Exploring the paradoxical role of selenium as both a vital nutrient and toxic element in biological systems
In the world of essential elements, selenium presents a fascinating paradox—it's both vital for life and toxic in excess. This unique metalloid, discovered in 1817 by Swedish chemist Jöns Jacob Berzelius, was initially considered only as a poisonous substance. Its identity as an essential element for human health wasn't established until 1957, when scientists recognized its crucial role in preventing tissue damage in animals 1 .
Atomic Number: 34
Group: 16 (Chalcogens)
Discovered: 1817
Today, we understand that selenium plays an indispensable role in our biology, primarily through specialized proteins that protect our cells from damage. What makes selenium truly remarkable is its incredibly narrow range between deficiency and toxicity—one of the smallest among all essential elements.
This article explores why nature selected this paradoxical element for critical biological functions and how recent scientific discoveries are unlocking its potential in cutting-edge cancer treatments.
Selenium discovered by Jöns Jacob Berzelius
Recognized as essential for preventing tissue damage in animals
25 selenoproteins identified in humans with crucial biological roles
At first glance, selenium appears chemically similar to sulfur, residing directly below it in the periodic table. However, subtle differences in their electronic structures give selenium distinct advantages in biological systems, particularly for redox chemistry—the chemical reactions involving electron transfer that are crucial for life.
The key distinction lies in selenium's inferior ability to form π bonds compared to sulfur. This apparent weakness becomes a strength in biological contexts. Selenium is a better nucleophile than sulfur, meaning it more readily donates electrons to reactive oxygen species. More importantly, while both elements form oxides during antioxidant reactions, the selenium-oxygen bond lacks the π-bond character of sulfur-oxygen bonds, making selenoxides much more readily reduced back to their active form 4 .
This chemical property means that selenium-containing biomolecules resist permanent oxidation, creating more efficient catalytic cycles in enzymes that protect our cells from oxidative damage. Essentially, nature chose selenium over sulfur for specific functions because it creates more resilient and efficient molecular machines for handling oxidative stress.
Selenium exerts its biological effects primarily through selenoproteins—specialized proteins that incorporate selenium in the form of the amino acid selenocysteine. What makes these proteins remarkable is that they're genetically encoded—selenium is the only trace element whose incorporation into proteins is directed by our DNA 1 .
Humans possess 25 genes that code for selenoproteins, each performing crucial physiological roles with selenium at their active centers. These proteins are particularly abundant in tissues with high metabolic activity and oxygen consumption.
| Selenoprotein | Primary Functions | Tissue Distribution |
|---|---|---|
| Glutathione Peroxidases (GPx) | Antioxidant defense, reducing hydrogen peroxide and organic hydroperoxides | Throughout body, especially kidneys, liver, red blood cells |
| Thioredoxin Reductases (TR) | Regulation of redox state, DNA synthesis, apoptosis | Intracellular, various isoforms in different compartments |
| Iodothyronine Deiodinases | Activation and deactivation of thyroid hormones | Thyroid, central nervous system, pituitary gland |
| Selenoprotein P (SelP) | Selenium transport and distribution, antioxidant defense | Plasma, primarily produced in liver |
| Selenoprotein W (SepW) | Muscle metabolism, stress response | Skeletal muscle, brain |
The glutathione peroxidase family represents one of the most important groups of selenoproteins. These enzymes catalyze the reduction of hydrogen peroxide and organic hydroperoxides using glutathione, converting potentially damaging oxidants into harmless water and alcohols 5 . This function is crucial for protecting cell membranes from lipid peroxidation, a process that can damage cellular integrity and lead to cell death.
Meanwhile, thioredoxin reductases maintain the redox balance within cells and play vital roles in DNA synthesis and apoptosis—the programmed cell death essential for eliminating damaged cells 3 . The deiodinases regulate thyroid hormone activity, activating and deactivating these crucial metabolic regulators as needed 5 .
Selenoprotein P stands out as particularly remarkable—it contains multiple selenocysteine residues and serves as the primary selenium transport protein in plasma, distributing this essential element to various tissues throughout the body 3 .
Selenium maintains one of the most delicate balancing acts in human nutrition. The recommended daily intake for adults is approximately 55 micrograms per day, while the maximum tolerable intake without side effects is only 400 micrograms per day—less than a tenfold safety margin 1 .
