Houston, Texas, USA : Acetaminophen is a common pain reliever found in every pharmacy. However, it is also the No. 1 cause of acute liver failure in the United States. In the liver, acetaminophen is converted into a new compound that covalently binds to proteins at an amino acid called cysteine. These covalent binding events are known to contribute to the toxicity of acetaminophen, but they cannot fully account for its role in liver failure. The compound is known to impair the activity of mitochondria, the cell’s energy supplier, but does not bind directly to some of the enzymes in mitochondria whose activity it affects. Now researchers have found a new way that the breakdown product affects proteins in the liver.
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.
Other authors on the study included Alex Cheow Khoon Soh, Dorinda Yan Qin Kioh, Jianguo Li, Chandra Verma, Siew Kwan Koh, Roger Wilmer Beuerman, Lei Zhou and Eric Chun Yong Chan.
The research was funded by the Singapore Ministry of Education, and the Singapore National Medical Resesarch Council Centre.
Dr. David Juurlink, head of the division of clinical pharmacology and toxicology, department of medicine, at the University of Toronto, said he believes that if acetaminophen was brought to the market today, it would not be approved because it offers minimal pain relief, although it works reasonably well at reducing fevers, and can be toxic at levels not much higher than recommended doses. There is also “emerging concern” he said about its use among pregnant women.
“The less acetaminophen the population uses the better, and the more a regulator helps people understand the potential harms and limited benefits, the better.”
Dr. David Juurlink was not part of this study.