title: Metabonomic analysis of the toxic effects of TM208 in rat urine by HPLC-ESI-IT-TOF/MS.
abstract: 4-Methylpiperazine-1-carbodithiocacid-3-cyano-3,3-diphenylpropyl ester hydrochloride (TM208) was a potential antitumor new drug with many preliminary studies in pharmacokinetics and pharmacodynamics. This study aims to determine whether TM208 elicits toxic effects by metabonomics for the first time. Sprague Dawley (SD) rats were exposured to TM208 at a single therapeutic dose (100mg/kg/d) for 5 days, metabolites of urine samples from both control and TM208-treated groups were analyzed using high performance liquid chromatography-electrospray ionization source in combination with hybrid ion trap and high-resolution time-of-flight mass spectrometry (HPLC-ESI-IT-TOF/MS). Metabolites such as aminoadipic acid, creatine, gluconic acid, cis-aconitic acid, succinic acid and pipecolic acid which changed significantly, were identified as potential biomarkers. These results suggest that the changes in urinary metabolites of rats after exposure to TM208 were mainly related to energy metabolism and amino acid metabolism, which may be helpful to further understand the mechanism of TM208 toxicity in rats and a new drug development.
authors.affiliation: State Key Laboratory of Natural and Biomimetic and Drugs and Department of Pharmaceutical Analysis, School of Pharmaceutical Sciences and Peking University, Beijing 100191, PR China.
authors.forename: Haisong
authors.initials: H
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Natural and Biomimetic and Drugs and Department of Pharmaceutical Analysis, School of Pharmaceutical Sciences and Peking University, Beijing 100191, PR China.
authors.forename: Wensi
authors.initials: W
authors.lastname: Lin
authors.affiliation: State Key Laboratory of Natural and Biomimetic and Drugs and Department of Pharmaceutical Analysis, School of Pharmaceutical Sciences and Peking University, Beijing 100191, PR China.
authors.forename: Jianmei
authors.initials: J
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Natural and Biomimetic and Drugs and Department of Pharmaceutical Analysis, School of Pharmaceutical Sciences and Peking University, Beijing 100191, PR China.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Lin
authors.affiliation: State Key Laboratory of Natural and Biomimetic and Drugs and Department of Pharmaceutical Analysis, School of Pharmaceutical Sciences and Peking University, Beijing 100191, PR China.
authors.forename: Peng
authors.initials: P
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Natural and Biomimetic and Drugs and Department of Pharmaceutical Analysis, School of Pharmaceutical Sciences and Peking University, Beijing 100191, PR China.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: State Key Laboratory of Natural and Biomimetic and Drugs and Department of Pharmaceutical Analysis, School of Pharmaceutical Sciences and Peking University, Beijing 100191, PR China. Electronic address: lingxm@bjmu.edu.cn.
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Ling
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000633:toxicity / Q000652:urine*; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D008297:Male; D055432:Metabolomics / Q000379:methods*; D010879:Piperazines / Q000378:metabolism / Q000633:toxicity / Q000652:urine*; D051381:Rats; D017207:Rats, Sprague-Dawley; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods; D053719:Tandem Mass Spectrometry / Q000379:methods*
chemical_list: C522133:4-methylpiperazine-1-carbodithioc acid 3-cyano-3,3-diphenylpropyl ester hydrochloride; D000970:Antineoplastic Agents; D010879:Piperazines
keywords: HPLC-ESI-IT-TOF/MS; Metabonomics; TCA cycle; TM208; Toxicity