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Exploration of potential biomarkers for amoxicillin/clavulanate-induced liver injury in humans through multi-omics approaches
다중오믹스 분석법 기반 아목시실린/클라불란산 유발 인체 간손상 생체지표 탐색

DC Field Value Language
dc.contributor.advisor조주연-
dc.contributor.authorJieon Lee-
dc.date.accessioned2017-07-14T01:16:50Z-
dc.date.available2017-07-14T01:16:50Z-
dc.date.issued2017-02-
dc.identifier.other000000140942-
dc.identifier.urihttps://hdl.handle.net/10371/121793-
dc.description학위논문 (박사)-- 서울대학교 대학원 : 협동과정임상약리학전공, 2017. 2. 조주연.-
dc.description.abstractIntroduction: Drug-induced liver injury (DILI) is a major challenge in the development and use of therapeutic drugs. The exploration for more sensitive biomarkers of DILI requires multidirectional approaches. However, a comprehensive clinical study has not been conducted in healthy volunteers. To explore potential biomarkers for and mechanisms of amoxicillin/clavulanate-induced liver injury (AC-DILI), we conducted a clinical trial based on multi-omics approaches.
Methods: Thirty-two healthy Korean male volunteers were enrolled and grouped according to 4 GSTT1/M1 genotypes (8 subjects per group). Blood and urine samples were collected before and after 14 days of amoxicillin/clavulanic acid administration for liver function tests and quantification of biomarkers. The approaches used throughout this study included a liver function test, pharmacokinetic analysis, microRNA quantification, pharmacometabolomics analysis, human leukocyte antigen (HLA) typing, and lymphocyte transformation test (LTT). We evaluated the correlations between liver function parameters and multi-omics biomarkers.
Results: Comparative analyses between Responder and Non-Responder groups classified by the alanine aminotransferase (ALT) elevation level revealed no statistically significant differences in primary pharmacokinetic (PK) parameters of amoxicillin or clavulanate. Liver-specific microRNA-122 (miR-122) was highly correlated with ALT. Urinary metabolites, including 7-methylxanthine, 7-methyluric acid, 3-methylxanthine, and azelaic acid, showed significantly different levels between the two groups (P<0.05). Lymphocyte proliferation in response to the drug was also observed. These findings demonstrate sequential changes in the process of AC-DILI, including metabolic changes, increased miR-122 level, increased liver enzyme activity and enhanced lymphocyte proliferation after drug administration.
Conclusion: This is the first study to evaluate potential AC-DILI biomarkers in healthy volunteers. The results confirm miR-122 and four urinary metabolites as early and sensitive biomarkers for AC-DILI, suggesting hepatocellular injury, liver inflammation, and mitochondrial oxidative stress as mechanisms underlying AC-DILI. Proliferation of lymphocytes in response to the drug also suggests a role for the adaptive immune response in AC-DILI. The biomarkers evaluated in this study by integrating omics data could enable more sensitive and earlier prediction of liver injury in drug development and usage of therapeutics.
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dc.description.tableofcontents1 INTRODUCTION 1
2 MATERIALS AND METHODS 6
2.1 Study Subjects 6
2.2 Study Design 7
2.3 Ethical Consideration 10
2.4 Quantification of the amoxicillin/clavulanate concentrations 13
2.5 PK Analyses 15
2.6 GSTT1/GSTM1 and HLA typing 16
2.7 Measurement of serum miRNAs 17
2.8 Pharmacometabolomic analyses 20
2.9 Lymphocyte transformation test (LTT) 21
2.10 Statistical analysis 22
3 RESULTS 23
3.1 Demographics 23
3.2 Group classification 25
3.3 Correlation of PK parameters with ALT elevations 32
3.4 Correlation between miR-122 and ALT elevation 36
3.5 Localization of miR-122 43
3.6 Pharmacometabolomic analyses 44
3.7 Lymphocyte proliferation against amoxicillin and clavulanate 53
3.8 HLA genotyping 54
4 DISCUSSION 57
5 CONCLUSION 63
6 References 64
7 국문초록 71
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dc.formatapplication/pdf-
dc.format.extent4261141 bytes-
dc.format.mediumapplication/pdf-
dc.language.isoen-
dc.publisher서울대학교 대학원-
dc.subjectDrug-induced liver injury-
dc.subjectbiomarker-
dc.subjectpharmacogenomics-
dc.subjectpharmacometabolomics-
dc.subjectmicroRNA-
dc.subjectclinical trials-
dc.subject.ddc615-
dc.titleExploration of potential biomarkers for amoxicillin/clavulanate-induced liver injury in humans through multi-omics approaches-
dc.title.alternative다중오믹스 분석법 기반 아목시실린/클라불란산 유발 인체 간손상 생체지표 탐색-
dc.typeThesis-
dc.contributor.AlternativeAuthor이지언-
dc.description.degreeDoctor-
dc.citation.pages73-
dc.contributor.affiliation의과대학 협동과정임상약리학전공-
dc.date.awarded2017-02-
Appears in Collections:
College of Medicine/School of Medicine (의과대학/대학원)Program in Clinical Pharmacology (협동과정-임상약리학전공)Theses (Ph.D. / Sc.D._협동과정-임상약리학전공)
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