Evaluation of miR-122 and Other Biomarkers in Distinct Acute Liver Injury in Rats

Abstract

The detection of drug-induced hepatotoxicity remains an important safety issue in drug development. A liver-specific microRNA species, microRNA-122 (miR-122), has recently shown potential for predicting liver injury in addition to the standard hepatic injury biomarkers. The objective of this study was to measure miR-122 together with several other liver markers in distinct settings of acute liver toxicity in rats to determine the value of miR-122 as a biomarker for liver injury in this species. Rats were exposed to 3 well-established liver toxicants (acetaminophen, allyl alcohol, and a-naphthyl isothiocyanate), a liver-enzyme inducer (phenobarbital), or a cardiotoxicant (doxorubicin). There was a clear increase in plasma miR-122 following administration of acetaminophen, allyl alcohol, and a-naphthyl isothiocyanate. The response of miR-122 paralleled that of other markers and was consistent with liver injury as indicated by histopathological evaluation. Furthermore, the changes in miR-122 were detected earlier than standard liver injury markers and exhibited a wide dynamic range. In contrast, miR-122 responses to phenobarbital and doxorubicin were low. Based on these findings, miR-122 shows significant promise and may provide added value for assessing liver toxicity in drug development.

miR‐122‐5p as a plasma biomarker of liver injury in fish exposed to microcystin‐LR

“…), as well as after administration of allyl alcohol or α‐naphthyl isothiocyanate (Starckx et al . ). Laterza et al .…”

Absolute quantification of serum microRNA-122 and its correlation with liver inflammation grade and serum alanine aminotransferase in chronic hepatitis C patients

“…[9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26] Among these studies, microRNA-122 is of particular interest. MicroRNA-122 is an abundant liver-specific microRNA, accounting for approximately 70% of the total hepatic microRNA.…”

Comparison of microRNA expressions for the identification of chemical hazards in in vivo and in vitro hepatic injury models

“…The potential of miRNAs as toxicological biomarkers was recently explored (Harrill et al, ; Li et al, ). In particular, the availability of miRNA biomarkers of hepatotoxicity, which is an important issue for the development of new drugs, was reported in many studies (Bala et al, ; Starckx et al, ; Vliegenthart, Shaffer, et al, ; Wolenski et al, ; Yamaura et al, ). The aim of this study was to explore the potential of miRNAs as toxicological biomarkers in in vivo hepatotoxicity models, and their applicability to link in vitro experiments to in vivo animal data.…”

“…Acetaminophen (AAP) overdose causes acute liver injury, and its mechanism of action is clear (Hinson, Roberts, & James, ). AAP has been widely studied as a representative hepatotoxicant in experimental models (in vitro and in vivo) (Bala et al, ; Starckx et al, ; Vliegenthart, Shaffer, et al, ; Wolenski et al, ; Yamaura et al, ). In this experimental study, rats or hepatocytes were exposed to <25% of the lethal dose of AAP (NIH TOXNET; Kang et al, ).…”