An Effective Assessment of Simvastatin-Induced Toxicity with NMR-Based Metabonomics Approach 英文参考文献.docVIP

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An Effective Assessment of Simvastatin-Induced Toxicity with NMR-Based Metabonomics Approach 英文参考文献.doc

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An Effective Assessment of Simvastatin-Induced Toxicity with NMR-Based Metabonomics Approach 英文参考文献

AnEffectiveAssessmentofSimvastatin-InducedToxicity withNMR-BasedMetabonomicsApproach Hye-jiYang1.,Myung-JooChoi2.,HeWen1.,HyukNamKwon1,KyungHeeJung2,Sang-WonHong2, JoonMeeKim3,Soon-SunHong2*,SunghyoukPark1* 1DepartmentofBiochemistry,InhaUniversityHospitalandCenterforAdvancedMedicalEducationbyBK21project,CollegeofMedicine,InhaUniversity,Incheon,Korea, 2DepartmentofBiomedicalSciences,InhaUniversityHospitalandCenterforAdvancedMedicalEducationbyBK21project,CollegeofMedicine,InhaUniversity,Incheon, Korea,3DepartmentofPathology,InhaUniversityHospitalandCenterforAdvancedMedicalEducationbyBK21project,CollegeofMedicine,InhaUniversity,Incheon, Korea Abstract Background:Simvastatin,whichisusedtocontrolelevatedcholesterollevels,isoneofthemostwidelyprescribeddrugs. However,adailyexcessivedosecaninducedrug-toxicity,especiallyinmuscleandliver.Currentmarkersfortoxicityreflect mostlythelatestagesoftissuedamage;thus,moreefficientmethodsoftoxicityevaluationaredesired. Methodology/PrincipalFindings:Asanewwaytoevaluatetoxicity,weperformedNMR-basedmetabonomicsanalysisof urinesamples.Comparedtoconventionalmarkers,suchasAST,ALT,andCK,theurinemetabolicprofileprovidedclearer distinction between the pre- and post-treatment groups treated with toxic levels of simvastatin. Through multivariate statistical analysis, we identified marker metabolites associated with the toxicity. Importantly, we observed that the treatmentgroupcouldbefurthercategorizedintotwosubgroupsbasedontheNMRprofiles:weaktoxicity(WT)andhigh toxicity(HT).Thedistinctionbetweenthesetwogroupswasconfirmedbytheenzymevaluesandhistopathologicalexams. Time-dependentstudiesshowedthatthetoxicityat10dayscouldbereliablypredictedfromthemetabolicprofilesat6 days. Conclusions/Significance: This metabonomics approach may provide a non-invasive and effective way to evaluate the simvastatin-inducedtoxicityinamannerthatcancomplementcurrentmeasures.Theapproachisexpectedtofindbroader applicationinotherdrug-inducedtoxicityassessments. Citation:Ya