Circulating microRNAs, potential biomarkers for drug-induced liver injury

TLDR

Drug‑induced liver injury is a frequent, costly complication of many medications, yet current early detection relies almost exclusively on serum aminotransferases, which have limited sensitivity. In a mouse acetaminophen‑overdose model, the authors compared liver tissue and plasma microRNA profiles between control and injured animals, revealing pronounced differences in microRNA spectra and levels. They found that liver‑specific microRNAs, particularly mir‑122 and mir‑192, increased in plasma in a dose‑dependent manner earlier than aminotransferases and correlated with histopathology, suggesting these circulating microRNAs could serve as sensitive biomarkers for drug‑induced liver injury.

Abstract

Drug-induced liver injury is a frequent side effect of many drugs, constitutes a significant threat to patient health and has an enormous economic impact on health care expenditures. Numerous efforts have been made to identify reliable and predictive markers to detect the early signs of drug-induced injury to the liver, one of the most vulnerable organs in the body. These studies have, however, not delivered any more informative candidates than the serum aminotransferase markers that have been available for ≈30 years. Using acetaminophen overdose-induced liver injury in the mouse as a model system, we have observed highly significant differences in the spectrum and levels of microRNAs in both liver tissues and in plasma between control and overdosed animals. Based on our survey of microRNA expression among normal tissues, some of the microRNAs, like messenger RNAs, display restricted tissue distributions. A number of elevated circulating microRNAs in plasma collected from acetaminophen-overdosed animals are highly expressed in the liver. We have demonstrated that specific microRNA species, such as mir-122 and mir-192, both are enriched in the liver tissue and exhibit dose- and exposure duration-dependent changes in the plasma that parallel serum aminotransferase levels and the histopathology of liver degeneration, but their changes can be detected significantly earlier. These findings suggest the potential of using specific circulating microRNAs as sensitive and informative biomarkers for drug-induced liver injury.