title: Potential urinary biomarkers of nephrotoxicity in cyclophosphamide-treated rats investigated by NMR-based metabolic profiling.
abstract: The anticancer-drug cyclophosphamide (CP) is known to have nephrotoxicity. The aim of this study was to identify urinary biomarkers indicating CP-induced nephrotoxicity. We investigated the urine metabolic profiles using nuclear magnetic resonance spectrometry of rats administered with single high-doses of CP (0, 30, and 100 mg/kg body weight) and daily low-doses over a 4-week period (0, 1, 3, and 10 mg/kg body weight). Among 18 identified urinary metabolites, 2-oxoglutarate, citrate, hippurate, formate, valine, and alanine for short-term and 2-oxoglutarate, citrate, hippurate, isoleucine, leucine, allantoin, valine, and lysine for long-term were selected as potential biomarkers. Pathway-enrichment analysis suggested that the urinary metabolism of CP is related to valine, leucine, and isoleucine biosynthesis; taurine and hypotaurine metabolism; glyoxylate and dicarboxylate metabolism; citrate cycle; and alanine, aspartate, and glutamate metabolism, with high pathway impact. The potential biomarkers obtained in this study could be used to monitor CP-induced nephrotoxicity relative to dose and treatment time.
authors.affiliation: College of Pharmacy, Chung-Ang University, Seoul, 156-756, Republic of Korea.
authors.forename: Sa Rang
authors.initials: SR
authors.lastname: Lim
authors.affiliation: College of Pharmacy, Chung-Ang University, Seoul, 156-756, Republic of Korea.
authors.forename: Sun-Hee
authors.initials: SH
authors.lastname: Hyun
authors.affiliation: College of Pharmacy, Chung-Ang University, Seoul, 156-756, Republic of Korea.
authors.forename: Seul Gi
authors.initials: SG
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Chung-Ang University, Seoul, 156-756, Republic of Korea.
authors.forename: Jin-Young
authors.initials: JY
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Chung-Ang University, Seoul, 156-756, Republic of Korea.
authors.forename: So-Hyun
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Korea Institute of Toxicology, Daejeon, 305-600, Republic of Korea.
authors.forename: Sang-Jin
authors.initials: SJ
authors.lastname: Park
authors.affiliation: Korea Institute of Toxicology, Daejeon, 305-600, Republic of Korea.
authors.forename: Kyoung-Sik
authors.initials: KS
authors.lastname: Moon
authors.affiliation: Graduate School of Medicine, Korea University, Seoul, 136-705, Republic of Korea.
authors.forename: Donggeun
authors.initials: D
authors.lastname: Sul
authors.affiliation: College of Medicine, Inje University, Busan, 614-735, Republic of Korea.
authors.forename: Dong Hyun
authors.initials: DH
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Chung-Ang University, Seoul, 156-756, Republic of Korea.
authors.forename: Hyung-Kyoon
authors.initials: HK
authors.lastname: Choi
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000652:urine*; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000009:adverse effects*; D006801:Humans; D007532:Isoleucine / Q000652:urine; D007668:Kidney / Q000187:drug effects* / Q000473:pathology; D007930:Leucine / Q000652:urine; D009682:Magnetic Resonance Spectroscopy; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D055432:Metabolomics; D009369:Neoplasms / Q000188:drug therapy / Q000652:urine*; D051381:Rats; D013654:Taurine / Q000031:analogs & derivatives / Q000652:urine; D014633:Valine / Q000652:urine
chemical_list: D015415:Biomarkers; D007532:Isoleucine; D013654:Taurine; C003949:hypotaurine; D003520:Cyclophosphamide; D007930:Leucine; D014633:Valine
keywords: 1H-NMR; Cyclophosphamide; Metabolic profiling; Nephrotoxicity; Urine