title: (1)H NMR based metabolomic profiling revealed doxorubicin-induced systematic alterations in a rat model.
abstract: Doxorubicin (DOX) is used as a chemotherapy drug with severe carditoxicity. In this study, an integrated echocardiography along with pathological examination and (1)H NMR analysis of multiple biological matrices (urine, serum, heart, and kidney) was employed to systemically assess the toxicity of DOX. Echocardiographic results showed that impaired left ventricular contractility and degenerative pathology lesions in DOX group, which were in consistent with pathology. The endogenous metabolites in the urine, serum, heart and kidney was identified by comparison with the data from the literature and databases. Multivariate analysis, including PCA and OPLS, revealed 8 metabolites in urine, including succinate, 2-ketoglutarate, citrate, hippurate, methylamine, benzoate, allantion, and acetate were the potential changed biomarkers. In serum, perturbed metabolites include elevation of leucine, β-glucose, O-acetyl-glycoprotein, creatine, lysine, glycerin, dimethylglycine, trimethylamine-N-oxide, myo-inositol, and N-acetyl-glycoprotein, together with level decreases of acetone, lipid, lactate, glutamate, phosphocholine, acetoacetate and pyruvate. For heart, DOX exposure caused decline of lipid, lactate, leucine, alanine, glutamate, choline, xanthine, glycerin, carnitine, and fumarate, together with elevation of glutamine, creatine, inosine, taurine and malate. Metabolic changes of kidney were mainly involved in the accumulation of α-glucose, lactate, phosphocholine, betaine, threonine, choline, taurine, glycine, urea, hypoxanthine, glutamate, and nicotinamide, coupled with reduction of asparagine, valine, methionine, tyrosine, lysine, alanine, leucine, ornithine, creatine, lipid, and acetate. In addition, alterations of urinary metabolites exhibited a time-dependent manner. Complementary evidences by multiple matrices revealed disturbed pathways concerning energy metabolism, fatty acids oxidation, amino acids and purine metabolism, choline metabolism, and gut microbiota-related metabolism. In addition, the change of endogenous metabolites in rats urine, serum, heart and kidney were correlated with the echocardiography parameters. This integrative study should help to develop a systematic understanding of cardiomyopathy-related diseases and their metabolic events.
authors.affiliation: Modern Research Center for Traditional Chinese Medicine of Shanxi University, No. 92, Wucheng Road, Taiyuan 030006, Shanxi, People's Republic of China; College of Chemistry and Chemical Engineering of Shanxi University, No. 92, Wucheng Road, Taiyuan 030006, Shanxi,People's Republic of China.
authors.forename: Qian-Yun
authors.initials: QY
authors.lastname: Niu
authors.affiliation: Modern Research Center for Traditional Chinese Medicine of Shanxi University, No. 92, Wucheng Road, Taiyuan 030006, Shanxi, People's Republic of China. Electronic address: lizhenyu@sxu.edu.cn.
authors.forename: Zhen-Yu
authors.initials: ZY
authors.lastname: Li
authors.affiliation: Modern Research Center for Traditional Chinese Medicine of Shanxi University, No. 92, Wucheng Road, Taiyuan 030006, Shanxi, People's Republic of China; Institute of Materia Medica, Chinese Academy of Medical Sciences, Beijing 100050, People's Republic of China.
authors.forename: Guan-Hua
authors.initials: GH
authors.lastname: Du
authors.affiliation: Modern Research Center for Traditional Chinese Medicine of Shanxi University, No. 92, Wucheng Road, Taiyuan 030006, Shanxi, People's Republic of China. Electronic address: qinxm@sxu.edu.cn.
authors.forename: Xue-Mei
authors.initials: XM
authors.lastname: Qin
mesh_terms: D000818:Animals; D004317:Doxorubicin / Q000378:metabolism* / Q000633:toxicity*; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology; D006859:Hydrogen; D008297:Male; D055432:Metabolomics / Q000379:methods*; D023421:Models, Animal; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D019906:Nuclear Magnetic Resonance, Biomolecular / Q000379:methods*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D006859:Hydrogen; D004317:Doxorubicin
keywords: Doxorubicin; Metabolomic; Multivariate data analysis; NMR; Rats; Toxicity