title: Urinary Time- or Dose-Dependent Metabolic Biomarkers of Aristolochic Acid-Induced Nephrotoxicity in Rats.
abstract: The metabolic mechanisms underlying aristolochic acid (AA)-induced nephrotoxicity are inconclusive. A Gas Chromatography-Mass Spectrometer (GC-MS)-based metabolomic study was performed to analyze urinary metabolites in AA-treated rats at different dosages (10, 20, and 40 mg/kg) and time points (2, 4, and 6 days). Serum blood urea nitrogen (BUN), creatinine, and kidney injury were significantly changed only on the 6th day in 40 mg/kg AA group, whereas metabolic alternation appeared even on the 2nd day in 10 mg/kg AA group. A total of 84 differential metabolites were identified in 40 mg/kg AA groups time-dependently and 81 in 10, 20, and 40 mg/kg AA groups dose-dependently (6 days) compared with control group. Eight metabolites were selected as potential metabolic biomarkers including methylsuccinic acid, nicotinamide, 3-hydroxyphenylacetic acid, citric acid, creatinine, uric acid, glycolic acid, and gluconic acid. Four of them were dose-dependently altered including methylsuccinic acid, citric acid, creatinine, and 3-hydroxyphenylacetic acid, which were defined as "early metabolic biomarker." The alteration of nicotinamide, uric acid, and gluconic acid was time- and dose-dependent, whereas the change of glycolic acid was time- or dose-independent. The latter 4 metabolites were defined as "late metabolic biomarker" because of the obvious reduction on the 6th day in 40 mg/kg AA group. In summary, the urinary metabolic alterations were more sensitive than conventional biomarkers of renal injury. The identified metabolites suggested pathways of energy metabolism, gut microbiota, and purine metabolism were associated with AA-induced nephrotoxicity time- or dose-dependently. Further investigation was warranted to determine the roles of the 8 potential metabolic biomarkers in AA-induced nephrotoxicity.
authors.affiliation: Center for Drug Safety Evaluation and Research.
authors.forename: Xueqing
authors.initials: X
authors.lastname: Hu
authors.affiliation: Center for Drug Safety Evaluation and Research.
authors.forename: Jiaying
authors.initials: J
authors.lastname: Shen
authors.affiliation: Center for Drug Safety Evaluation and Research.
authors.forename: Xueyan
authors.initials: X
authors.lastname: Pu
authors.affiliation: Chinese Medical Therapy and Systems Biology, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
authors.forename: Ningning
authors.initials: N
authors.lastname: Zheng
authors.affiliation: Center for Drug Safety Evaluation and Research.
authors.forename: Zhongping
authors.initials: Z
authors.lastname: Deng
authors.affiliation: Center for Drug Safety Evaluation and Research.
authors.forename: Zean
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Chinese Medical Therapy and Systems Biology, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
authors.forename: Houkai
authors.initials: H
authors.lastname: Li
mesh_terms: D000818:Animals; D034341:Aristolochic Acids / Q000008:administration & dosage / Q000633:toxicity*; D015415:Biomarkers / Q000652:urine; D002273:Carcinogens / Q000008:administration & dosage / Q000633:toxicity*; D019343:Citric Acid / Q000652:urine; D003404:Creatinine / Q000652:urine; D004305:Dose-Response Relationship, Drug; D007274:Injections, Intraperitoneal; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008297:Male; D055432:Metabolomics / Q000379:methods; D010648:Phenylacetates / Q000652:urine; D025341:Principal Component Analysis; D011897:Random Allocation; D017208:Rats, Wistar; D051437:Renal Insufficiency / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D013047:Specific Pathogen-Free Organisms; D013386:Succinates / Q000652:urine; D066007:Toxicokinetics; D015430:Weight Gain / Q000187:drug effects
chemical_list: D034341:Aristolochic Acids; D015415:Biomarkers; D002273:Carcinogens; D010648:Phenylacetates; D013386:Succinates; D019343:Citric Acid; C000228:aristolochic acid I; D003404:Creatinine; C039138:methylsuccinic acid; C008069:3-hydroxybenzeneacetic acid
keywords: aristolochic acid; metabolic biomarkers; metabolomics.; nephrotoxicity