Glutathione S-transferases (GST) may provide a means for treating fatal liver damage caused by paracetamol overdose. In a paper published in 7 November Proceedings of the National Academy of Sciences, Henderson et al provide a new insight into how the enzyme GST Pi may moderate the toxic effects of paracetamol (acetaminophen).
When overdoses of paracetamol are taken, too much of the compound N-acetyl-p-benzoquinoneimine (NAPQI) is produced; it covalently binds to proteins and other macromolecules to cause cellular damage. NAPQI can be inactivated by binding to glutathione but in paracetamol overdoses there is not enough free glutathione to prevent NAPQI accumulating.
Henderson et al compared paracetamol metabolism in two groups of mice: one normal, the other lacking GST Pi. The mice without any GST Pi were much more resistant to liver damage than normal ones. In both cases when paracetamol was given, free glutathione was quickly depleted. In normal mice this level remained low, leading to liver damage as the amount of NAPQI went unchecked. But in mice that didn't have any GST Pi the level of free glutathione recovered and the amount of liver damage was far less.
Roland Wolf, one of the authors from the Imperial Cancer Research Fund's Molecular Pharmacology Unit in Dundee, explained: "GST Pi may be interrupting a pathway that protects a cell against the stress of cytotoxic compounds. Therefore, a lack of GST Pi would mean a cell would be less sensitive to toxic attack while the presence of GST Pi interferes with a cell's defences, making it more susceptible to paracetamol toxicity."
There are an estimated 70,000 cases of intentional paracetamol overdose in the UK each year, and more than 350 deaths. Blocking GST Pi could provide a step towards developing effective treatments against paracetamol poisoning.
Another author, Colin Henderson, pointed out: "This study doesn't just have implications for paracetamol overdoses. Because GST Pi is found in nearly all normal cells and cancer cells, it looks like an important factor in cell sensitivity to toxic chemicals in general."