title: Predictive genomic biomarkers for drug-induced nephrotoxicity in mice.
abstract: The present study aimed to establish candidate biomarker genes for the early detection of nephrotoxicity in mice, with a particular focus on nephrotoxicity caused by polyene macrolides. Comprehensive gene expression changes were evaluated using microarrays in a mouse model in which acute nephrotoxicity was induced by amphotericin B deoxycholate, trade name Fungizone. The upregulated genes identified through microarray analysis of kidney tissue of Fungizone-treated mice included several genes that have been reported as nephrotoxicity biomarkers in rats, and 14 genes were selected as candidate nephrotoxicity biomarkers. The usefulness of these genes as nephrotoxicity biomarkers in mice was evaluated further through expression profiling under several experimental conditions using real time RT-PCR. Expression of genes encoding kidney injury molecule 1, lipocalin 2, tissue inhibitor of metalloproteinase 1, and secreted phosphoprotein 1 was highly upregulated by Fungizone, nystatin, natamycin, amphotericin B methyl ester, and liposomal amphotericin B, and their area under the ROC curve values were more than 0.95. These genes were more sensitive at detecting nephrotoxicity than traditional clinical chemistry and histopathology parameters. This study provides novel evidence that these nephrotoxicity biomarker genes identified are translatable to mice, and that they are useful for early and sensitive detection of nephrotoxicity.
authors.affiliation: Drug Developmental Research Laboratories, Shionogi & Co., Ltd., Osaka, Japan.
authors.forename: Chiaki
authors.initials: C
authors.lastname: Kondo
authors.forename: Miwa
authors.initials: M
authors.lastname: Aoki
authors.forename: Emi
authors.initials: E
authors.lastname: Yamamoto
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Tonomura
authors.forename: Minoru
authors.initials: M
authors.lastname: Ikeda
authors.forename: Masako
authors.initials: M
authors.lastname: Kaneto
authors.forename: Jyoji
authors.initials: J
authors.lastname: Yamate
authors.forename: Mikinori
authors.initials: M
authors.lastname: Torii
authors.forename: Takeki
authors.initials: T
authors.lastname: Uehara
mesh_terms: D000209:Acute-Phase Proteins / Q000235:genetics / Q000378:metabolism; D000666:Amphotericin B / Q000031:analogs & derivatives / Q000633:toxicity*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000633:toxicity; D003840:Deoxycholic Acid / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D015870:Gene Expression; D020869:Gene Expression Profiling; D005819:Genetic Markers; D000072596:Hepatitis A Virus Cellular Receptor 1; D017403:In Situ Hybridization; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D000071068:Lipocalin-2; D054834:Lipocalins / Q000235:genetics / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D046228:Microarray Analysis; D023421:Models, Animal; D010866:Natamycin / Q000633:toxicity; D009761:Nystatin / Q000633:toxicity; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D053495:Osteopontin / Q000235:genetics / Q000378:metabolism; D011090:Polyenes / Q000009:adverse effects; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D000209:Acute-Phase Proteins; D000900:Anti-Bacterial Agents; D004338:Drug Combinations; D005819:Genetic Markers; C442240:Havcr1 protein, mouse; D000072596:Hepatitis A Virus Cellular Receptor 1; D000071068:Lipocalin-2; D054834:Lipocalins; D008565:Membrane Proteins; D015513:Oncogene Proteins; D011090:Polyenes; C506896:Spp1 protein, mouse; C560825:Timp1 protein, mouse; D019715:Tissue Inhibitor of Metalloproteinase-1; C068538:liposomal amphotericin B; D003840:Deoxycholic Acid; C017501:methylamphotericin B; D053495:Osteopontin; C071332:Lcn2 protein, mouse; D009761:Nystatin; D000666:Amphotericin B; C059765:amphotericin B, deoxycholate drug combination; D010866:Natamycin