Acetaminophen (Tylenol) kicks off widespread glutathionylation, researchers find
James Chun Yip Chan and colleagues at the National University of Singapore examined glutathionylation, a post-translational modification made to cysteine residues, in response to acetaminophen toxicity. In a study published in the journal Molecular & Cellular Proteomics, the researchers reported a new proteomic approach to isolate and identify glutathionylated proteins and applied it in cells treated with acetaminophen. They found that an acetaminophen breakdown product can cause glutathionylation, suggesting a new mechanism for the damage the drug causes.
Usually, glutathione is added to cysteine residues to protect them from damage by oxygen under stressful conditions. Chan and colleagues showed that acetaminophen and its breakdown product activate glutathionylation in a dose-dependent way. The modification affects proteins involved in mitochondrial fuel uptake and energy production, leading to metabolic dysfunction and other effects linked to acetaminophen toxicity. This research helps explain the drug's toxicity at high doses, especially among enzymes that are impaired by acetaminophen treatment without binding directly to the drug or its metabolites. The findings may also apply to other drugs with similar structures.