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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 |
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dc.contributor.advisor | 조주연 | - |
dc.contributor.author | Jieon Lee | - |
dc.date.accessioned | 2017-07-14T01:16:50Z | - |
dc.date.available | 2017-07-14T01:16:50Z | - |
dc.date.issued | 2017-02 | - |
dc.identifier.other | 000000140942 | - |
dc.identifier.uri | https://hdl.handle.net/10371/121793 | - |
dc.description | 학위논문 (박사)-- 서울대학교 대학원 : 협동과정임상약리학전공, 2017. 2. 조주연. | - |
dc.description.abstract | Introduction: 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. | - |
dc.description.tableofcontents | 1 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 | - |
dc.format | application/pdf | - |
dc.format.extent | 4261141 bytes | - |
dc.format.medium | application/pdf | - |
dc.language.iso | en | - |
dc.publisher | 서울대학교 대학원 | - |
dc.subject | Drug-induced liver injury | - |
dc.subject | biomarker | - |
dc.subject | pharmacogenomics | - |
dc.subject | pharmacometabolomics | - |
dc.subject | microRNA | - |
dc.subject | clinical trials | - |
dc.subject.ddc | 615 | - |
dc.title | Exploration of potential biomarkers for amoxicillin/clavulanate-induced liver injury in humans through multi-omics approaches | - |
dc.title.alternative | 다중오믹스 분석법 기반 아목시실린/클라불란산 유발 인체 간손상 생체지표 탐색 | - |
dc.type | Thesis | - |
dc.contributor.AlternativeAuthor | 이지언 | - |
dc.description.degree | Doctor | - |
dc.citation.pages | 73 | - |
dc.contributor.affiliation | 의과대학 협동과정임상약리학전공 | - |
dc.date.awarded | 2017-02 | - |
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