Ergothioneine: Therapeutic Constituents in Medicinal Mushrooms, part 4

Ergothioneine is an amino acid derivative, specifically a crystalline betaine derivative of histidine. Etymologically, the name comes from ergot- (found in ergot/fungus), thione- (double bond to a sulfur), and -ine (amine-containing). In other words, a sulfur-containing amine found in fungi. Ergothioneine is also found in actinobacteria and cyanobacteria, or blue-green algae (1).

Ergothioneine

Evolution has coincided so synchronously with humans and mushrooms that humans have specific transporters and receptors uniquely equipped to transport ergothioneine. While we have specific transporters for ergothioneine, humans can’t synthesize it ourselves, and the benefits are dependent on exogenous intake. The ergothioneine transporter, OCTN1, is found in red blood cells, fetal liver and bone marrow, the ileum of the small intestine, trachea, kidney, cerebellum, lung, monocytes, seminal vesicles and the lens and cornea of the eye (2). The ergothioneine transporter seems to be concentrated in the mitochondria of cells, suggesting a role in protecting mitochondrial components from DNA damage (3). OCTN1 has only one known role, which is to sequester as much ergothioneine within the cell as is available, and only cells with this transporter can absorb, distribute and retain this compound (4). Research has demonstrated that restricting cells’ access to ergothioneine increases oxidative stress, leading to mitochondrial damage, protein oxidation and lipid peroxidation. Once taken up into the cell, ergothioneine is extremely bioavailable and is retained for up to one month within the body.

Bioavailability

Once consumed in the diet, whether from an isolated molecule or from whole mushrooms, ergothioneine is quickly absorbed into the bloodstream. In one study, participants consumed 8g and 16g of mushrooms and increases in red blood cell ergothioneine were observed after 1 hour and 4 hours of consumption. After only 2 hours of consuming 16g of mushrooms, the red blood cell concentration of ergothioneine was significantly increased - variability in bioavailability was due to genetic variation of the SLC22A4 gene responsible for OCTN1 transporter synthesis (5). Genetic variations in the ergothioneine transporter gene have been identified in various autoimmune diseases including rheumatoid arthritis and Crohn’s disease as well as neurodegenerative disease (3).

Antioxidant and cytoprotective

The distribution of ergothioneine transporters may seem random, but on closer inspection, they are mostly present in tissues predisposed to high levels of oxidative stress and inflammation (2). In animal studies, animals who were completely deficient in ergothioneine had higher levels of reactive oxygen species and were therefore more susceptible to oxidative stress. In vitro, ergothioneine is a powerful scavenger of hydroxyl radical and has been shown to deactivate singlet oxygen at a higher rate than glutathione (7,8).

Similar results were demonstrated in vivo – rats supplemented with ergothioneine had lower levels of lipid peroxidation and higher levels of glutathione and alpha-tocopherol. As one might surmise, ergothioneine and glutathione seem to have an intimate relationship within the cell. Glutathione is considered the major intracellular antioxidant in almost all organisms and has important functions in detoxification and immune function. It has been proposed, based on current research, that ergothioneine can help maintain glutathione levels in the presence of oxidative burden by interacting with other cellular defense systems. The maintenance of glutathione tissue levels is important in maintaining health as depletion will impair immune function.

Conveniently, mushrooms contain both glutathione and ergothioneine. In fact, mushrooms have been observed to have higher glutathione amounts than any vegetable or fruit. Grifola frondosa (maitake), Hericium erinaceus (lions mane), Pleurotus ostreatus (oyster mushroom), Boletus edulis (porcini) and Lentinus edodes (shitake) contain the most, respectively (9). Considering the relationship between ergothioneine and glutathione in mushrooms, a correlation analysis found that mushrooms high in glutathione were also high in ergothioneine, specifically the caps, or pileus, of the mushrooms (9). Taken together, it is clear that mushrooms are an important stimulator of cellular antioxidant capacity.

Cation chelator

Ergothioneine chelates divalent metal cations – specifically, copper, mercury, sinc, cadmium, cobalt, iron and nickel (10,11). Binding these cations in the body may help prevent their participation in the generation of reactive oxygen species. For example, ergothioneine has been found to protect DNA and protein against copper-induced oxidative damage through formation of a redox-inactive ergothioneine-copper complex. In fact, high levels of ergothioneine in semen, due to the high concentration of OCTN1 transporter on the seminal vesicles, has been shown to prevent copper-inhibition of sperm motility (12). There is likely more to be explored between the relationship of ergothioneine and semen viability.

