A longitudinal assessment of miR-122 and GLDH as biomarkers of drug-induced liver injury in the rat |
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Authors: | Petra Thulin Robert J Hornby Mariona Auli Gunnar Nordahl Daniel J Antoine Philip Starkey Lewis |
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Institution: | 1. Drug Safety &2. Metabolism, Discovery Safety, AstraZeneca, M?lndal, Sweden;3. MRC Centre for Drug Safety Science, University of Liverpool, Liverpool, UK;4. Pathology and Predictive Toxicology Section, Almirall, Barcelona, Spain;5. Operations, AstraZeneca, S?dert?lje, Sweden;6. MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK |
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Abstract: | Context: There is an ongoing search for specific and translational biomarkers of drug-induced liver injury (DILI). MicroRNA-122 (miR-122) has previously shown potential as a sensitive, specific, and translational biomarker of DILI in both rodent, and human studies. Objective: To build on previous work within the field, we examined biomarker kinetics in a rat model of acetaminophen (APAP)-induced liver injury to confirm the sensitivity, and specificity of miR-122 and glutamate dehydrogenase (GLDH). Materials and methods: qRT-PCR and a standard enzymatic assay were used for biomarker analysis. Results: Both miR-122 and GLDH were demonstrated to be more readily-detectable biomarkers of APAP-DILI than alanine aminotransferase (ALT). Peak levels for all biomarkers were detected at 2 days after APAP. At day 3, miR-122 had returned to baseline; however, other biomarkers remained elevated between 3 and 4 days. We were also able to demonstrate that, although miR-122 is present in greater quantities in exosome-free form, both exosome-bound and non-vesicle bound miR-122 are released in a similar profile throughout the course of DILI. Discussion and conclusions: Together, this study demonstrates that both GLDH and miR-122 could be used during preclinical drug-development as complementary biomarkers to ALT to increase the chance of early detection of hepatotoxicity. |
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Keywords: | Hepatotoxicity acetaminophen exosomes ALT GLDH miR-122 |
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