Quantitative Analyses and Transcriptomic Profiling of Circulating Messenger Rnas As Biomarkers of Rat Liver Injury

Wetmore, Barbara A.; Brees, Dominique; Singh, Reetu; Watkins, Paul B.; Andersen, Melvin E.; Loy, James; Thomas, Russell S.

doi:10.1002/hep.23574

Cited by 78 publications

(63 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…S3C). Although direct comparisons across model systems are difficult because of variation in experimental design, the results presented are broadly comparable with prior observations in murine models of APAP toxicity (7,(18)(19)(20)(21)(22), indicating conservation of the xenobiotic response.…”

supporting

confidence: 80%

PGE2-regulated wnt signaling and N -acetylcysteine are synergistically hepatoprotective in zebrafish acetaminophen injury

North

Babu²,

Vedder³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

140

View full text Add to dashboard Cite

Acetaminophen (APAP) toxicity is the most common drug-induced cause of acute liver failure in the United States. The only available treatment, N-acetylcysteine (NAC), has a limited time window of efficacy, indicating a need for additional therapeutic options. Zebrafish have emerged as a powerful tool for drug discovery. Here, we developed a clinically relevant zebrafish model of APAP toxicity. APAP depleted glutathione stores, elevated aminotransferase levels, increased apoptosis, and caused dose-dependent hepatocyte necrosis. These outcomes were limited by NAC and conserved in zebrafish embryos. In a targeted embryonic chemical screen, prostaglandin E2 (PGE2) was identified as a potential therapeutic agent; in the adult, PGE2 similarly decreased APAP-associated toxicity. Significantly, when combined with NAC, PGE2 extended the time window for a successful intervention, synergistically reducing apoptosis, improving liver enzymes, and preventing death. Use of a wnt reporter zebrafish line and chemical genetic epistasis showed that the effects of PGE2 are mediated through the wnt signaling pathway. Zebrafish can be used as a clinically relevant toxicological model amenable to the identification of additional therapeutics and biomarkers of APAP injury; our data suggest combinatorial PGE2 and NAC treatment would be beneficial for patients with APAP-induced liver damage.acetaminophen liver toxicity | chemical screen A cetaminophen (N-acetyl-p-aminophenol; APAP) is a commonly used analgesic and antipyretic. Although safe at therapeutic doses, accidental or suicidal drug overdose can cause dosedependent liver damage. APAP is the most common cause for liver transplantation for toxin-induced fulminant hepatic failure and results in more than 300 deaths annually in the United States (1). The only antidote in clinical use is N-acetylcysteine (NAC), which reduces mortality by ∼20-28% (2); however, the time interval of effective intervention after ingestion is typically <12 h, and delayed or prolonged treatment can negatively impact clinical outcome and survival (3). Therapeutic options for hepatic failure are limited to best supportive care and liver transplantation.APAP toxicity results from a hepatotoxic metabolite, N-acetylp-benzoquinone imine (NAPQI), produced by the cytochrome P450 enzymes CYP1A2, 2E1, and 3A4 (4). At therapeutic doses, NAPQI is efficiently inactivated in the liver by glutathione (GSH) conjugation (5). At toxic doses, excess production of NAPQI depletes hepatic GSH. Unconjugated NAPQI causes dysfunction of critical liver proteins, oxidative stress, and mitochondrial damage (6-8). NAC is a true antidote and limits damage by repleting GSH. Clinical efficacy of NAC treatment was shown for patients presenting after APAP ingestion; however, no conclusive clinical trials were conducted to elucidate its efficacy and optimal treatment window. Therapeutic benefits have been shown in mammalian models for other antioxidants (9, 10) that function to restore GSH levels. Compounds that support liver recovery from AP...

show abstract

supporting

confidence: 80%

PGE2-regulated wnt signaling and N -acetylcysteine are synergistically hepatoprotective in zebrafish acetaminophen injury

