Liver biomarker and in vitro assessment confirm the hepatic origin of aminotransferase elevations lacking histopathological correlate in beagle dogs treated with GABAA receptor antagonist NP260

Harrill, Alison H.; Eaddy, J. Scott; Rose, Kelly; Cullen, John M.; Ramanathan, Lakshmi; Wanaski, S.; Collins, Stephen; Ho, Yu Cheng; Watkins, Paul B.; LeCluyse, Edward L.

doi:10.1016/j.taap.2014.03.015

Cited by 26 publications

(26 citation statements)

References 13 publications

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“…In humans, urinary miRNA has been assessed in patients with kidney damage (Konta et al , ; Maluf et al , ). One example of an established predictive miRNA biomarker is miR‐122, which has been used to assess hepatotoxicity in rodents (Wang et al , ), dogs (Harrill et al , ; Koenig et al , ) and humans (Starkey Lewis et al , ).…”

Section: Introductionmentioning

confidence: 99%

Identification of microRNA biomarker candidates in urine and plasma from rats with kidney or liver damage

et al. 2016

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MicroRNAs (miRNA) are short single‐stranded RNA sequences that have a role in the post‐transcriptional regulation of genes. The identification of tissue specific or enriched miRNAs has great potential as novel safety biomarkers. One longstanding goal is to associate the increase of miRNA in biofluids (e.g., plasma and urine) with tissue‐specific damage. Next‐generation sequencing (miR‐seq) was used to analyze changes in miRNA profiles of tissue, plasma and urine samples of rats treated with either a nephrotoxicant (cisplatin) or one of two hepatotoxicants (acetaminophen [APAP] or carbon tetrachloride [CCL4]). Analyses with traditional serum chemistry and histopathology confirmed that toxicant‐induced organ damage was specific. In animals treated with cisplatin, levels of five miRNAs were significantly altered in the kidney, 14 in plasma and six in urine. In APAP‐treated animals, five miRNAs were altered in the liver, 74 in plasma and six in urine; for CCL4 the changes were five, 20 and 6, respectively. Cisplatin treatment caused an elevation of miR‐378a in the urine, confirming the findings of other similar studies. There were 17 in common miRNAs elevated in the plasma after treatment with either APAP or CCL4. Four of these (miR‐122, −802, −31a and −365) are known to be enriched in the livers of rats. Interestingly, the increase of serum miR‐802 in both hepatotoxicant treatments was comparable to that of the well‐known liver damage marker miR‐122. Taken together, comparative analysis of urine and plasma miRNAs demonstrated their utility as biomarkers of organ injury. Copyright © 2016 The Authors. Journal of Applied Toxicology published by John Wiley & Sons Ltd.

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Section: Introductionmentioning

confidence: 99%

Identification of microRNA biomarker candidates in urine and plasma from rats with kidney or liver damage

et al. 2016

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“…Further, miR‐122 levels in samples collected at presentation in AILI patients were enhanced in those who experienced a poor outcome (death or liver transplant) compared with those who spontaneously recovered. In both this clinical study and in a preclinical study utilizing dogs with DILI unrelated to acetaminophen, miR‐122 appeared to return to baseline faster than ALT, suggesting miR‐122 has a shorter serum half‐life than ALT and could therefore more accurately reflect the extent of ongoing liver injury …”

Section: Newer Dili Biomarkersmentioning

confidence: 75%

“…In a recent AILI study conducted in rodents, GLDH slightly outperformed ALT for identification of hepatocellular necrosis and demonstrated improved correlation with injury severity . Similarly, in a canine study, serum GLDH levels, when compared to ALT levels, were found to more accurately reflect the absence of injury histologically observed liver injury at study termination . A clinical study demonstrated a strong correlation between serum GLDH and ALT levels and showed that GLDH displayed high diagnostic power for predicting hepatic injury in a large cohort of patients with liver damage resulting from various aetiologies .…”

Section: Newer Dili Biomarkersmentioning

confidence: 89%

“…34 Similarly, in a canine study, serum GLDH levels, when compared to ALT levels, were found to more accurately reflect the absence of injury histologically observed liver injury at study termination. 35 A clinical study demonstrated a strong correlation between serum GLDH and ALT levels and showed that GLDH displayed high diagnostic power for predicting hepatic injury in a large cohort of patients with liver damage resulting from various aetiologies. 36 It is suggested that because the half-life of GLDH is shorter than that of ALT (~16h vs ~47h respectively), serum levels of GLDH more accurately reflect ongoing liver injury.…”

Section: Gldhmentioning

confidence: 99%

“…In both this clinical study and in a preclinical study utilizing dogs with DILI unrelated to acetaminophen, miR-122 appeared to return to baseline faster than ALT, suggesting miR-122 has a shorter serum half-life than ALT and could therefore more accurately reflect the extent of ongoing liver injury. 35,44 Large miRNA profiling studies have also been conducted in clinical AILI datasets obtained from both adults and children. [45][46][47][48] In all studies, miR-122 was among the highest elevated miRNAs in circulation.…”

Section: Mir-122mentioning

confidence: 99%

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The transformation in biomarker detection and management of drug‐induced liver injury

Church

Watkins

2017

Liver International

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Drug-induced liver injury (DILI) is a major concern for patients, care givers and the pharmaceutical industry. Interpretation of the serum biomarkers routinely used to detect and monitor DILI, which have not changed in almost 50 years, can be improved with recently proposed models employing quantitative systems pharmacology. In addition, several newer serum biomarkers are showing great promise. Studies in rodents indicate that the ratio of the caspase cleaved fragment of cytokeratin 18 to total K18 in serum (termed the “apoptotic index”) estimates the relative proportions of apoptosis vs necrosis during drug-induced liver injury. Glutamate dehydrogenase can reliably differentiate liver from muscle injury and, when serum is properly prepared, may also detect mitochondrial toxicity as a mechanism of liver injury. MicroRNA-122 is liver-specific, but recent data suggests it can be actively released from hepatocytes in the absence of overt toxicity limiting enthusiasm for it as a DILI biomarker. Finally, damage associated molecular patterns, particularly high mobility group box 1 and its various modified forms, are promising biomarkers of innate immune activation, which may be useful in distinguishing benign elevations in aminotransferases from those that portend clinically important liver injury. These new biomarkers are already being measured in early clinical trials, but broad acceptance will require widespread archiving of serum from diverse clinical trials and probably pre-competitive analysis efforts. We believe that utilization of a panel of traditional and newer biomarkers in conjunction with quantitative systems pharmacology modeling approaches will transform DILI detection and risk management.

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General Toxicology: Principle, Methods, and Applications

Yanni¹

2015

Translational ADMET for Drug Therapy

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Liver biomarker and in vitro assessment confirm the hepatic origin of aminotransferase elevations lacking histopathological correlate in beagle dogs treated with GABAA receptor antagonist NP260

Cited by 26 publications

References 13 publications

Identification of microRNA biomarker candidates in urine and plasma from rats with kidney or liver damage

Identification of microRNA biomarker candidates in urine and plasma from rats with kidney or liver damage

The transformation in biomarker detection and management of drug‐induced liver injury

General Toxicology: Principle, Methods, and Applications

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