Drug-induced liver injury (DILI) is a severe adverse drug reaction which is of major concern to patients, clinicians and the pharmaceutical industry. Accurate and rapid detection of DILI is important for patient stratification and treatment in the clinic and benefits preclinical drug design and risk assessment. MicroRNAs (miRNAs) offer a potential new and improved class of circulating biomarkers of DILI over the current gold standard biomarkers. Areas covered: This review highlights the shortcomings of the currently used panel of biomarkers and how miRNAs, primarily miR-122, show an improved level of specificity and sensitivity in the prediction of DILI. Furthermore, the use of miRNAs as potential markers of progression of DILI and specific zonated damage within the liver is discussed. Expert commentary: MiRNAs offer more sensitive and specific markers over the current biomarkers for DILI. Combinations of different miRNAs may be able to relay the location of DILI and the progression of disease. More studies using different hepatotoxins apart from acetaminophen will ultimately strengthen the case for the clinical introduction of miRNAs as biomarkers of DILI.

Drug-induced liver injury (DILI) is a common form of adverse drug reaction seen within the clinic. Sensitive, specific and non-invasive biomarkers of liver toxicity are required to help diagnose hepatotoxicity and also to identify safety liabilities during drug development. Limitations exist in the current gold standard DILI biomarkers: alanine aminotransferase is not liver-specific and therefore gives rise to false-positive signals. Interest has grown in the potential of microRNAs (miRNAs) as biomarkers of DILI. Some miRNAs display remarkable organ specificity, can be measured sensitively and are stable in a wide range of biofluids. However, little is currently known about the mechanisms through which miRNAs are released from cells. Furthermore, a clinically suitable method to measure miRNAs has not yet been developed. This review aims to highlight the current research surrounding these markers and areas in which further work is required to establish these markers within clinical and pre-clinical settings.

Background & Aims: The transcription factor Nuclear factor erythroid 2-related factor 2 (Nrf2) regulates an array of cytoprotective genes, yet studies in transgenic mice have led to conflicting reports on its role in liver regeneration. We aimed to test the hypothesis that

Paracetamol is the commonest cause of acute liver failure in the Western world and biomarkers are needed that report early hepatotoxicity. The liver enriched microRNA, miR-122, is a promising biomarker currently being qualified in humans. For biomarker development and drug toxicity screening the zebrafish has advantages over rodents, however, blood acquisition in this model remains technically challenging. We developed a method for collecting blood from the adult zebrafish by retro-orbital (RO) bleeding and compared it to the commonly used 'lateral incision' (LI) method. The RO technique was more reliable in terms of the blood yield and minimum amount per fish. This new RO technique was used in a zebrafish model of paracetamol toxicity. Paracetamol induced dose-dependent increases in liver cell necrosis, serum ALT activity and mortality. In situ hybridization localised expression of miR-122 to the cytoplasm of zebrafish hepatocytes. After collection by RO bleeding, serum miR-122 could be measured and this microRNA was substantially increased by paracetamol 24 hours after exposure, an increase that was prevented by delayed (3 hours post start of paracetamol exposure) treatment with acetylcysteine. In summary, collection of blood by RO bleeding facilitated measurement of miR-122 in a zebrafish model of paracetamol hepatotoxicity. The zebrafish represents a new species for measurement of circulating microRNA biomarkers that are translational and can bridge between fish and humans.