title: Metabolic profiling study on potential toxicity and immunotoxicity-biomarker discovery in rats treated with cyclophosphamide using HPLC-ESI-IT-TOF-MS.
abstract: Despite the recent advances in understanding toxicity mechanism of cyclophosphamide (CTX), the development of biomarkers is still essential. CTX-induced immunotoxicity in rats by a metabonomics approach was investigated using high-performance liquid chromatography coupled with ion trap time-of-flight mass spectrometry (HPLC-ESI-IT-TOF-MS). The rats were orally administered CTX (30 mg/kg/day) for five consecutive days, and on the fifth day samples of urine, thymus and spleen were collected and analyzed. A significant difference in metabolic profiling was observed between the CTX-treated group and the control group by partial least squares-discriminant analysis (PLS-DA), which indicated that metabolic disturbances of immunotoxicity in CTX-treated rats had occurred. One potential biomarker in spleen, three in urine and three in thymus were identified. It is suggested that the CTX-toxicity mechanism may involve the modulation of tryptophan metabolism, phospholipid metabolism and energy metabolism. This research can help to elucidate the CTX-influenced pathways at a low dose and can further help to indicate the patients' pathological status at earlier stages of toxicological progression after drug administration.
authors.affiliation: The State Key Laboratory of Natural and Biomimetic and Drugs and Department of Pharmaceutical Analysis, School of Pharmaceutical Sciences and Peking University, Beijing, 100191, People's Republic of China.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.forename: Wensi
authors.initials: W
authors.lastname: Lin
authors.forename: Weiwei
authors.initials: W
authors.lastname: Lin
authors.forename: Peng
authors.initials: P
authors.lastname: Xu
authors.forename: Jianmei
authors.initials: J
authors.lastname: Zhang
authors.forename: Haisong
authors.initials: H
authors.lastname: Yang
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Ling
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000633:toxicity*; D015415:Biomarkers / Q000032:analysis* / Q000378:metabolism / Q000652:urine; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000633:toxicity*; D006801:Humans; D008297:Male; D055432:Metabolomics / Q000379:methods*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013154:Spleen / Q000737:chemistry / Q000187:drug effects*; D053719:Tandem Mass Spectrometry / Q000379:methods*; D013950:Thymus Gland / Q000737:chemistry / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D003520:Cyclophosphamide
keywords: HPLC-ESI-IT-TOF-MS; cyclophosphamide; immunotoxicity biomarkers; metabolic pathways; metabonomics