Master Anti-Oxidant

Ergothioneine (ET) is an unusual sulfur-containing derivative of the amino acid, histidine, which is derived exclusively through the diet. Although ET was isolated a century ago, its physiologic function has not been clearly established. Recently, a highly specific transporter for ET (ETT) was identified in mammalian tissues, which explains abundant tissue levels of ET and implies a physiologic role. Using RNA interference, we depleted cells of its transporter. Cells lacking ETT are more susceptible to oxidative stress, resulting in increased mitochondrial DNA damage, protein oxidation, and lipid peroxidation. ETT is concentrated in mitochondria, suggesting a specific role in protecting mitochondrial components such as DNA from oxidative damage associated with mitochondrial generation of superoxide. In combating cytotoxic effects of pyrogallol, a known superoxide generator, ET is as potent as glutathione. Because of its dietary origin and the toxicity associated with its depletion, ET may represent a new vitamin whose physiologic roles include antioxidant cytoprotection. and tissues frequently exposed to oxidative stress with highest levels in the millimolar range occurring in blood, lens of the eye, liver, bone marrow and seminal fluid.8–10

ET is tautomeric and exists predominantly in the thione form in neutral aqueous solutions which may account for ET’s resistance to autooxidation,11 in contrast to glutathione, the other major water-soluble thiol which is rapidly oxidized. ET’s sulfhydryl group implies an antioxidant role.8–11 Exogenous ET can scavenge reactive oxygen and nitrogen species and protect cells from a variety of apoptotic insults. Earlier studies of ET’s antioxidant actions have been conducted in vitro or using overexpression systems with no evidence for a physiologic function.

An important advancement in understanding ET physiology was the discovery by Schomig and associates that the putative transporter protein OCTN1, a product of the gene SLC22A4 (solute carrier family 22, member 4) that had been implicated in rheumatoid arthritis, is primarily a physiologic ET transporter (ETT).12 This transporter was first cloned and characterized earlier in 1997 and shown to transport organic cations such as tetraethyl ammonium, carnitine, and verapamil.13 Using a liquid chromatography mass spectroscopy difference shading approach, Schomig and colleagues showed a very high specificity for ET. 12–14 ETT occurs in a variety of tissues,12–15 with a high level of expression in the cells of the hematopoietic lineage and CD14+ cells, such as monocytes and macrophages. 12–16 Levels of the transporter correlate closely with those of ET. Mutations in the ET transporter locus have been identified as susceptibility factors for autoimmune disorders such as rheumatoid arthritis and Crohn’s disease.17,18 Interestingly, the gene for ETT lies in close proximity to genes involved in inflammatory responses such as caspase recruitment domain family, member 15, CARD 15. ETT is abundantly expressed in CD14+ macrophages and monocytes consistent with a role in inflammation.12–19

ET inhibits tumor necrosis factor-α-induced release of the inflammatory cytokine interleukin-8 (IL-8) in alveolar macrophages. 20 ETT expression is upregulated by inflammatory cytokines. 17–21 The transcription factor nuclear factor-kappa B, which regulates inflammatory genes, has binding sites in the promoter of human ETT and regulates its expression, further supporting a role for ETT in modulating inflammatory processes.21 Patients with rheumatoid arthritis accumulate ET in their synoviocytes. ETT influences cell proliferation and differentiation22 and treatment of intestinal Caco-2 cells with ET stimulates cell proliferation.23 ETT is also one of the genes upregulated during liver regeneration.

Although ET is not made by the body, it is taken up from the diet and retained preferentially in cells exposed to oxidative stress and involved in inflammatory responses. The presence of a high-affinity transporter in conjunction with its non-random distribution implies physiologic function. In this study, we depleted endogenous ETT in HeLa cells and show marked augmentation of oxidative stress and cell death providing strong evidence for a physiological role of ET as a physiological antioxidant.

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