The Cogence Clinical Pearls Series

Iron and Glutathione – A Trap to Avoid

A bit of background… 

We know that giving iron can be crucial in some cases. And, on the other side of the coin, iron can also significantly increase oxidative stress, driving inflammation. This is because iron catalyzes the Fenton Reaction, which converts hydrogen peroxide into hydroxyl radical, the nastiest free radical in the body. The body uses glutathione to quench hydroxyl radical. So glutathione has crucial anti-inflammatory effects in the body that can offset the risks of giving iron. 

What the research says…

This paper from Cellular and Molecular Life Sciences, describes ferroptosis, a newly identified form of cell death, driven by iron-induced oxidation of cellular lipids and inhibited by glutathione.

Application…

The identification of ferroptosis as a new form of cellular death emphasizes the clinical importance of glutathione support in patients for whom iron supplementation is necessary. Giving iron without glutathione support may increase cellular death through ferroptosis, by providing a higher concentration of the iron substrate by which ferroptosis is induced. In patients who do not have single nucleotide polymorphisms (snips) related to the glutathione system, it may be adequate to give NAC, selenium, vitamin C, etc. In patients with snips, it may be necessary to give glutathione. 

Mechanisms of ferroptosis.
Cao JY, Dixon SJ. Cell Mol Life Sci. 2016 Jun;73(11-12):2195-209.

Abstract
Ferroptosis is a non-apoptotic form of cell death that can be triggered by small molecules or conditions that inhibit glutathione biosynthesis or the glutathione-dependent antioxidant enzyme glutathione peroxidase 4 (GPX4). This lethal process is defined by the iron-dependent accumulation of lipid reactive oxygen species and depletion of plasma membrane polyunsaturated fatty acids. Cancer cells with high level RAS-RAF-MEK pathway activity or p53 expression may be sensitized to this process. Conversely, a number of small molecule inhibitors of ferroptosis have been identified, including ferrostatin-1 and liproxstatin-1, which can block pathological cell death events in brain, kidney and other tissues. Recent work has identified a number of genes required for ferroptosis, including those involved in lipid and amino acid metabolism. Outstanding questions include the relationship between ferroptosis and other forms of cell death, and whether activation or inhibition of ferroptosis can be exploited to achieve desirable therapeutic ends.