CD44 Variants Linked to Paracetamol Toxicity

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country micetown miceDifferences in individual responses to drug treatment are generally assumed to have a strong genetic component but identifying individuals who may be at higher risk of adverse reactions from studies conducted entirely in people is fraught with difficulty. Looking at variations in susceptibility to paracetamol (acetaminophen)-induced hepatotoxicity, a team led by researchers at North Carolina State University has now shown how inbred mouse strains can be used to model genetic diversity in human populations.

Paracetamol is a widely available over-the-counter treatment for pain and fevers. Although generally considered safe at recommended doses, paracetamol has a narrow therapeutic index and overdoses can cause potentially fatal liver failure. For a significant number of people, even the recommended dose can cause serious liver damage and recent studies have shown that relatively short term use of paracetamol leads to increased levels of alanine transaminase (ALT) in about a third of healthy individuals. These individuals may be at increased risk of liver injury from high doses of paracetamol and the team have now identified a genetic marker linked to the risk of paracetamol-induced liver damage. Using 36 different strains of mice with well characterised genetic differences, the team were able to link specific genes to liver damage following paracetamol treatment. When they sequenced the corresponding genes in people who showed an increase in ALT after taking paracetamol, they found that a variation in one of the candidate genes, CD44, was significantly associated with elevated ALT levels.

Hepatotoxicity following paracetamol overdose is attributed not to the drug itself but to a minor alkylating metabolite, N-acetyl-p-benzoquinone imine (NARQI). NARQI is formed primarily by the action of cytochrome P450 enzymes, and differences in susceptibility to paracetamol poisoning have previously been linked to polymorphisms in P450 genes. CD44 is a cell surface glycoprotein involved in cell/cell and cell/matrix interactions and, although its role in liver toxicity is not yet understood, it could serve as a useful marker to identify people at high risk of paracetamol-induced liver damage. The team believe that routine use of genetic differences in early safety testing will provide more accurate predictions of clinical responses. The study is published in full in the journal Genome Research.

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