{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T20:41:14Z","timestamp":1790023274515,"version":"4.0.1"},"reference-count":30,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2021,11,11]],"date-time":"2021-11-11T00:00:00Z","timestamp":1636588800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/ijms222212201","type":"journal-article","created":{"date-parts":[[2021,11,11]],"date-time":"2021-11-11T23:02:41Z","timestamp":1636671761000},"page":"12201","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Investigation of Ifosfamide Toxicity Induces Common Upstream Regulator in Liver and Kidney"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7957-7448","authenticated-orcid":false,"given":"Hyoung-Yun","family":"Han","sequence":"first","affiliation":[{"name":"Department of Predictive Toxicology, Korea Institute of Toxicology, 141 Gajeong-ro, Yuseong-gu, Daejeon 34114, Korea"},{"name":"Department of Human and Environmental Toxicology, University of Science and Technology, Daejeon 34113, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mi-Sun","family":"Choi","sequence":"additional","affiliation":[{"name":"Department of Predictive Toxicology, Korea Institute of Toxicology, 141 Gajeong-ro, Yuseong-gu, Daejeon 34114, Korea"},{"name":"College of Pharmacy, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon 34131, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seokjoo","family":"Yoon","sequence":"additional","affiliation":[{"name":"Department of Predictive Toxicology, Korea Institute of Toxicology, 141 Gajeong-ro, Yuseong-gu, Daejeon 34114, Korea"},{"name":"Department of Human and Environmental Toxicology, University of Science and Technology, Daejeon 34113, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Je-Won","family":"Ko","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine & Institute of Veterinary Science, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon 34134, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sang-Kyum","family":"Kim","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon 34131, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5239-3833","authenticated-orcid":false,"given":"Tae-Won","family":"Kim","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine & Institute of Veterinary Science, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon 34134, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,11,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Palmerini, E., Setola, E., Grignani, G., D\u2019Ambrosio, L., Comandone, A., Righi, A., Longhi, A., Cesari, M., Paioli, A., and Hakim, R. (2020). High dose ifosfamide in relapsed and unresectable high-grade osteosarcoma patients: A retrospective series. Cells, 9.","DOI":"10.3390\/cells9112389"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1159\/000073351","article-title":"Side effects of ifosfamide","volume":"65","author":"Klastersky","year":"2003","journal-title":"Oncology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1093\/ckj\/sfaa017","article-title":"The growing pains of ifosfamide","volume":"13","author":"Sprangers","year":"2020","journal-title":"Clin. Kidney J."},{"key":"ref_4","first-page":"83","article-title":"High-dose ifosfamide\/carboplatin\/etoposide with autologous hematopoietic stem cell support: Safety and future directions","volume":"21","author":"Elias","year":"1994","journal-title":"Semin. Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1055\/s-2007-1023278","article-title":"Sequential course and prospective management of ifosfamide-induced multi-organ toxicity","volume":"56","author":"Mollenkopf","year":"1996","journal-title":"Geburtshilfe Frauenheilkd."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"872","DOI":"10.1007\/s00467-004-1807-3","article-title":"Cytochrome P450 3A and 2B6 in the developing kidney: Implications for ifosfamide nephrotoxicity","volume":"20","author":"Aleksa","year":"2005","journal-title":"Pediatr. Nephrol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1097\/FPC.0000000000000019","article-title":"PharmGKB summary: Ifosfamide pathways, pharmacokinetics and pharmacodynamics","volume":"24","author":"Lowenberg","year":"2014","journal-title":"Pharmacogenet. Genom."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1016\/j.cbi.2012.11.017","article-title":"Acrolein and chloroacetaldehyde: An examination of the cell and cell-free biomarkers of toxicity","volume":"202","author":"MacAllister","year":"2013","journal-title":"Chem. Biol. Interact."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Kim, J., and Shin, M. (2014). An integrative model of multi-organ drug-induced toxicity prediction using gene-expression data. BMC Bioinform., 15.","DOI":"10.1186\/1471-2105-15-S16-S2"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1039\/C8MO00042E","article-title":"Developments in toxicogenomics: Understanding and predicting compound-induced toxicity from gene expression data","volume":"14","author":"Pruteanu","year":"2018","journal-title":"Mol. Omics"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s13273-016-0001-6","article-title":"Construction of a predictive model for evaluating multiple organ toxicity","volume":"12","author":"An","year":"2016","journal-title":"Mol. Cell Toxicol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1159\/000073353","article-title":"Ifosfamide and cyclophosphamide: Effects on immunosurveillance","volume":"65","author":"Binotto","year":"2003","journal-title":"Oncology"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1007\/s00467-005-2006-6","article-title":"Chloroacetaldehyde- and acrolein-induced death of human proximal tubule cells","volume":"21","author":"Schwerdt","year":"2006","journal-title":"Pediatr. Nephrol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"660","DOI":"10.1093\/ckj\/sfz183","article-title":"Ifosfamide nephrotoxicity in adult patients","volume":"13","author":"Ensergueix","year":"2020","journal-title":"Clin. Kidney J."