Prediction of Clinically Relevant Safety Signals of Nephrotoxicity through Plasma Metabolite Profiling

Mattes, William B.; Kamp, Hennicke; Fabian, Eric; Herold, Michael; Krennrich, G.; Looser, Ralf; Mellert, W.; Prokoudine, A.; Strauss, Volker; Ravenzwaay, Bennard van; Walk, T.; Naraoka, Hitoshi; Omura, Ko; Schuppe-Koistinen, Ina; Nadanaciva, Sashi; Bush, Ernest D.; Moeller, Niels; Ruiz-Noppinger, P; Piccoli, Steven P.

doi:10.1155/2013/202497

Cited by 18 publications

(11 citation statements)

References 65 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our study revealed changes in metabolites of purines, glutathione and amino acids upon exposure to tubular neurotoxicants. Similar alterations were also described in plasma and kidney tissue of rats exposed to different drugs associated with tubular damage ( Boudonck et al, 2009 ; Zgoda-Pols et al, 2011 ; Mattes et al, 2013 ). Those metabolic changes can be linked with alterations in energy metabolism, xenobiotic metabolism and protein catabolism, which have already been described in the pathophysiology of acute kidney injury ( Druml, 2013 ).…”

Section: Discussionsupporting

confidence: 72%

“…The COMET and MetaMap ® To x projects are two examples of the potential of toxicometabolomics as a drug toxicity screening tool. Those studies generated metabolic databases from urine and plasma samples of rats exposed to different toxicants that were further used to predict specific organ toxicity, including DIRI ( Ebbels et al, 2007 ; van Ravenzwaay et al, 2012 ; Mattes et al, 2013 ). Toxicometabolomics proved also to be useful to identify new biomarkers and/or elucidate the mechanisms underlying DIRI.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Zebrafish Larvae Are a Suitable Model to Investigate the Metabolic Phenotype of Drug-Induced Renal Tubular Injury

et al. 2018

View full text Add to dashboard Cite

Prevention and treatment of drug-induced renal injury (DIRI) rely on the availability of sensitive and specific biomarkers of early kidney injury and predictive animal models of human pathophysiology. This study aimed to evaluate the potential of zebrafish larvae as translational model in metabolic profiling of DIRI. Zebrafish larvae were exposed to the lethal concentration for 10% of the larvae (LC10) or ½ LC10 of gentamicin, paracetamol and tenofovir as tenofovir disoproxil fumarate (TDF) and tenofovir (TFV). Metabolites were extracted from whole larvae and analyzed by liquid chromatography-mass spectrometry. Principal component analysis showed that drug exposition to the LC10 of paracetamol, TFV, and TDF was the main source of the variance of the data. To identify the metabolites responsible for the toxic effects of the drugs, partial least squares discriminant analyses were built between the LC10 and ½ LC10 for each drug. Features with variable importance in projection> 1.0 were selected and Venn diagrams were built to differentiate between the common and drug specific metabolites of DIRI. Creatine, tyrosine, glutamine, guanosine, hypoxanthine were identified as common metabolites, adenosine and tryptophan as paracetamol-specific and xanthine and oxidized glutathione as tenofovir-specific. Those metabolic changes can be associated with alterations in energy metabolism, xenobiotic detoxification and protein catabolism, all described in the human pathophysiology of DIRI. Thus, zebrafish proved to be a suitable model to characterize the metabolic changes associated with DIRI. This information can be useful to early diagnose DIRI and to improve our knowledge on the mechanisms of DIRI.

show abstract

Section: Discussionsupporting

confidence: 72%

Section: Introductionmentioning

confidence: 99%

Zebrafish Larvae Are a Suitable Model to Investigate the Metabolic Phenotype of Drug-Induced Renal Tubular Injury

et al. 2018

View full text Add to dashboard Cite

show abstract

“…A biomarker panel based on pathways or common mechanisms of hepatotoxicity would be ideal for the prediction of liver injury [40] . The metabolic profiling has been successfully used to predict drug induced kidney injury in a preclinical study [41] . Hence, our efforts to discover a metabolic biomarker panel for prediction of liver injury will be based on the common pathways underlying hepatotoxicity: i) bile acid metabolism; ii) oxidative stress, iii) energy pathways related to mitochondrial impairment and iv) other hepatic cell regeneration pathways [40] .…”

