MicroRNAs as potential circulating biomarkers of drug-induced liver injury: key current and future issues for translation to humans

Abstract

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.

Keywords::

• acetaminophen
• DILI
• exosome
• hepatocyte
• injury
• liver
• miR-122
• miRNA

Financial & competing interests disclosure

The authors’ research is supported by the BBSRC, MIP-DILI and the MRC. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Drug-induced liver injury (DILI) is a leading adverse drug reaction experienced in the clinic.

• Sensitive biomarkers of DILI are required in clinical diagnosis and in drug development.

• The current gold-standard biomarkers for DILI have well-recognized limitations. New specific, sensitive and robust markers of DILI must be found to aid in clinical diagnosis and pre-clinical drug development.

• miRNAs, a class of small non-coding RNAs hold many of the properties required for potential biomarkers; certain miRNAs are tissue specific, non-invasive, sensitive and easily quantifiable.

• miRNAs are released into the circulation in several forms, including vesicle-bound and protein-bound forms; however, the physiological function of these mechanisms is still not understood in DILI.

• Current PCR-based assays are liable to bioanalytical, biological and sample variance. Therefore, both endogenous and exogenous miRNA normalizers must be used to reduce variation in the current assays.

• The current assays for miRNA quantification are time-consuming and vary between laboratories; therefore, new robust assays must be developed before these markers could be used in the clinic.

• Techniques using bioluminescence and label-free miRNA quantification are under development; however, robust testing will first be required before they have application in the clinic.

Notes