Introduction
Heme-binding hemopexin provides a multitude of protection against toxicity induced by free heme. The first evidence of hemopexin's role in heme transport and iron recovery was first described in 1988. Currently, several clinical studies are ongoing to better understand hemopexin. A thorough understanding of hemopexin biochemistry may enable the prevention of heme-related pathologies.
What Is Hemopexin?
Hemopexin, also termed beta - 1B - glycoprotein, is a protein in the plasma that exhibits a high affinity to bind with heme among all proteins. It is a blood transport protein encoded by the HPX (hemopexin) gene. The protein is expressed in the liver. It belongs to acute phase reactants synthesized after inflammation or infection to minimize tissue damage. Hemopexin has a transport function in the body. Heme derived from hemoglobin cannot bind to haptoglobin and forms hemopexin or albumin complexes. However, hemopexin has a higher affinity for binding with heme. The heme-hemopexin complex is eliminated from circulation by hepatocytes within several hours, reducing hemopexin concentrations.
The normal hemopexin level in humans is 500 to 1000 micrograms per millimeter.
What Is Heme Toxicity?
Heme and hemoglobin can induce damage to lipoproteins present in the circulation of the cell membranes. Heme levels are seen to be elevated in various hemolytic disorders. Heme toxicity includes inhibition of the proteasome, generation of aggresome-like structure, activation of unfolded protein response, activation of the systems like coagulation cascade, binding to immunoglobulin, and alternative pathway of complement activation. Heme toxicity can induce severe complications of a stroke, deep venous thrombosis (blood clots formed in deep veins of legs), and pulmonary embolism (blockage of lung arteries by a clot).
How Does Hemopexin Bind to Heme?
In healthy individuals, a small amount of hemoglobin is released into circulation. Haptoglobin binds with these released hemoglobin and transports them to liver cells (hepatocytes) and macrophages for destruction. However, a large amount of hemoglobin is released into the blood in hemolytic conditions. The scavenging capacity of haptoglobin becomes completely exhausted. Therefore, hemoglobin is oxidized into methemoglobin, and heme is released into circulation. Serum albumin binds to heme and transports it to hemopexin. The hemopexin binds with heme and transports it to the liver for degradation.
What Is the Function of Hemopexin?
Hemopexin has two main functions: Firstly, it acts as an antioxidant by binding with free heme to prevent oxidative damage to the vasculature, and secondly, it regulates the heme uptake by hepatocytes through endocytosis.
Free heme radicals are toxic due to their participation in the Fenton reaction to produce hydroxyl ions. However, hemopexin binds with free heme to prevent iron loss or oxidative damage. It also prevents the binding of heme to more reactive biomolecules. Hemopexin forms a second line of defense against hemoglobin-induced oxidative damage. Hemopexin also plays a role in transporting free heme to the liver, where the heme is degraded to avoid any toxic symptoms and to recover iron. Hemopexin ensures that heme is not eliminated through urine to inhibit iron loss. The free hemopexin is released back into circulation. When heme is bound to hemopexin, bacteria cannot utilize iron, inhibiting their growth.
Which Conditions Cause Variation in Hemopexin Levels?
Reduction
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In newborns, the hemopexin concentration is low but reaches adult levels by the first year of life. However, children may experience a depletion of hemopexin since it is a developmentally regulated protein.
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In severe intravascular hemolysis, there is a depletion of haptoglobin, causing reduced or absent hemopexin levels.
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There is a reduction in hemopexin in hemolytic diseases like malaria, thalassemia major, and sickle cell disease.
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In individuals with porphyria.
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In individuals with extensive blood transfusions. The red blood cells undergo lysis when stored for longer periods. This causes an overload of heme and hemoglobin, potentially leading to organ damage.
Elevation: The concentration of hemopexin is elevated in medical conditions like diabetes, infections, or carcinoma.
How to Diagnose Hemopexin?
Hemopexin is estimated using methods similar to those used for haptoglobin measurement.
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Radial Immunodiffusion: Radial immunodiffusion is a reaction in which antigen and antibody react to form precipitates in liquid or semi-liquid media. The precipitate formed depends on the antigen sample in the tube.
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Immunoelectrophoresis: It is a technique in which proteins are separated and identified based on differences in electrical charge and reactivity with antibodies. Agarose gel is used as a separating media.
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Hemopexin ELISA Kit: They are highly sensitive two-site enzyme-linked immunoassay (ELISA) that helps measure hemopexin levels in serum. The test can effectively identify natural and recombinant human hemopexin.
What Is the Role of Hemopexin in Medical Conditions?
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Sepsis: Studies have shown that hemopexin has the potential to be used as a biomarker for sepsis to prevent mortality and health issues. However, more studies need to be conducted to determine its exact role.
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Intracerebral Hemorrhage: Extracellular heme can induce irreversible damage to the brain that can be irreversible, leading to neurological deficits. Recent studies have proven the neuroprotective potential for intracerebral hemorrhage. When hemopexin levels were increased in the brain with recombinant technology, brain recovery improved, and hematoma was reduced.
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Blood-Brain Barrier Protection: Hemopexin in cerebrospinal fluid helps protect the blood-brain barrier. Hemopexin is also used as a diagnostic biomarker for sports-related head injuries. It also protects against bleeding and blood loss in traumatic injuries.
How Are Low Hemopexin Levels Replenished?
The following procedures are used for hemopexin replenishment to protect from heme toxicity.
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Plasma Protein Replenishment Therapy: Various studies conducted on animals have proven that replenishment with hemopexin and haptoglobin is therapeutically useful.
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Plasma Exchange: Plasmapheresis or therapeutic plasma exchange can increase hemopexin levels and is cost-effective. Plasmapheresis is a procedure in which blood is centrifuged to separate plasma and blood cells. The plasma deficiency of hemopexin is swapped with plasma containing an adequate concentration of haptoglobin and hemopexin.
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During Brain Hemolysis, the Scavenger Receptor Is Targeted for Therapies: The scavenger receptor plays a role in the uptake of the heme-hemopexin complex. Targeting them may elevate hemopexin concentration in circulation.
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Recombinant Hemopexin: Hemopexin is manufactured to replenish depleted hemopexin in the body. It is produced in E. coli (Escherichia coli) by prokaryotic expression. However, they are currently being used for research purposes.
Conclusion
Hemopexin has a multifaceted function in the body. It protects various body organs from oxidative stress that heme could induce. The binding and transport of heme are its predominant functions. A deeper understanding of hemopexin with adequate research is essential to better understand the potential of hemopexin.
