Metabolomics approaches for discovering biomarkers of drug-induced hepatotoxicity and nephrotoxicity

Beger, Richard D.; Sun, Jinchun; Schnackenberg, Laura K.

doi:10.1016/j.taap.2009.11.019

Cited by 197 publications

(132 citation statements)

References 141 publications

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“…Those molecules, related to glutathione production, were detected in urine analysis and in liver extracts from in vivo studies. They have also been reported as APAP toxicity biomarkers (Beger et al 2010;Soga et al, 2006). Furthermore, increased levels of 3-hydroxybutyrate in the APAP treated biochip cultures demonstrated an intense lipid metabolism through the ketone degradation pathway.…”

Section: Identification Of Specific Apap Toxicity Biomarkers In Biochipsmentioning

confidence: 95%

Predictive toxicology using systemic biology and liver microfluidic “on chip” approaches: Application to acetaminophen injury

Prot

Bunescu

Elena-Herrmann

et al. 2012

Toxicology and Applied Pharmacology

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Snouber, et al.. Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: Application to acetaminophen injury. Toxicology and Applied Pharmacology, Elsevier, 2012, 259 (3) ABSTRACTWe -analyzed transcriptomic, proteomic and metabolomic profiles of hepatoma cells cultivated inside a microfluidic biochip with or without acetaminophen (APAP).Without APAP, the results show an adaptive cellular response to the microfluidic environment, leading to the induction of anti-oxidative stress and cytoprotective pathways. In presence of APAP, calcium homeostasis perturbation, lipid peroxidation and cell death are observed. These effects can be attributed to APAP metabolism into its highly reactive metabolite, N-acetyl-p-benzoquinone imine (NAPQI). . That toxicity pathway was confirmed by the detection of GSH-APAP, the large production of 2-hydroxybutyrate and 3-hydroxybutyrate, and methionine, cystine, and histidine consumption in the treated biochips. Those metabolites have been reported as specific biomarkers of hepatotoxicity and glutathione depletion in the literature. In addition, the integration of the metabolomic, transcriptomic and proteomic profiles collected allowed a more complete reconstruction of the APAP injury pathways. To our knowledge, this work is the first example of a global integration of microfluidic biochip data in toxicity assessment. Our results demonstrate the potential of that new approach to predictive toxicology.

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Section: Identification Of Specific Apap Toxicity Biomarkers In Biochipsmentioning

confidence: 95%

Predictive toxicology using systemic biology and liver microfluidic “on chip” approaches: Application to acetaminophen injury

Prot

Bunescu

Elena-Herrmann

et al. 2012

Toxicology and Applied Pharmacology

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“…Pharmacovigilance The detection of hepatotoxicity during the drug development phase is complicated. One of the reasons is that an effi cient biomarker of liver damage is not available to detect liver injury in the early stages (34) . Alanine aminotransferase values have been traditionally used to diagnose patients with acute liver injury after paracetamol intoxication; however, in acute overdose, the elevation of this biomarker may be delayed 48-72 h after ingestion, hindering prompt recognition of the overdose.…”

Section: Ethical Aspectsmentioning

confidence: 99%

Acute and chronic paracetamol overdose in paediatric population: Protocol of a prospective study of cohort to evaluate clinic factor and biomarkers to predict development of hepatotoxicity

