“Lightning protectors” protect cells from oxidative damage

Acetylcysteine (also known as N-acetyl cysteine, or NAC) is a well-known non-prescription cough medicine available in any pharmacy. Another, less widely known use of this agent is as an antidote in the treatment of paracetamol (acetaminophen) overdose, which can lead to severe liver damage. If given in time in these cases, acetylcysteine can prevent the worst damage from happening.

Acetylcysteine is generally credited to have cell protection and antioxidative effects, which has been confirmed in numerous experiments. Acetylcysteine reduces the level of endogenous cellular oxidants and lessens the toxic effect of oxidizing exogenous substances. Therefore, acetylcysteine is one of the most commonly used antioxidants in experimental biomedical research.

However, little has been understood so far about exactly how acetylcysteine unfolds its antioxidative effect. A previous hypothesis saying that its effect is based on a direct reaction with oxidants has not been confirmed. Even though acetylcysteine is so widely used, the mechanisms behind its mode of action have remained largely in the dark.

Researchers at the DKFZ have now found a completely new explanation for acetylcysteine’s antioxidative and cell protection effect. In their study, the investigators traced the breakdown of the compound in human cells and noticed that acetylcysteine is converted into hydrogen sulfide. Hydrogen sulfide is known to be a very toxic gas, but it is also known by now that endogenous hydrogen sulfide fulfills physiological functions.

In fact, levels of hydrogen sulfide produced from acetylcysteine do not become toxic, because it is swiftly transformed into another type of sulfur compounds called persulfides. Their function in the cell is largely unknown to date. The findings by the DKFZ researchers suggest that persulfides are the true antioxidative agents. Treatment of cells with synthetic persulfides mimicked the antioxidative effects of acetylcysteine, even at substantially lower levels. “Persulfides bind to proteins and protect them, presumably by diverting oxidation towards themselves, similar to a lightning protector,” said DKFZ’s Tobias Dick, who has led the study.

“We now understand much better how acetylcysteine can protect cells from oxidative stress,” said Daria Ezerina, PhD student and first author of the study. “But this should not lead one to conclude that it would be a good idea to take acetylcysteine as a dietary supplement long-term and at high doses. Because tumor cells under stress might also benefit from this cell protection.” A couple of years ago, cancer researchers in Sweden already showed that long-term administration of acetylcysteine can promote tumor growth and metastasis in mice.

Ezerina D, Takano Y, Hanaoka K, Urano Y, Dick TP (2018) N-acetyl cysteine functions as a fast-acting antioxidant by triggering intracellular H2S and sulfane sulfur production.
Cell Chemical Biology, doi:10.1016/j.chembiol.2018.01.011