A longitudinal assessment of miR-122 and GLDH as biomarkers of drug-induced liver injury in the rat

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.

Keywords:

• Hepatotoxicity
• acetaminophen
• exosomes
• ALT
• GLDH
• miR-122

Disclosure statement

The authors report no declarations of interest.

Additional information

Funding

This work was supported by the European Union, as part of the SAFE-T consortium. Additional funding was provided by the AstraZeneca, the BBSRC, and Almirall.