Tong

Garcia²,

Garcia³

et al. 2017

IBJ Clin Pharmacol

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I., Borobia Pérez AM., Carcas Sansuán AJ., Martí nez Ávila JC., Ramírez García E. Acute and chronic paracetamol overdose in paediatric populati on: Protocol of a prospecti ve study of cohort to evaluate clinic factor and biomarkers to predict development of hepatotoxicity. IBJ Clin Pharmacol 2017 1(1):e0007. Funding: The authors have no fi nancial relati onships relevant to this arti cle to disclose. Competi ng Interests:The authors declare no confl icts of interest. Background:In Spain, 30% of cases of acute liver failure remaining undetermined. Paracetamol is the main drug causing acute liver failure in children of some countries like the United States, UK and other European countries. The key factors to assess in paracetamol toxicity, the ingested dose and the ti me from the poisoning, are diffi cult to assess in children where accidental acute poisoning or medicati on errors are not rare. Metabolomics technology may be able to identi fy specifi c biomarkers of toxicity and adverse events in early stages. The identi fi cati on of paracetamol toxicity biomarkers could have important clinical implicati ons for pati ents who can not apply the Rumack-Matt hew nomogram and could be useful in the evaluati on of children with acute liver failure of unknown eti ology, and to predict liver damage before elevati on of transaminases. Methods and design:This is an observati onal prospecti ve study of case control. The protocol was approved by the Clinical Research Ethics Committ ee of the La Paz University Hospital. It will recruit pati ents who will be att ending in the emergency paediatric at La Paz University Hospital, at Niño Jesus University Hospital, and at Gregorio Marañón University hospital with suspected acute or chronic intake of paracetamol. Likewise, two cohorts of control will be recruited. It is expected to recruit at least 36 cases and 144 controls, matched for age and clinical characteristi cs. Peripheral blood, plasma, serum and urine samples will be collected, paracetamol serum concentrati ons, hepati c and renal functi on, coagulati on and metabolomic analysis. Discussion:It is important to determine the clinical factors and biomarkers that predict the development of hepatotoxicity in paediatric populati on following acute and chronic intake of paracetamol and develop a predicti ve model to assess the risk of hepatotoxicity in both type of intoxicati on by paracetamol suited to paediatric pati ents for use in clinical practi ce. Study registrati on: Editor: Jesús Frías IniestaCite as: Tong HY., Díaz García L., García García S., Ruiz Domínguez JA., Martí n Sánchez J., Storch de Gracias P., Rivas A., Muñoz M., Hernández Zabala R., García García I., Borobia Pérez AM., Carcas Sansuán AJ., Martí nez Ávila JC., Ramírez García E. Acute and chronic paracetamol overdose in paediatric populati on: Protocol of a prospecti ve study of cohort to evaluate clinic factor and biomarkers to predict development of hepatotoxicity. IBJ Clin Pharmacol 2017 1(1):e0007. Funding: The authors have no fi nancial relati onships...

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“…56 The noninvasive nature of metabolomics markers in different types of body fluid samples makes them attractive; however, as with any biomarker identified, they require extensive validation with a large number of biological samples. 57 …”

Section: Metabolite Markersmentioning

confidence: 99%

“…57 The small molecules in samples are usually fractionated via gas chromatography, high performance liquid chromatography, or capillary electrophoresis before injection into the MS for measurement. 88 The human metabolome database (http://www.hmdb.ca) contains over 7000 small molecule metabolites derived from degradation of endogenous biomolecules, xenobiotics, and food components detected in the body.…”

Section: Approaches For New Biomarker Discoverymentioning

confidence: 99%

“…However, identifying the metabolites that reflect the type and severity of injury remains a challenge. 57 Blood also contains a diverse range of RNA and DNA molecules. 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.…”

Section: Approaches For New Biomarker Discoverymentioning

confidence: 99%

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Biomarkers for drug-induced liver injury

Shi

Hong

Senior

et al. 2010

Expert Review of Gastroenterology & Hepatology

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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.

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Metabolomics approaches for discovering biomarkers of drug-induced hepatotoxicity and nephrotoxicity

Cited by 197 publications

References 141 publications

Predictive toxicology using systemic biology and liver microfluidic “on chip” approaches: Application to acetaminophen injury

Predictive toxicology using systemic biology and liver microfluidic “on chip” approaches: Application to acetaminophen injury

Acute and chronic paracetamol overdose in paediatric population: Protocol of a prospective study of cohort to evaluate clinic factor and biomarkers to predict development of hepatotoxicity

Biomarkers for drug-induced liver injury

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