GPX3

GPX3 encodes glutathione peroxidase 3, a selenium-dependent enzyme that neutralizes reactive oxygen species and protects extracellular fluids from oxidative damage. 

As the only secreted member of the glutathione peroxidase family, GPX3 plays important roles in cardiovascular health, kidney function, cancer biology, and metabolic regulation.

What is GPX3 (Glutathione Peroxidase 3)?

The GPX3 gene provides instructions for making glutathione peroxidase 3 (GPX3), a selenium-containing enzyme that protects the body from oxidative damage. It is also known as plasma glutathione peroxidase, and it belongs to the glutathione peroxidase family.

Antioxidant Function

GPX3 is a selenoprotein containing the amino acid selenocysteine, which is critical for its activity. The enzyme uses glutathione (GSH) to neutralize harmful molecules called reactive oxygen species (ROS), including hydrogen peroxide (H₂O₂) and organic hydroperoxides.

GPX3 is upregulated in hypoxic conditions.

Catalytic Reaction

GPX3 catalyzes the following key antioxidant reaction:

2 GSH + H₂O₂ → GSSG + 2 H₂O

This reduces harmful peroxides to water and protects cells from oxidative stress.

Extracellular Location

Unlike other members of its family, GPX3 is secreted and found mainly in extracellular fluids, including plasma, lymph, and lung fluid. 

It is produced primarily by kidney proximal tubule cells and is also expressed in the liver, lungs, and gastrointestinal tract.

When is GPX3 Testing Relevant?

GPX3 testing may be relevant in the following scenarios:

Research Studies on Oxidative Stress-Related Diseases

GPX3 is not a routine lab test but is often measured in research or specialized clinical studies exploring its role in:

• Cardiovascular disease (e.g., heart failure, atherosclerosis)
• Kidney disease, where GPX3 levels may drop due to impaired kidney function
• Cancer, particularly gastric and other cancers
• Diabetes, due to its role in insulin sensitivity and glucose metabolism
• Selenium Status (Indirectly)

Since GPX3 is a selenium-dependent enzyme, dietary selenium can influence its levels. However, direct selenium testing is more accurate for assessing selenium status.

What Do Low Levels of GPX3 Mean?

Low GPX3 may have the following consequences:

Increased Oxidative Stress

Low GPX3 levels may indicate a reduced ability to neutralize ROS, which can contribute to:

• Inflammation
• Vascular damage
• Insulin resistance

Disease Associations (Research Context)

Research has linked low GPX3 levels with:

• Poor outcomes in chronic kidney disease
• Higher cardiovascular risk
• Increased cancer progression due to loss of tumor-suppressive function

Selenium Deficiency

Low dietary selenium can impair GPX3 production and function.

What Do High Levels of GPX3 Mean?

Elevated GPX3 levels are poorly understood but may represent a compensatory response to oxidative stress. In some cancers (e.g., clear cell ovarian cancer), high GPX3 levels may support tumor survival, though this is context-dependent.

Key Takeaways for Clinicians

GPX3 is the only extracellular glutathione peroxidase, vital for protecting plasma and tissues from oxidative stress.

It plays key roles in cardiovascular health, renal function, cancer biology, and insulin signaling in adipose tissue.

Low GPX3 levels may reflect oxidative stress, selenium deficiency, or disease progression.

GPX3 expression is regulated by selenium availability, transcription factors (e.g., Sp1, HIF-1), and promoter methylation.

It shows promise as a biomarker and potential therapeutic target in diseases related to oxidative stress and metabolism.