<20 μg/day
>400 μg/day
| Selenium Status | Daily Intake | Health Effects | At-Risk Populations |
|---|---|---|---|
| Deficient | <20 μg | Keshan disease (cardiomyopathy), Kashin-Beck disease (osteoarthropathy), weakened immunity, cognitive decline, thyroid dysfunction | Areas with selenium-poor soil (parts of China, Russia, some European countries) |
| Adequate | 55-60 μg (adults) | Proper immune function, thyroid health, antioxidant protection, reduced risk of certain cancers | Populations with balanced diet including selenium-rich foods |
| Excessive/Toxic | >400 μg | Selenosis: hair loss, nail brittleness, garlic breath odor, neurological abnormalities, increased diabetes risk | Areas with selenium-rich soil, individuals taking high-dose supplements |
Selenium deficiency affects approximately one billion people worldwide and is particularly problematic in regions with selenium-poor soil 1 . The most dramatic manifestations are Keshan disease, which causes heart muscle damage and can be fatal, and Kashin-Beck disease, a degenerative joint condition that primarily affects children 1 .
On the other end of the spectrum, selenium toxicity—selenosis—manifests with symptoms including hair loss, nail changes, gastrointestinal disturbances, and a characteristic garlic odor on the breath due to the excretion of volatile dimethyl selenide 1 5 . Chronic excess selenium intake has also been linked to an increased risk of type 2 diabetes and neurological problems 1 .
In 2024, a groundbreaking study from the University of Würzburg, in collaboration with research institutions in Germany and Brazil, revealed unexpected pathways in selenium metabolism that open new avenues for cancer treatment, particularly for childhood neuroblastoma 2 6 .
The research team employed sophisticated techniques to unravel the complexities of selenium metabolism in cancer cells:
This advanced analytical technique enabled the scientists to precisely identify and quantify proteins and their interactions within cells, particularly focusing on selenium-binding proteins 2 .
The team cultured various cancer cell lines, including neuroblastoma cells, under conditions where different selenium metabolism pathways were inhibited, observing how the cells adapted and survived 2 .
Using specialized biochemical techniques, the researchers mapped how different proteins interact in selenium metabolic pathways, revealing previously unknown connections 6 .
The conventional understanding was that selenocysteine lyase (SCLY) was the primary enzyme responsible for releasing selenium atoms from selenocysteine for incorporation into new selenoproteins. However, the research team discovered that when SCLY was absent, cancer cells could still produce selenoproteins through an alternative pathway involving peroxiredoxin 6 (PRDX6) 2 6 .
PRDX6 binds directly to selenium and acts as a molecular "shuttle," transporting the trace element and enabling the production of crucial selenoproteins like glutathione peroxidase 4 (GPX4) 6 . This protein is particularly important in cancer biology because it protects cancer cells from a specific type of cell death called ferroptosis, allowing tumors to survive despite treatment with chemotherapy drugs 2 .
Most significantly, the researchers demonstrated that inhibiting PRDX6 could impair cancer cell survival, especially in neuroblastomas—childhood tumors that have historically been difficult to treat 6 . This discovery provides a promising new therapeutic target for making cancer cells more vulnerable to treatment.
| Research Tool | Function in Experiment | Scientific Application |
|---|---|---|
| CRISPR-Cas9 System | Gene editing to disable specific selenium metabolism genes | Identifying essential genes in selenium metabolic pathways |
| Mass Spectrometry | Precise identification and quantification of selenium-containing proteins | Mapping protein interactions and selenium incorporation |
| SCLY Inhibitors | Blocking the conventional selenium release pathway | Studying alternative selenium metabolism routes |
| PRDX6 Antibodies | Detecting and quantifying PRDX6 protein levels | Assessing expression in different cancer cell types |
| Selenium Isotopes | Tracing selenium movement through metabolic pathways | Understanding selenium distribution and incorporation |
From its initial identification as a toxic element to its current status as a crucial micronutrient and potential cancer therapy target, selenium continues to fascinate and surprise the scientific community. Nature's choice of selenium for specific biological functions reflects elegant chemical optimization—harnessing its unique redox properties for essential protective processes while navigating its potential toxicity through sophisticated regulatory mechanisms.
Selenium's story exemplifies how nature often chooses unexpected solutions to biological problems, and how continued scientific exploration reveals these solutions in increasingly sophisticated detail. As research progresses, we can anticipate even more surprising revelations about why nature chose selenium and how we can better harness its unique properties for human health.