Ingenuity pathways analysis of urine metabonomics phenotypes toxicity of gentamicin in multiple organs

Abstract

We introduce the use of Ingenuity Pathway Analysis to analyzing global metabonomics in order to characterize phenotypically biochemical perturbations and the potential mechanisms of the gentamicin-induced toxicity in multiple organs. A single dose of gentamicin was administered to Sprague Dawley rats (200 mg/kg, n = 6) and urine samples were collected at -24-0 h pre-dosage, 0-24, 24-48, 48-72 and 72-96 h post-dosage of gentamicin. The urine metabonomics analysis was performed by UPLC/MS, and the mass spectra signals of the detected metabolites were systematically deconvoluted and analyzed by pattern recognition analyses (Heatmap, PCA and PLS-DA), revealing a time-dependency of the biochemical perturbations induced by gentamicin toxicity. As result, the holistic metabolome change induced by gentamicin toxicity in the animal's organisms was characterized. Several metabolites involved in amino acid metabolism were identified in urine, and it was confirmed that gentamicin biochemical perturbations can be foreseen from these biomarkers. Notoriously, it was found that gentamicin induced toxicity in multiple organs system in the laboratory rats. The proof-of-knowledge based Ingenuity Pathway Analysis revealed gentamicin induced liver and heart toxicity, along with the previously known toxicity in kidney. The metabolites creatine, nicotinic acid, prostaglandin E2, and cholic acid were identified and validated as phenotypic biomarkers of gentamicin induced toxicity. Altogether, the significance of the use of metabonomics analyses in the assessment of drug toxicity is highlighted once more; furthermore, this work demonstrated the powerful predictive potential of the Ingenuity Pathway Analysis to study of drug toxicity and its valuable complementation for metabonomics based assessment of the drug toxicity.

Metabolomics in Nephrotoxicity

“…Other results showed increased urinary 6-hydroxymelatonin that directly correlated with histopathologic findings [21]. Metabolomics successfully identified valine, hydroxyproline, HVA-SO 4, and HVrA-SO 4 as early injury or adaptive biomarkers [26,27]. Melatonin supplementation has also been shown to protect the rat kidney from gentamicin and HgCl 2 -induced nephrotoxicity [23,24].…”

EGR1 decreases the malignancy of human non-small cell lung carcinoma by regulating KRT18 expression

“…Transcripts with more than a 2.0-fold difference in expression level were defined as differentially expressed. Specifically designed online tools, including David bioinformatics resource37 and Ingenuity system analysis (IPA)38, were used to classify the functions of the identified differentially expressed genes.…”

The Transcriptional Profiling of Glycogenes Associated with Hepatocellular Carcinoma Metastasis

“…Glycogene with differences greater than 2-fold (P≤0.05) was considered as the differentially transcribed glycogenes and they were divided into six clusters by a K- means approach, which is a kind of clustering algorithm for grouping genes or proteins with a similar expression pattern [17], [18] and the GO was used to describe. IPA (Ingenuity System Inc, USA) is a proof of knowledge based comprehensive software of data analysis that can help researchers model, analyze, and understand the complex biological and chemical systems in life science research [19], [20]. The differentially transcribed glycogenes were uploaded to the database to explore regulatory network.…”