression, inflammation, cell growth, and apoptosis by catalyzing the conversion of O2− to H2O2. This process prevents oxidative stress and maintains cellular function.

In pathological conditions like hypertension and atherosclerosis, SOD1 and SOD3 can be inactivated by their peroxidase activity, where H2O2 reacts with the copper center of these enzymes, forming highly reactive radicals that further oxidative stress and hypertension. [6.] 

SODs in Vascular Function [6.] 

• SOD1: protects against endothelial dysfunction by preserving NO levels, reducing vascular permeability, and counteracting vasoconstriction.

• SOD2: maintains mitochondrial function and prevents endothelial dysfunction under pathological conditions.

• SOD3: critical for preventing extracellular O2−-mediated NO destruction, enhancing endothelial function and reducing hypertension.

Alterations in superoxide dismutase (SOD) function have been strongly linked to cardiovascular disease. SOD enzymes, particularly extracellular superoxide dismutase (SOD3), play a crucial role in regulating vascular levels of superoxide (O2−) and protecting against oxidative stress in the cardiovascular system. [6.] 

Atherosclerosis

Superoxide dismutases (SODs) are protective in atherosclerosis by mitigating oxidative stress, preserving nitric oxide (NO) levels, and preventing the oxidative modification of lipoproteins and endothelial cells. 

However, the impact of SODs on atherosclerosis can vary depending on the specific isoform, genetic background, and experimental conditions. 

• SOD1 (Cu/Zn SOD)

• Increased expression of SOD1 (Cu/ZnSOD) generally protects against oxidative injury, but overexpression in some studies has been linked to increased fatty-streak deposition in high-cholesterol diets due to the formation of reactive hydroxyl radicals. [6.] 

• Overexpression of both SOD1 and catalase, which degrades H2O2, reduces atherosclerosis, highlighting the complex interplay between different ROS and antioxidant enzymes. 

• SOD2 (MnSOD)

• SOD2 primarily protects against mitochondrial oxidative stress, with its deficiency leading to increased mitochondrial DNA damage and accelerated atherosclerosis. 

• SOD2 also helps maintain endothelial function by regulating mitochondrial ROS and NO levels. 

• SOD3 (ecSOD)

• SOD3 is abundant in the vascular extracellular matrix and protects against O2−-mediated NO destruction, preserving endothelial function and reducing the potential for endothelial damage and atherosclerotic development. 

• SOD3 is upregulated in lipid-laden macrophages within atherosclerotic lesions but decreased in vascular smooth muscle cells. 

• SOD3 reduces LDL oxidation, attenuates tyrosine nitration, and supports NO bioavailability, reducing oxidative stress and inflammatory responses in atherosclerosis. 

Each SOD isoform contributes uniquely to protecting vascular tissues, and their activity is influenced by various factors including gene expression, post-translational modifications, and interactions with other antioxidants. 

Understanding these mechanisms can help develop targeted antioxidant therapies to combat atherosclerosis.

Hypertension

Superoxide dismutases (SODs) are essential in managing hypertension by mitigating oxidative stress, preserving nitric oxide (NO) levels, and protecting against vascular dysfunction. Each SOD isoform (SOD1, SOD2, and SOD3) contributes uniquely to combating hypertension.

• SOD1 (Cu/ZnSOD)

• SOD1 expression inhibits increases in vascular superoxide (O2−) and arterial pressure in mouse models. [6.] 

• SOD1 also plays a role in neuronal regulation of hypertension, as its overexpression can modulate sympathetic nervous system activity, reducing blood pressure.

• SOD2 (MnSOD)

• SOD2 protects against mitochondrial oxidative stress, with mitochondrial dysfunction and increased ROS production linked to hypertension.

• SOD2 deficiency leads to endothelial dysfunction, higher blood pressure, and increased mitochondrial ROS, particularly with aging or high-salt diets. [6.] 

• It also plays a role in the central nervous system's regulation of blood pressure, as demonstrated in animal models. [6.] 

• SOD3 (ecSOD)

• Located in the extracellular matrix, SOD3 protects against extracellular O2−-mediated NO destruction, maintaining endothelial function and regulating blood pressure. 

• Deficiency in SOD3 leads to increased vascular O2− levels, impaired endothelium-dependent relaxation, and elevated blood pressure. It also plays a role in central blood pressure regulation in animal models. [6.] 

