MiR-122 and other microRNAs as potential circulating biomarkers of drug-induced liver injury.

INTRODUCTION: 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.

Circulating levels of miR-122 increase post-mortem, particularly following lethal dosing with pentobarbital sodium: implications for pre-clinical liver injury studies.

microRNA-122 (miR-122) is increasingly being measured in pre-clinical and clinical settings due to greater sensitivity and hepatic specificity compared to the gold standard liver injury biomarker alanine aminotransferase (ALT). In pre-clinical studies, various culling methods can be employed prior to collection of blood samples, including lethal injection with pentobarbital sodium (Pentoject). However, little is known about whether such an approach could alter the circulating levels of miR-122 and compromise the interpretation of data. We therefore exposed C57BL/6J mice to saline or the model hepatotoxin paracetamol and collected blood samples pre-cull (via tail bleed) and post-cull (via cardiac puncture following exposure to a rising concentration of CO2 or intraperitoneal injection of Pentoject). Compared to pre-cull levels there was a significant increase in serum miR-122 level in mice culled with CO2 and, to a much greater extent, in mice culled with Pentoject. As a result, whilst the serum level of miR-122 increased in Pentoject-culled animals exposed to paracetamol, the higher level in saline-treated mice rendered this difference statistically non-significant, in contrast to findings in animals culled with CO2. ALT levels were unaffected by sacrifice method. Consistent with the in vivo findings, exposure of primary mouse hepatocytes to Pentoject provoked a rapid and concentration-dependent release of miR-122 into the culture media. Thus, for optimal design and interpretation of data from pre-clinical liver injury studies in which miR-122 is to be used as a biomarker, we recommend that blood samples are collected pre-cull whenever possible, and that lethal injection with Pentoject is avoided.