title: Branched-Chain Amino Acids as Predictors for Individual Differences of Cisplatin Nephrotoxicity in Rats: A Pharmacometabonomics Study.
abstract: Nephrotoxicity is the dose-limiting adverse effect of cisplatin with large individual differences. Up to now, little has been done on how to recognize and predict the individual differences in either preclinical or clinical research. In the present study, important postdose indicators were screened out first and integrated into a grouping factor, according to which rats were recognized as lowly or highly sensitive individuals. Then, mass-spectrometry-based untargeted metabolomics approach was performed to dissect the metabolic differences in predose serum of the two groups. Eventually, branched-chain amino acids (BCAAs) were found to be most significant with the lowest p value of Mann-Whitney U test and the highest area under receiving operating characteristic curve (AUC-ROC). The findings were further confirmed by absolute quantitation of BCAAs using liquid chromatography-tandem mass spectrometry. Binary logistic regression showed that in the discovery set absolute BCAA contents in rat predose serum could predict cisplatin nephrotoxicity with accuracy of 85%. This result was validated by another two independent external validation sets with accuracy of 81.8 and 78.8%, respectively. This study could provide new insight into cisplatin nephrotoxicity and may help expedite personalized medicine of cisplatin or other antitumor drugs in future clinical studies.
authors.affiliation: Key Laboratory of Drug Quality Control and Pharmacovigilance (Ministry of Education), China Pharmaceutical University , Nanjing 210009, P. R. China.|Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University , Nanjing 210009, P. R. China.|State Key Laboratory of Natural Medicine, China Pharmaceutical University , Nanjing 210009, P. R. China.
authors.forename: Pei
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Drug Quality Control and Pharmacovigilance (Ministry of Education), China Pharmaceutical University , Nanjing 210009, P. R. China.|Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University , Nanjing 210009, P. R. China.|State Key Laboratory of Natural Medicine, China Pharmaceutical University , Nanjing 210009, P. R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: Key Laboratory of Drug Quality Control and Pharmacovigilance (Ministry of Education), China Pharmaceutical University , Nanjing 210009, P. R. China.|Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University , Nanjing 210009, P. R. China.|State Key Laboratory of Natural Medicine, China Pharmaceutical University , Nanjing 210009, P. R. China.
authors.forename: Jiaqing
authors.initials: J
authors.lastname: Chen
authors.affiliation: Key Laboratory of Drug Quality Control and Pharmacovigilance (Ministry of Education), China Pharmaceutical University , Nanjing 210009, P. R. China.|Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University , Nanjing 210009, P. R. China.|State Key Laboratory of Natural Medicine, China Pharmaceutical University , Nanjing 210009, P. R. China.
authors.forename: Ruiting
authors.initials: R
authors.lastname: Li
authors.affiliation: Key Laboratory of Drug Quality Control and Pharmacovigilance (Ministry of Education), China Pharmaceutical University , Nanjing 210009, P. R. China.|Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University , Nanjing 210009, P. R. China.|State Key Laboratory of Natural Medicine, China Pharmaceutical University , Nanjing 210009, P. R. China.
authors.forename: Zunjian
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Drug Quality Control and Pharmacovigilance (Ministry of Education), China Pharmaceutical University , Nanjing 210009, P. R. China.|Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University , Nanjing 210009, P. R. China.|State Key Laboratory of Natural Medicine, China Pharmaceutical University , Nanjing 210009, P. R. China.
authors.forename: Yin
authors.identifier: 0000-0001-9678-2630
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Key Laboratory of Drug Quality Control and Pharmacovigilance (Ministry of Education), China Pharmaceutical University , Nanjing 210009, P. R. China.|Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University , Nanjing 210009, P. R. China.|State Key Laboratory of Natural Medicine, China Pharmaceutical University , Nanjing 210009, P. R. China.
authors.forename: Fengguo
authors.identifier: 0000-0001-9999-0128
authors.initials: F
authors.lastname: Xu
mesh_terms: D000597:Amino Acids, Branched-Chain / Q000097:blood*; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D002945:Cisplatin / Q000009:adverse effects*; D006801:Humans; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D013058:Mass Spectrometry; D055432:Metabolomics; D009369:Neoplasms / Q000097:blood* / Q000188:drug therapy / Q000473:pathology; D057285:Precision Medicine; D051381:Rats
chemical_list: D000597:Amino Acids, Branched-Chain; D000970:Antineoplastic Agents; D002945:Cisplatin
keywords: BCAA; cisplatin; individual differences; metabolomics; nephrotoxicity; prediction