North

Babu²,

Vedder³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

140

View full text Add to dashboard Cite

show abstract

“…A few publications have paved the route to success, which promises to be labor-intensive (Wetmore et al 2010). In this endeavor, the collaborative consortia across the pharmaceutical industry and academia have a critical role (Roberts 2009).…”

Section: Resultsmentioning

confidence: 99%

Frontiers in Preclinical Safety Biomarkers

et al. 2012

View full text Add to dashboard Cite

The measurement of plasma microRNAs (miRNAs) and messenger RNAs (mRNAs) is the most recent effort to identify novel biomarkers in preclinical safety. These genomic markers often display tissue-specific expression, may be released from the tissues into the plasma during toxic events, change early and with high magnitude in tissues and in the blood during specific organ toxicities, and can be measured using multiplex formats. Their validation as biomarkers has been challenged by the technical difficulties. In particular, the concentration of miRNAs in the plasma depends on contamination by miRNAs originating from blood cells and platelets, and the relative fraction of miRNAs in complexes with Argonaute 2, high-density lipoproteins, and in exosomes and microvesicles. In spite of these hurdles, considerable progress has recently been made in assessing the potential value of miRNAs in the clinic, especially in cancer patients and cardiovascular diseases. The future of miRNAs and mRNAs as biomarkers of disease and organ toxicity depends on our ability to characterize their kinetics and to establish robust collection and measurement methods. This review covers the basic biology of miRNAs and the published literature on the use of miRNAs and mRNAs as biomarkers of specific target organ toxicity.

show abstract

“…However, in bupivacaine-treated rats, the levels of aminotransferase activity increased significantly in blood. 67 This demonstrated the specificity of using mRNA-based biomarkers over traditional aminotransferase (protein)-based biomarkers to detect DILI.…”

Section: Rna Markersmentioning

confidence: 98%

“…Several studies have already demonstrated the usefulness of using specific DNA or RNA sequences in the circulation, such as transcripts highly enriched in the liver, as markers to reflect DILI. 11,67,91 The concentrations of these molecules are too low to conduct a global survey using traditional nucleic acid profiling approaches like microarray. Besides microRNA, due to its small repertoire, no systematic survey of the DNA or RNA spectrum in the circulation has been done.…”

Section: Approaches For New Biomarker Discoverymentioning

confidence: 99%

Biomarkers for drug-induced liver injury

Shi

Hong

Senior

et al. 2010

Expert Review of Gastroenterology & Hepatology

View full text Add to dashboard Cite

Abstract:The liver plays a central role in metabolizing xenobiotics; therefore, it is highly susceptible to toxicity from these chemicals. Certain drugs, when taken in overdose and sometimes even when used within therapeutic range, may cause injury to the organ. Druginduced liver injury is now not only a leading cause of acute liver failure in the US, but is also a leading reason for discontinuation of drugs in development and for regulatory actions against previously approved drugs. The current clinical biomarkers to detect and monitor drug-induced liver injury are inadequate in terms of sensitivity and/or specificity, prompting the need for more informative biomarkers. The development of high throughput proteomics, genomics, and metabolomics technologies has the potential to fulfill such demand. The discipline of systems toxicology may add to our understanding of perturbed xenobiotic networks, which may lead to network-specific surrogate markers and therapeutic means to stop or reverse xenobiotic-induced liver injury.

show abstract

Quantitative Analyses and Transcriptomic Profiling of Circulating Messenger Rnas As Biomarkers of Rat Liver Injury

Cited by 78 publications

References 37 publications

PGE2-regulated wnt signaling and N -acetylcysteine are synergistically hepatoprotective in zebrafish acetaminophen injury

PGE2-regulated wnt signaling and N -acetylcysteine are synergistically hepatoprotective in zebrafish acetaminophen injury

Frontiers in Preclinical Safety Biomarkers

Biomarkers for drug-induced liver injury

Contact Info

Product

Resources

About