Cardiac Fibrosis [1.] 

Extracellular superoxide dismutase (SOD3) plays a crucial role in mitigating cardiac fibrosis induced by chronic hypoxic stress by regulating gene methylation and reducing oxidative stress. 

Chronic hypoxia triggers epigenetic changes, particularly DNA methylation in cardiac fibroblasts, leading to the inactivation of tumor suppressor genes and activation of kinases which promote fibroblast proliferation and cardiac fibrosis. 

SOD3 overexpression significantly reduces oxidative stress, decreases global DNA methylation, and lowers the activity of DNA methylation enzymes. This results in the attenuation of fibroblast proliferation and fibrosis markers. 

These findings suggest that SOD3 ameliorates cardiac fibrosis by reversing hypoxia-induced epigenetic changes, offering a potential therapeutic strategy to combat fibrosis.

Diabetes Mellitus

In diabetic patients, persistent hyperglycemia increases the production of oxygen-free radicals through glucose autoxidation and nonenzymatic glycation, while the antioxidant capacity is typically decreased. 

SOD enzyme function has been observed to decrease in diabetes, particularly in type II diabetes. [13.] 

Increasing SOD capacity may provide therapeutic benefit in diabetes. [9.] 

Diabetic rats treated with L-SOD, or liposome-embedded SOD, showed significant improvements in oxidative stress markers, such as lower malondialdehyde (MDA) levels and a reduced GSSG/GSH ratio, compared to untreated diabetic rats. [9.] 

These improvements correlated with better blood glucose control and reduced physical damage to the intestinal barrier. L-SOD also reduced levels of some inflammatory cytokines. [9.] 

The results of this particular study demonstrated that orally-administered liposome-embedded SOD functioned better than natural SOD or SOD hydrosylate. [9.] 

Genetic Alterations in the SOD Gene

The gene for the SOD protein may contain alterations or mutations that cause increase or decrease of function of the SOD protein.  

Testing for genetic alterations in the form of SNPs is increasingly available and can shed light on an individual’s potential for health and disease.  

What is a SNP?

A SNP, or single nucleotide polymorphism, refers to a variation at a single position in a gene along its DNA sequence.  A gene encodes a protein, so an alteration in that gene programs the production of an altered protein.  

As a type of protein with great functionality in human health, alterations in genes for enzymes may confer a difference in function of that enzyme.  The function of that enzyme may be increased or decreased, depending on the altered protein produced.  

SNPs are the most common type of genetic variation in humans and can occur throughout the genome, influencing traits, susceptibility to diseases, and response to medications.

The completion of the Human Genome Project has significantly expanded opportunities for genetic testing by providing a comprehensive map of the human genome that facilitates the identification of genetic variations associated with various health conditions, including identifying SNPs that may cause alterations in protein structure and function.  

Genetic testing for SNPs enables the identification of alterations in genes, shedding light on their implications in health and disease susceptibility.

Laboratory Testing for SOD

Test Information, Sample Collection and Preparation

SOD testing may be performed in a variety of ways.  Assessing superoxide dismutase activity can be done in blood, including erythrocytes, serum, and whole blood analysis. This is commonly done in research settings.  

Assessing the presence of genetic mutations in SOD genes that would alter their function can also be done; this requires a blood, saliva, or cheek swab sample. 

Blood tests require a venipuncture. Saliva or cheek swab samples may be collected from the comfort of home. 

It is important to consult with the ordering provider prior to sample collection, as special preparation including alterations in supplement or medication regimens may be required. Do not adjust any medication doses prior to consulting a licensed healthcare professional. 

Genetic Test Preparation

Prior to undergoing genetic testing, it's important to consult with a healthcare provider or genetic counselor to understand the purpose, potential outcomes, and implications of the test.  This consultation may involve discussing medical history, family history, and any specific concerns or questions. 

Additionally, individuals may be advised to refrain from eating, drinking, or chewing gum for a short period before providing a sample to ensure the accuracy of the test results.  Following sample collection, the DNA is processed in a laboratory where it undergoes analysis to identify specific genetic variations or SNPs. 

Once the testing is complete, individuals will typically receive their results along with interpretation and recommendations from a healthcare professional. 

It's crucial to approach genetic testing with proper understanding and consideration of its implications for one's health and well-being.