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"428","DOI":"10.2165\/00003495-199142030-00006","article-title":"Ifosfamide\/mesna. A review of its antineoplastic activity, pharmacokinetic properties and therapeutic efficacy in cancer","volume":"42","author":"Dechant","year":"1991","journal-title":"Drugs"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1038\/bjc.1998.24","article-title":"Phase I study on docetaxel and ifosfamide in patients with advanced solid tumours","volume":"77","author":"Pronk","year":"1998","journal-title":"Br. J. Cancer."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1002\/mpo.10336","article-title":"Chronic ifosfamide nephrotoxicity in children","volume":"41","author":"Skinner","year":"2003","journal-title":"Med. Pediatr Oncol."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Sharp, P., and Vilano, J.S. (2012). The Laboratory Rat, CRC Press.","DOI":"10.1201\/b13862"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1186\/1752-1947-5-180","article-title":"Acute liver toxicity with ifosfamide in the treatment of sarcoma: A case report","volume":"5","author":"Cheung","year":"2011","journal-title":"J. Med. Case Rep."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"573","DOI":"10.2217\/pgs.10.37","article-title":"Use of transcriptomics in understanding mechanisms of drug-induced toxicity","volume":"11","author":"Cui","year":"2010","journal-title":"Pharmacogenomics"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.ygeno.2012.05.001","article-title":"Transcriptomic analysis of the effect of ifosfamide on MDCK cells cultivated in microfluidic biochips","volume":"100","author":"Snouber","year":"2012","journal-title":"Genomics"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1021\/tx00049a012","article-title":"Glutathione conjugation of the cytostatic drug ifosfamide and the role of human glutathione S-transferases","volume":"8","author":"Dirven","year":"1995","journal-title":"Chem. Res. Toxicol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/j.freeradbiomed.2017.05.019","article-title":"Mesna (2-mercaptoethane sodium sulfonate) functions as a regulator of myeloperoxidase","volume":"110","author":"Jeelani","year":"2017","journal-title":"Free Radic. Biol. Med."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Alnahdi, A., John, A., and Raza, H. (2019). N-acetyl cysteine attenuates oxidative stress and glutathione-dependent redox imbalance caused by high glucose\/high palmitic acid treatment in pancreatic Rin-5F cells. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0226696"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"5748","DOI":"10.1128\/MCB.17.10.5748","article-title":"IRF-7, a new interferon regulatory factor associated with Epstein\u2013Barr virus latency","volume":"17","author":"Zhang","year":"1997","journal-title":"Mol. Cell Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1056\/NEJMp020056","article-title":"Viruses and lymphomas","volume":"347","author":"Pagano","year":"2002","journal-title":"N. Engl. J. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"10576","DOI":"10.1158\/0008-5472.CAN-06-1279","article-title":"Distinct roles for IFN regulatory factor (IRF)-3 and IRF-7 in the activation of antitumor properties of human macrophages","volume":"66","author":"Solis","year":"2006","journal-title":"Cancer Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1038\/gene.2011.21","article-title":"IRF7: Activation, regulation, modification and function","volume":"12","author":"Ning","year":"2011","journal-title":"Genes Immun."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"61958","DOI":"10.18632\/oncotarget.18740","article-title":"Swine IRF3\/IRF7 attenuates inflammatory responses through TLR4 signaling pathway","volume":"8","author":"Chen","year":"2017","journal-title":"Oncotarget"},{"key":"ref_30","first-page":"6747","article-title":"Aging impairs IFN regulatory factor 7 up-regulation in plasmacytoid dendritic cells during TLR9 activation","volume":"181","author":"Yang","year":"2008","journal-title":"J. Immunol. Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/22\/12201\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:28:32Z","timestamp":1760167712000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/22\/12201"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,11]]},"references-count":30,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2021,11]]}},"alternative-id":["ijms222212201"],"URL":"https:\/\/doi.org\/10.3390\/ijms222212201","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,11]]}}}