HAN Li-wen1, ZHAO Liang2, CHU Jie1, HE Qiu-xia1, WANG Xue1, WANG Xi-min1, LIU Ke-chun1*
1.Biology Institute of Shandong Academy of Sciences, Key Laboratory for Biosensors of Shandong Province, Jinan 250014, China; 2. Pharmacy Department,Qilu Hospital of Shandong University,Jinan 250012,China
Abstract��
OBJECTIVE To analysis metabolic changes of zebrafish treated by astemizole, and to find potential cardiotoxicity related biomarkers. METHODS Forty-eight hpf zebrafish was treated by astemizole and cardiac toxicity was denoted with heart rate, sinus venous(SV)-bulbus arteriosus(BA) distance and heart phenotype. Meanwhile, zebrafish tissue samples were obtained and subjected to GC-MS analysis to find potential biomarkers of cardiotoxicity. RESULTS Heart rate of zebrafish treated by astemizole decreased significantly compared with the control groups accompanied with apparent atrioventricular block and cardiac morphological changes. Metabonomics analysis show that the metabolic profiling distinguished astemizole group from the control group and 12 potential biomarkers, glucose, glycine, lactic acid, creatinine, glutamine, N-acetyl-L-lysine, L-proline, citric acid, L-tyrosine, phosphate, cholesterol, palmitic acid, are identified. CONCLUSION These RESULTS showed that metabonomics based on new model organism, zebrafish, can be used to express the astemizole-induced cardiotoxicity. The biomarkers found contribute to the early warning for drug-induced cardiotoxicity.
HAN Li-Wen-,
ZHAO Liang-,
CHU Jie- etc
.Endogenous Metabolites Investigation of Cadiotoxicity Induced by Astemizole on Zebrafish Using GC-MS Metabonomics[J] Chinese Pharmaceutical Journal, 2015,V50(1): 45-50
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[1]
COECKE S, AHR H, BLAAUBOER B J, et al. Metabolism: A bottleneck in in vitro toxicological test development. The report and recommendations of ECVAM workshop 54. Altern Lab Anim, 2006,34(1):49-84.[2] FISHMAN M C, CHIEN K R. Fashioning the vertebrate heart: Earliest embryonic decisions. Development, 1997,124(11):2099-2117.[3] BERGHMANS S, BULER P, GOLDSMITH P, et al. Zebrafish based assays for the assessment of cardiac, visual and gut function--potential safety screens for early drug discovery.J Pharmacol Toxicol Methods, 2008,58(1):59-68.[4] BISHOP R O,GAUDRY P L.Prolonged Q-T interval following astemizole overdose. Arch Emerg Med, 1989, 6(1):63-65.[5] MCGRATH P, LI C Q. Zebrafish: A predictive model for assessing drug-induced toxicity. Drug Discov Today, 2008,13(9-10):394-401.[6] WU X M,HE Q X, HAN L W, et al. Preliminary study of astemizole��s cardiotoxicity to zebrafish. Chin Pharmacol Bull(�й�ҩ��ѧͨ��),2013,29(9):1251-1254.[7] JANG G H, PARK I S, LEE S H, et al. Malachite green induces cardiovascular defects in developing zebrafish(Danio rerio) embryos by blocking VEGFR-2 signaling.Biochem Biophys Res Commun, 2009,382(3):486-491[8] WANG S F, LIU K C, WANG X M, et al. Preliminary study on cardiotoxicity of celastrol to zebrafish embryo. Chin Pharmacol Bull(�й�ҩ��ѧͨ��),2009,25(5):634-636.[9] BRYAN C, BERGMAN, TATIANA T, et al. Myocardial glucose and lactate metabolism during rest and atrial pacing in humans. J Physiol,2009,587(9): 2087-2099. WANG Y,LI C,GUO S Z,et al. Serum metabolomics of blood-stasis syndrome of chronic myocardial ischemia based on CPMG pulse sequence. J Beijing Univ Tradit Chin Med(������ҽҩ��ѧѧ��), 2011,34(12):819-822. ZIMA T, TESAR V, MANTLE D, et al. Acute doxorubicin (adriamycin) dosage does not reduce cardiac protein synthesis in vivo, but decreases diaminopeptidase I and proline endopeptidase activities. Exp Mol Pathol, 2001,70(2):154-161. TAKEMURA G, FUJIWARA H. Doxorubicin-induccd cardiomyopathy from the cardiotoxic mechanisms to management. Prog Cardiovasc Dis, 2007,49(1):330-352. GIANNI L, HERMAN E H, LIPSHULTZ S E, et al. Anthracycline cardiotoxicity: From bench to bedside. J Clin Oncol, 2008, 26(22):3777-3784. YELLON D M, HAUSENLOR D J. Mechanisms of disease: Myocardial reperfusion injury.N Engl J Med, 2007, 357(11):1121-1135. HALESTRAP A P. What is the mitochondrial permeability transition pore.J Mol Cell Cardiol, 2009, 46(6):821-831. HALESTRAP A P, PASDOIS P. The role of the mitochondrial permeability transition pore in heart disease. Biochim Biophys Acta, 2009, 1787(11):1402-1415. GAVA F N, ZACCHE E, ORTIZ E M G, et al. Doxorubicin induced dilated cardiomyopathy in a rabbit model: An update. Res Vet Sci, 2013, 94(1):115-121. ZHOU J L,HUANG Y S, DANG Y M, et al. Protective effects of glycine in cardiomyocyte subjected to ischemia and hrpoxia. Prog Mod Biomed(�ִ�����ҽѧ��չ), 2008,8(6):1093-1095. JIANG H Z, BAO Y C, LIU L L, et al.1H-NMR Spectroscopy-based metabonomic research on serum of model rats of Wilson��s disease. J Liangning Univ Tradit Chin Med(������ҽҩ��ѧѧ��), 2010,12(9):19-22. YAN B, A J Y, HAO H P, et al. Evaluation of myocardial ischemia rat model based onmetabonomic method of small molecule metabolitesof plasma and cardiac muscle.Acta Pharm Sin(ҩѧѧ��), 2013, 48 (1): 104-112.
2015, Vol. 50 