title: Characterization of urinary metabolites as biomarkers of colistin-induced nephrotoxicity in rats by a liquid chromatography/mass spectrometry-based metabolomics approach.
abstract: Colistin is a polypeptide antibiotic that effectively treats infections caused by multidrug-resistant Gram-negative bacteria, but its clinical use is limited due to nephrotoxicity. The purpose of the present study was to identify biomarkers of colistin-induced nephrotoxicity and to further characterize the mechanisms underlying this process by analyzing urinary metabolites using untargeted metabolomic approach. Rats receiving intraperitoneal administration of colistin sodium methanesulfonate (CMS) (25 or 50mg/kg) exhibited histopathological changes in the kidney and increased blood urea nitrogen levels. Additionally, the levels of phenylalanine, tryptophan, and tyrosine in the urine of the CMS-treated group were significantly higher than those of the control group, suggesting that colistin caused proximal tubular damage. Urinary acetylcarnitine and butyrylcarnitine levels also increased after CMS treatment, but the levels of purine metabolites and metabolites related to the tricarboxylic acid cycle were reduced. The most significant increase in the CMS-treated groups was observed in creatine levels. CMS-induced selective nephrotoxicity may be attributed to relatively high tissue concentrations of colistin in the kidney. Taken together, our results indicate that high levels of colistin in the kidney caused perturbations in the tricarboxylic acid cycle, amino acid metabolism, creatine metabolism, and purine metabolism and ultimately led to kidney injury.
authors.affiliation: Department of Pharmacology and Pharmacogenomics Research center, Inje University, College of Medicine, Bokjiro 75, Busanjin-Gu, Busan 614-735 South Korea.
authors.forename: Eun Sook
authors.initials: ES
authors.lastname: Jeong
authors.affiliation: Department of Pharmacology and Pharmacogenomics Research center, Inje University, College of Medicine, Bokjiro 75, Busanjin-Gu, Busan 614-735 South Korea.
authors.forename: Gabin
authors.initials: G
authors.lastname: Kim
authors.affiliation: Korea Institute of Toxicology, 141 Gajeong-ro, Yuseong-gu, Daejeon, 305-343, South Korea.
authors.forename: Kyoung-Sik
authors.initials: KS
authors.lastname: Moon
authors.affiliation: Korea Institute of Toxicology, 141 Gajeong-ro, Yuseong-gu, Daejeon, 305-343, South Korea.
authors.forename: Yong-Bum
authors.initials: YB
authors.lastname: Kim
authors.affiliation: Korea Institute of Toxicology, 141 Gajeong-ro, Yuseong-gu, Daejeon, 305-343, South Korea.
authors.forename: Jung-Hwa
authors.initials: JH
authors.lastname: Oh
authors.affiliation: Department of Pharmacology and Pharmacogenomics Research center, Inje University, College of Medicine, Bokjiro 75, Busanjin-Gu, Busan 614-735 South Korea.
authors.forename: Ho-Sook
authors.initials: HS
authors.lastname: Kim
authors.affiliation: Ministry of Food and Drug Safety, Osong-eup, Heungdeok-gu, Cheongju-si, Chungcheongbuk-do 361-951, South Korea.
authors.forename: Jayoung
authors.initials: J
authors.lastname: Jeong
authors.affiliation: Department of Pharmacology and Pharmacogenomics Research center, Inje University, College of Medicine, Bokjiro 75, Busanjin-Gu, Busan 614-735 South Korea.
authors.forename: Jae-Gook
authors.initials: JG
authors.lastname: Shin
authors.affiliation: Department of Pharmacology and Pharmacogenomics Research center, Inje University, College of Medicine, Bokjiro 75, Busanjin-Gu, Busan 614-735 South Korea. Electronic address: dhkim@inje.ac.kr.
authors.forename: Dong Hyun
authors.initials: DH
authors.lastname: Kim
mesh_terms: D000596:Amino Acids / Q000652:urine; D000818:Animals; D000900:Anti-Bacterial Agents / Q000097:blood / Q000652:urine*; D015415:Biomarkers / Q000652:urine; D002851:Chromatography, High Pressure Liquid; D003091:Colistin / Q000031:analogs & derivatives* / Q000097:blood / Q000652:urine; D003404:Creatinine / Q000652:urine; D007674:Kidney Diseases / Q000473:pathology / Q000652:urine*; D008297:Male; D055432:Metabolomics / Q000295:instrumentation / Q000379:methods*; D015999:Multivariate Analysis; D017207:Rats, Sprague-Dawley; D053719:Tandem Mass Spectrometry; D014018:Tissue Distribution
chemical_list: D000596:Amino Acids; D000900:Anti-Bacterial Agents; D015415:Biomarkers; D003404:Creatinine; C004691:colistinmethanesulfonic acid; D003091:Colistin
keywords: Colistin; Creatine; Metabolomics; Nephrotoxicity; Urinary amino acid