Section: Resultsmentioning

confidence: 99%

Identification of a metabolic biomarker panel in rats for prediction of acute and idiosyncratic hepatotoxicity

Sun¹,

Slavov²,

Schnackenberg³

et al. 2014

Computational and Structural Biotechnology Journal

View full text Add to dashboard Cite

It has been estimated that 10% of acute liver failure is due to “idiosyncratic hepatotoxicity”. The inability to identify such compounds with classical preclinical markers of hepatotoxicity has driven the need to discover a mechanism-based biomarker panel for hepatotoxicity. Seven compounds were included in this study: two overt hepatotoxicants (acetaminophen and carbon tetrachloride), two idiosyncratic hepatotoxicants (felbamate and dantrolene), and three non-hepatotoxicants (meloxicam, penicillin and metformin). Male Sprague–Dawley rats were orally gavaged with a single dose of vehicle, low dose or high dose of the compounds. At 6 h and 24 h post-dosing, blood was collected for metabolomics and clinical chemistry analyses, while organs were collected for histopathology analysis. Forty-one metabolites from previous hepatotoxicity studies were semi-quantified and were used to build models to predict hepatotoxicity. The selected metabolites were involved in various pathways, which have been noted to be linked to the underlying mechanisms of hepatotoxicity. PLS models based on all 41 metabolite or smaller subsets of 6 (6 h), 7 (24 h) and 20 (6 h and 24 h) metabolites resulted in models with an accuracy of at least 97.4% for the hold-out test set and 100% for training sets. When applied to the external test sets, the PLS models predicted that 1 of 9 rats at both 6 h and 24 h treated with idiosyncratic liver toxicants was exposed to a hepatotoxic chemical. In conclusion, the biomarker panel might provide information that along with other endpoint data (e.g., transcriptomics and proteomics) may diagnose acute and idiosyncratic hepatotoxicity in a clinical setting.

show abstract

“…2500 metabolites, 1200 drugs and 3500 food components encountered in the human body (Wishart et al, 2007), the MetaMap®-Tox developed at metabonomics and containing rat plasma metabolome for more than 500 references compounds Mattes et al, 2013). 2500 metabolites, 1200 drugs and 3500 food components encountered in the human body (Wishart et al, 2007), the MetaMap®-Tox developed at metabonomics and containing rat plasma metabolome for more than 500 references compounds Mattes et al, 2013).…”

Section: Principles Of Metabolomicsmentioning

confidence: 99%

Modern methodologies and tools for human hazard assessment of chemicals

2014

EFS2

View full text Add to dashboard Cite

This scientific report provides a review of modern methodologies and tools to depict toxicokinetic and toxicodynamic processes and their application for the human hazard assessment of chemicals. The application of these methods is illustrated with examples drawn from the literature and international efforts in the field. First, the concepts of mode of action/adverse outcome pathway are discussed together with their associated terminology and recent international developments dealing with human hazard assessment of chemicals. Then modern methodologies and tools are presented including in vitro systems, physiologically-based models, in silico tools and OMICs technologies at the level of DNA/RNA (transcriptomics), proteins (proteomics) and the whole metabolome (metabolomics). Future perspectives for the potential applications of these modern methodologies and tools in the context of prioritisation of chemicals, integrated test strategies and the future of risk assessment are discussed. The report concludes with recommendations for future work and research formulated from consultations of EFSA staff, expert Panels and other international organisations.

show abstract

Prediction of Clinically Relevant Safety Signals of Nephrotoxicity through Plasma Metabolite Profiling

Cited by 18 publications

References 65 publications

Zebrafish Larvae Are a Suitable Model to Investigate the Metabolic Phenotype of Drug-Induced Renal Tubular Injury

Zebrafish Larvae Are a Suitable Model to Investigate the Metabolic Phenotype of Drug-Induced Renal Tubular Injury

Identification of a metabolic biomarker panel in rats for prediction of acute and idiosyncratic hepatotoxicity

Modern methodologies and tools for human hazard assessment of chemicals

Contact Info

Product

Resources

About