Ergothioneine, aging, and cognitive decline

With age, humans are more vulnerable to the oxidative stress from environmental toxins that slowly damage DNA, which increases susceptibility to neurodegeneration. Low levels of glutathione have been linked to certain neurodegenerative diseases including Parkinson’s disease (13,14). Ergothioneine dose-dependently enhances glutathione activity in the rat liver cytosol, leading researchers to postulate that declining ergothioneine may play a role in age-related decline of glutathione levels. Furthermore, ergothioneine levels were found to be lower in the elderly with early stages of dementia and in Parkinson’s disease patients relative to age matched healthy controls (9). In animal studies, oral administration of ergothioneine protects neurons and preserves cognitive function following administration of toxic amyloid beta, cisplatin (a chemotherapy agent), or D-galactose. It is now understood that the presence of OCTN1 transporters in the blood brain barrier are responsible for these neuroprotective actions. Researchers found that there is a direct relationship between whole blood and brain ergothioneine levels following consumption (9). It is rare for compounds to be bioavailable in this way and transported across the blood brain barrier so readily.

Human trials, uptake and metabolism

While there is undeniably a lack of human trials exploring the in vivo effects of ergothioneine, a recent study from 2017 explored ergothioneine uptake, metabolism, and effects on biomarkers of oxidative damage and inflammation in healthy human subjects (15). One of the more interesting aspects of ergothioneine discussed in this article is that ergothioneine is a tautomer, existing in two forms – thione and thiol (a thiol is a single bond to sulfur while a thione is a double bond). The researchers explain that in animal physiologic conditions, ergothioneine primarily exists as the thione tautomer, and under circumstances of low stress in the body, ergothioneine remains in its thione tautomer form and is not the first choice as an antioxidant; rather, endogenous antioxidants like glutathione are preferred (glutathione is a primary antioxidant thiol in the body). When cells undergo higher levels of oxidative stress, ergothioneine transforms into its thiol form and is then used for additional antioxidant support. Additionally, under levels of elevated stress, tissues have increased amounts of the ergothioneine, supposedly by upregulating expression of the OCTN1 transporter in response to inflammatory cytokines.

This study also found that ergothioneine can be stored in the cells for up to a month. It is theorized that ergothioneine is stored for an extended period of time following consumption until it is required as a stronger defense mechanism.

During administration of ergothioneine, plasma levels increased significantly, while whole blood levels steadily increased for up to four weeks after administration stopped, indicating that red blood cells could continue to take up ergothioneine as needed. Also, excretion of ergothioneine in the urine remained low, indicating that ergothioneine is absorbed and retained in the body after oral administration. While this study used pure ergothioneine, other studies previously mentioned prove this same high bioavailability of ergothioneine from dietary mushrooms (5).

Ergothioneine in mushrooms

In one study that explored the ergothioneine content in different fungi and fungal parts, ergothioneine content was most abundant in the fruiting body of Pleurotus ostreatus (Oyster mushroom) and in the mycelium of Pleurotus eryngii. Generally, fruiting bodies and mycelium contained different amounts of ergothioneine, with the Pleurotus genus containing the highest amounts overall (16). Among simple mushrooms, the fruiting body of White Button had the least (1.4mg per 85g mushroom) and Portabella the highest (2.7mg per 85g mushroom). Among specialty mushrooms, maitake had the least (16.3mg per 85g mushroom) and oyster the highest (26.4mg per 85g mushroom) (17). Fruiting bodies of gilled mushrooms, specifically the cap or pileus, contain the most ergothioneine, while polypore mushrooms like reishi contain very little. Interestingly, the mycelium of Ganoderma spp. contains more ergothioneine than the fruiting body, but still not as much as the fruiting bodies of shitake, matsutake, oyster, and maitake (18,19).

Summary

Ergothioneine is a bioavailable and impactful bolster to our natural antioxidant defenses. By elevating levels of glutathione, chelating metal ions, and absorbing free radicals, it prevents cellular damage throughout the body, in organs where it is needed the most. It shows promise in the treatment of neurodegenerative disease, and in maintaining memory and cognitive function in aging adults. Our best available source of ergothioneine is Oyster mushroom; check out our Oyster mushroom monograph to learn more.