Patient-Centric Approaches

A patient-centered approach to SNP genetic testing emphasizes individualized medicine, tailoring healthcare decisions and interventions based on an individual's unique genetic makeup.

When that is combined with the individual’s health status and health history, preferences, and values, a truly individualized plan for care is possible. 

By integrating SNP testing into clinical practice, healthcare providers can offer personalized risk assessment, disease prevention strategies, and treatment plans that optimize patient outcomes and well-being. 

Genetic testing empowers a deeper understanding of genetic factors contributing to disease susceptibility, drug response variability, and overall health, empowering patients to actively participate in their care decisions. 

Furthermore, individualized medicine recognizes the importance of considering socioeconomic, cultural, and environmental factors alongside genetic information to deliver holistic and culturally sensitive care that aligns with patients' goals and preferences. 

Through collaborative decision-making and shared decision-making processes, patients and providers can make informed choices about SNP testing, treatment options, and lifestyle modifications, promoting patient autonomy, engagement, and satisfaction in their healthcare journey.

Genetic Panels and Combinations

Integrating multiple biomarkers into panels or combinations enhances the predictive power and clinical utility of pharmacogenomic testing. Biomarker panels comprising a variety of transporter proteins and enzymes including drug metabolizing enzymes offer comprehensive insights into individual drug response variability and treatment outcomes. 

Combining genetic SNP testing associated with drug transport, metabolism, and pharmacodynamics enables personalized medicine approaches tailored to individual patient characteristics and genetic profiles.

SOD-Related Biomarkers

Oxidative Stress Markers

Oxidative stress is characterized by an imbalance between the production of reactive oxygen species (ROS) and the body's antioxidant defense mechanisms, which includes SOD as well as other antioxidant enzymes. 

Measuring markers of oxidative stress can complement SOD analysis and provide insights into the extent of oxidative damage.

Malondialdehyde (MDA) is a byproduct of lipid peroxidation and is widely used as a marker of oxidative stress. Elevated levels of MDA have been observed in various diseases. [8.] 

8-hydroxy-2'-deoxyguanosine (8-OHdG) is a biomarker of oxidative DNA damage, which can lead to genetic mutations and cellular dysfunction. Increased levels of 8-OHdG have been associated with various diseases. [5.] 

Inflammatory Markers

Inflammation and oxidative stress are closely intertwined processes, and measuring inflammatory markers can provide additional insights into disease pathogenesis and progression.

C-reactive protein (CRP) is a widely used marker of systemic inflammation, and elevated levels have been associated with various inflammatory conditions, including cardiovascular diseases, rheumatoid arthritis, and certain cancers. 

HIgh sensitivity CRP (hs-CRP) is considered a more specific marker for endothelial dysfunction and inflammation. [2.] 

How to Naturally Boost Antioxidant Levels

Diet and lifestyle factors are foundational to boost and improve antioxidant status.

Eat a Variety of Colorful Fruits and Vegetables

These are rich in vitamins, minerals; the bright colors of fruits and vegetables come from phytochemicals that act as antioxidants.

Consume Sulfur-Rich Foods

Sulfur compounds support glutathione production, a powerful antioxidant.

Include Nuts and Seeds in your Diet

Nuts and seeds are high in vitamin E and selenium, which are important antioxidants.

Drink Green Tea and Coffee in Moderation

Both beverages contain polyphenols, or plant-based antioxidants, that have strong antioxidant properties.

Add Herbs and Spices to your Meals

Many herbs and spices are extremely high in antioxidants.

Eat dark chocolate (70% cocoa or higher)

Cacao is rich in flavonoids, which are potent antioxidants. Moderate dark chocolate consumption is associated with a reduced risk of many diseases including cardiovascular disease, stroke, and diabetes. [18.] 

Incorporate Legumes into your Diet

Legumes are a good source of antioxidants and fiber, which supports gut health, detoxification, and antioxidant status. Many legumes also contain iron, which is important for catalase function. [19.]

Consume Fatty Fish Rich in Omega-3s

Omega-3s have anti-inflammatory properties and support overall health, and provide cellular protection against oxidation. 

Limit Alcohol Consumption and Avoid Smoking

Excessive alcohol and smoking can increase oxidative stress.

Avoid Processed Foods and Excessive Sugar Intake

These foods can increase inflammation and oxidative stress, and are increasingly linked to the development of chronic disease. [17.]

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