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Toxicogenomic multigene biomarker for predicting the future onset of proximal tubular injury in rats.
- Source :
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Toxicology [Toxicology] 2012 Jul 16; Vol. 297 (1-3), pp. 47-56. Date of Electronic Publication: 2012 Apr 06. - Publication Year :
- 2012
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Abstract
- Drug-induced renal tubular injury is a major concern in the preclinical safety evaluation of drug candidates. Toxicogenomics is now a generally accepted tool for identifying chemicals with potential safety problems. The specific aim of the present study was to develop a model for use in predicting the future onset of drug-induced proximal tubular injury following repeated dosing with various nephrotoxicants. In total, 41 nephrotoxic and nonnephrotoxic compounds were used for the present analysis. Male Sprague-Dawley rats were dosed orally or intravenously once daily. Animals were exposed to three different doses (low, middle, and high) of each compound, and kidney tissue was collected at 3, 6, 9, and 24 h after single dosing, and on days 4, 8, 15, and 29 after repeated dosing. Gene expression profiles were generated from kidney total RNA using Affymetrix DNA microarrays. Filter-type gene selection and linear classification algorithms were employed to discriminate future onset of proximal tubular injury. We identified genomic biomarkers for use in future onset prediction using the gene expression profiles determined on day 1, when most of the nephrotoxicants had yet to produce detectable histopathological changes. The model was evaluated using a five-fold cross validation, and achieved a sensitivity of 93% and selectivity of 90% with 19 probes. We also found that the prediction accuracy of the optimized model was substantially higher than that produced by any of the single genomic biomarkers or histopathology. The genes included in our model were primarily involved in DNA replication, cell cycle control, apoptosis, and responses to oxidative stress and chemical stimuli. In summary, our toxicogenomic model is particularly useful for predicting the future onset of proximal tubular injury.<br /> (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)
- Subjects :
- Acute Kidney Injury chemically induced
Acute Kidney Injury pathology
Animals
Biomarkers
Drug-Related Side Effects and Adverse Reactions pathology
Forecasting
Male
Multiprotein Complexes genetics
Predictive Value of Tests
Rats
Rats, Sprague-Dawley
Toxicogenetics
Acute Kidney Injury genetics
Drug-Related Side Effects and Adverse Reactions genetics
Genetic Markers genetics
Kidney Tubules, Proximal drug effects
Kidney Tubules, Proximal injuries
Multigene Family genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1879-3185
- Volume :
- 297
- Issue :
- 1-3
- Database :
- MEDLINE
- Journal :
- Toxicology
- Publication Type :
- Academic Journal
- Accession number :
- 22503706
- Full Text :
- https://doi.org/10.1016/j.tox.2012.03.014