Signs of an overdose – microRNAs identify drug toxicity

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When we think of drug overdoses, we typically think of controlled substances – e.g., illegal drugs or prescription drug abuse. It might come as a surprise, then, to hear that overdose of acetaminophen (APAP), the common over-the-counter analgesic used for headaches, fevers, and other minor ailments, is also a serious public health concern. Data from the 1990s implicates acetaminophen overdose in 56,000 visits to the emergency room and 458 deaths per year in the US. (http://www.regulations.gov/#!documentDetail;D=FDA-2011-N-0021-0001).

Hepatotoxicity from overdose of this seemingly innocuous drug is therefore a major topic of interest, and recent research has focused on finding better markers to assess liver damage and efficacy of treatment. Over the last few years, microRNAs in biofluids have stepped into the spotlight as possible candidates. Many microRNAs are abundantly expressed in liver tissue (see the list), and have roles in liver physiology and pathophysiology. Stable in circulation due to conjugation with proteins like Argonaute 2 (Ago2) or high-density lipoprotein (HDL), or carried by exosomes, microRNAs are easily accessible and potentially powerful markers for understanding hepatotoxicity. In a 2009 issue of PNAS, Wang et al. reported miR-122 and miR-192 as potentially promising plasma biomarkers for APAP toxicity (1), and recent findings have continued to expand on additional microRNA biomarker candidates.

Some highlights from the recent literature surrounding this topic include Ward et al.’s 2014 study, published in PNAS, which used a qPCR array for serum and plasma to define an 11-microRNA signature that could differentiate acetaminophen toxicity from ischemic hepatitis during treatment with N-acetyl cysteine (NAC), the antidote for APAP poisoning (2). Their findings suggested that these miRNAs were able to identify toxicity faster than the traditional biomarker ALT (alanine aminotransferase) and potentially give prognostic information about patient recovery.

This year in Toxicological Sciences, Krauskopf and colleagues published next-generation sequencing results from the serum of accidental APAP overdose patients, showing enrichment for 36 microRNAs that may be potential biomarker candidates (3). Also this year, a study from Yang et al. in Toxicology and Applied Pharmacology showed an increase in serum miR-122 and miR-375 in children with an acetaminophen overdose, as well as miR-375 and miR-940 in urine, suggesting that these microRNAs may be good biomarkers for overdose in this population (4).

Signatures like these will continue to be investigated, refined and validated, and someday may change the way we diagnose APAP overdose in clinical settings. How do you see circulating biomarkers affecting the way we evaluate drug toxicity?

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References

  1. Wang, K. et al. (2009) Circulating microRNAs, potential biomarkers for drug-induced liver injury. Proc. Natl. Acad. Sci. 106, 4402.
  2. Ward, J. et al. (2014) Circulating microRNA profiles in human patients with acetaminophen hepatotoxicity or ischemic hepatitis. Proc. Natl. Acad. Sci. 111, 12169.
  3. Krauskopf, J. et al. (2015) Application of high-throughput sequencing to circulating microRNAs reveals novel biomarkers for drug-induced liver injury. Toxicol. Sci. 143, 268.
  4. Yang, X. et al. (2015) Potential of extracellular microRNAs as biomarkers of acetaminophen toxicity in children. Toxicol. Appl. Pharmacol. 284, 180.
Ali Bierly

Ali Bierly, PhD is a Global Market Manager in Translational Sciences at QIAGEN, and has written on a number of scientific topics in the biotech industry as the author of QIAGEN's Reviews Online. She received her PhD from Cornell University in 2009, studying the immune response to a protozoan parasite, Toxoplasma gondii. Ali has a keen interest in the emerging importance of microRNA and other circulating nucleic acids as biomarkers for disease.

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