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Investigation of Ifosfamide Toxicity Induces Common Upstream Regulator in Liver and Kidney

Ifosfamide is an alkylating agent, a synthetic analogue of cyclophosphamide, used to treat various solid cancers. In this study, the toxicity of ifosfamide was evaluated using single-and multiple-dose intraperitoneal administration in rats under Good Laboratory Practice guidelines, and an additional...

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Autores principales: Han, Hyoung-Yun, Choi, Mi-Sun, Yoon, Seokjoo, Ko, Je-Won, Kim, Sang-Kyum, Kim, Tae-Won
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8617928/
https://www.ncbi.nlm.nih.gov/pubmed/34830083
http://dx.doi.org/10.3390/ijms222212201
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author Han, Hyoung-Yun
Choi, Mi-Sun
Yoon, Seokjoo
Ko, Je-Won
Kim, Sang-Kyum
Kim, Tae-Won
author_facet Han, Hyoung-Yun
Choi, Mi-Sun
Yoon, Seokjoo
Ko, Je-Won
Kim, Sang-Kyum
Kim, Tae-Won
author_sort Han, Hyoung-Yun
collection PubMed
description Ifosfamide is an alkylating agent, a synthetic analogue of cyclophosphamide, used to treat various solid cancers. In this study, the toxicity of ifosfamide was evaluated using single-and multiple-dose intraperitoneal administration in rats under Good Laboratory Practice guidelines, and an additional microarray experiment was followed to support toxicological findings. A single dose of ifosfamide (50 mg/kg) did not induce any pathological changes. Meanwhile, severe renal toxicity was observed in the 7 and 28 days consecutively administered groups, with significant increases in blood urea nitrogen and creatinine levels. In the tox-list analysis, cholesterol synthesis-related genes were mostly affected in the liver and renal failure-related genes were affected in the kidney after ifosfamide administration. Moreover, interferon regulatory factor 7 was selected as the main upstream regulator that changed in both the liver and kidney, and was found to interact with other target genes, such as ubiquitin specific peptidase 18, radical S-adenosyl methionine domain containing 2, and interferon-stimulated gene 15, which was further confirmed by real-time RT-PCR analysis. In conclusion, we confirmed kidney-biased ifosfamide organ toxicity and identified identically altered genes in both the liver and kidney. Further comprehensive toxicogenomic studies are required to reveal the exact relationship between ifosfamide-induced genes and organ toxicity.
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spelling pubmed-86179282021-11-27 Investigation of Ifosfamide Toxicity Induces Common Upstream Regulator in Liver and Kidney Han, Hyoung-Yun Choi, Mi-Sun Yoon, Seokjoo Ko, Je-Won Kim, Sang-Kyum Kim, Tae-Won Int J Mol Sci Article Ifosfamide is an alkylating agent, a synthetic analogue of cyclophosphamide, used to treat various solid cancers. In this study, the toxicity of ifosfamide was evaluated using single-and multiple-dose intraperitoneal administration in rats under Good Laboratory Practice guidelines, and an additional microarray experiment was followed to support toxicological findings. A single dose of ifosfamide (50 mg/kg) did not induce any pathological changes. Meanwhile, severe renal toxicity was observed in the 7 and 28 days consecutively administered groups, with significant increases in blood urea nitrogen and creatinine levels. In the tox-list analysis, cholesterol synthesis-related genes were mostly affected in the liver and renal failure-related genes were affected in the kidney after ifosfamide administration. Moreover, interferon regulatory factor 7 was selected as the main upstream regulator that changed in both the liver and kidney, and was found to interact with other target genes, such as ubiquitin specific peptidase 18, radical S-adenosyl methionine domain containing 2, and interferon-stimulated gene 15, which was further confirmed by real-time RT-PCR analysis. In conclusion, we confirmed kidney-biased ifosfamide organ toxicity and identified identically altered genes in both the liver and kidney. Further comprehensive toxicogenomic studies are required to reveal the exact relationship between ifosfamide-induced genes and organ toxicity. MDPI 2021-11-11 /pmc/articles/PMC8617928/ /pubmed/34830083 http://dx.doi.org/10.3390/ijms222212201 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Han, Hyoung-Yun
Choi, Mi-Sun
Yoon, Seokjoo
Ko, Je-Won
Kim, Sang-Kyum
Kim, Tae-Won
Investigation of Ifosfamide Toxicity Induces Common Upstream Regulator in Liver and Kidney
title Investigation of Ifosfamide Toxicity Induces Common Upstream Regulator in Liver and Kidney
title_full Investigation of Ifosfamide Toxicity Induces Common Upstream Regulator in Liver and Kidney
title_fullStr Investigation of Ifosfamide Toxicity Induces Common Upstream Regulator in Liver and Kidney
title_full_unstemmed Investigation of Ifosfamide Toxicity Induces Common Upstream Regulator in Liver and Kidney
title_short Investigation of Ifosfamide Toxicity Induces Common Upstream Regulator in Liver and Kidney
title_sort investigation of ifosfamide toxicity induces common upstream regulator in liver and kidney
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8617928/
https://www.ncbi.nlm.nih.gov/pubmed/34830083
http://dx.doi.org/10.3390/ijms222212201
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