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High-Density Real-Time PCR-Based in Vivo Toxicogenomic Screen to Predict Organ-Specific Toxicity

Toxicogenomics, based on the temporal effects of drugs on gene expression, is able to predict toxic effects earlier than traditional technologies by analyzing changes in genomic biomarkers that could precede subsequent protein translation and initiation of histological organ damage. In the present s...

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Autores principales: Fabian, Gabriella, Farago, Nora, Feher, Liliana Z., Nagy, Lajos I., Kulin, Sandor, Kitajka, Klara, Bito, Tamas, Tubak, Vilmos, Katona, Robert L., Tiszlavicz, Laszlo, Puskas, Laszlo G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Molecular Diversity Preservation International (MDPI) 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3189772/
https://www.ncbi.nlm.nih.gov/pubmed/22016648
http://dx.doi.org/10.3390/ijms12096116
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author Fabian, Gabriella
Farago, Nora
Feher, Liliana Z.
Nagy, Lajos I.
Kulin, Sandor
Kitajka, Klara
Bito, Tamas
Tubak, Vilmos
Katona, Robert L.
Tiszlavicz, Laszlo
Puskas, Laszlo G.
author_facet Fabian, Gabriella
Farago, Nora
Feher, Liliana Z.
Nagy, Lajos I.
Kulin, Sandor
Kitajka, Klara
Bito, Tamas
Tubak, Vilmos
Katona, Robert L.
Tiszlavicz, Laszlo
Puskas, Laszlo G.
author_sort Fabian, Gabriella
collection PubMed
description Toxicogenomics, based on the temporal effects of drugs on gene expression, is able to predict toxic effects earlier than traditional technologies by analyzing changes in genomic biomarkers that could precede subsequent protein translation and initiation of histological organ damage. In the present study our objective was to extend in vivo toxicogenomic screening from analyzing one or a few tissues to multiple organs, including heart, kidney, brain, liver and spleen. Nanocapillary quantitative real-time PCR (QRT-PCR) was used in the study, due to its higher throughput, sensitivity and reproducibility, and larger dynamic range compared to DNA microarray technologies. Based on previous data, 56 gene markers were selected coding for proteins with different functions, such as proteins for acute phase response, inflammation, oxidative stress, metabolic processes, heat-shock response, cell cycle/apoptosis regulation and enzymes which are involved in detoxification. Some of the marker genes are specific to certain organs, and some of them are general indicators of toxicity in multiple organs. Utility of the nanocapillary QRT-PCR platform was demonstrated by screening different references, as well as discovery of drug-like compounds for their gene expression profiles in different organs of treated mice in an acute experiment. For each compound, 896 QRT-PCR were done: four organs were used from each of the treated four animals to monitor the relative expression of 56 genes. Based on expression data of the discovery gene set of toxicology biomarkers the cardio- and nephrotoxicity of doxorubicin and sulfasalazin, the hepato- and nephrotoxicity of rotenone, dihydrocoumarin and aniline, and the liver toxicity of 2,4-diaminotoluene could be confirmed. The acute heart and kidney toxicity of the active metabolite SN-38 from its less toxic prodrug, irinotecan could be differentiated, and two novel gene markers for hormone replacement therapy were identified, namely fabp4 and pparg, which were down-regulated by estradiol treatment.
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spelling pubmed-31897722011-10-20 High-Density Real-Time PCR-Based in Vivo Toxicogenomic Screen to Predict Organ-Specific Toxicity Fabian, Gabriella Farago, Nora Feher, Liliana Z. Nagy, Lajos I. Kulin, Sandor Kitajka, Klara Bito, Tamas Tubak, Vilmos Katona, Robert L. Tiszlavicz, Laszlo Puskas, Laszlo G. Int J Mol Sci Article Toxicogenomics, based on the temporal effects of drugs on gene expression, is able to predict toxic effects earlier than traditional technologies by analyzing changes in genomic biomarkers that could precede subsequent protein translation and initiation of histological organ damage. In the present study our objective was to extend in vivo toxicogenomic screening from analyzing one or a few tissues to multiple organs, including heart, kidney, brain, liver and spleen. Nanocapillary quantitative real-time PCR (QRT-PCR) was used in the study, due to its higher throughput, sensitivity and reproducibility, and larger dynamic range compared to DNA microarray technologies. Based on previous data, 56 gene markers were selected coding for proteins with different functions, such as proteins for acute phase response, inflammation, oxidative stress, metabolic processes, heat-shock response, cell cycle/apoptosis regulation and enzymes which are involved in detoxification. Some of the marker genes are specific to certain organs, and some of them are general indicators of toxicity in multiple organs. Utility of the nanocapillary QRT-PCR platform was demonstrated by screening different references, as well as discovery of drug-like compounds for their gene expression profiles in different organs of treated mice in an acute experiment. For each compound, 896 QRT-PCR were done: four organs were used from each of the treated four animals to monitor the relative expression of 56 genes. Based on expression data of the discovery gene set of toxicology biomarkers the cardio- and nephrotoxicity of doxorubicin and sulfasalazin, the hepato- and nephrotoxicity of rotenone, dihydrocoumarin and aniline, and the liver toxicity of 2,4-diaminotoluene could be confirmed. The acute heart and kidney toxicity of the active metabolite SN-38 from its less toxic prodrug, irinotecan could be differentiated, and two novel gene markers for hormone replacement therapy were identified, namely fabp4 and pparg, which were down-regulated by estradiol treatment. Molecular Diversity Preservation International (MDPI) 2011-09-19 /pmc/articles/PMC3189772/ /pubmed/22016648 http://dx.doi.org/10.3390/ijms12096116 Text en © 2011 by the authors; licensee MDPI, Basel, Switzerland. http://creativecommons.org/licenses/by/3.0 This article is an open-access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).
spellingShingle Article
Fabian, Gabriella
Farago, Nora
Feher, Liliana Z.
Nagy, Lajos I.
Kulin, Sandor
Kitajka, Klara
Bito, Tamas
Tubak, Vilmos
Katona, Robert L.
Tiszlavicz, Laszlo
Puskas, Laszlo G.
High-Density Real-Time PCR-Based in Vivo Toxicogenomic Screen to Predict Organ-Specific Toxicity
title High-Density Real-Time PCR-Based in Vivo Toxicogenomic Screen to Predict Organ-Specific Toxicity
title_full High-Density Real-Time PCR-Based in Vivo Toxicogenomic Screen to Predict Organ-Specific Toxicity
title_fullStr High-Density Real-Time PCR-Based in Vivo Toxicogenomic Screen to Predict Organ-Specific Toxicity
title_full_unstemmed High-Density Real-Time PCR-Based in Vivo Toxicogenomic Screen to Predict Organ-Specific Toxicity
title_short High-Density Real-Time PCR-Based in Vivo Toxicogenomic Screen to Predict Organ-Specific Toxicity
title_sort high-density real-time pcr-based in vivo toxicogenomic screen to predict organ-specific toxicity
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3189772/
https://www.ncbi.nlm.nih.gov/pubmed/22016648
http://dx.doi.org/10.3390/ijms12096116
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