https://scholars.lib.ntu.edu.tw/handle/123456789/565167
標題: | Metabolomics analysis of plasma reveals voriconazole-induced hepatotoxicity is associated with oxidative stress | 作者: | Wu S.-L. Cheng C.-N. CHI-CHUAN WANG SHU-WEN LIN CHING-HUA KUO |
公開日期: | 2020 | 卷: | 403 | 起(迄)頁: | 115157 | 來源出版物: | Toxicology and Applied Pharmacology | 摘要: | Voriconazole is one of the most frequently used antifungal drugs for the initial treatment of invasive aspergillosis, but liver-related adverse events occur frequently and usually lead to drug discontinuation. Moreover, the mechanism of voriconazole-induced hepatotoxicity remains unsettled. A holistic understanding of its mechanism is critical to prevent liver-related adverse events. Metabolomics has been demonstrated to be a helpful strategy for investigating drug-induced toxicity. This study aimed to utilize human plasma samples to investigate the mechanism of voriconazole-induced hepatotoxicity through a metabolomics approach. Patients that were administered voriconazole were classified into a voriconazole-induced hepatotoxicity group and control group (n = 65, 18% hepatotoxicity). Plasma samples were analyzed by targeted metabolomics using ultra-performance liquid chromatography coupled with triple quadrupole mass spectrometry. The obtained peak areas for each metabolite were utilized for correlation analysis, fold change evaluation, and univariate statistical tests to identify metabolites associated with voriconazole-induced hepatotoxicity. This study showed a significantly lower glutamine-to-glutamate ratio (p = .04) and a higher β-N-acetylglucosamine (p = .003) in the voriconazole-induced hepatotoxicity group, implying the presence of oxidative stress. Other significant metabolites also indicated several adaptive responses to oxidative stress in patients with voriconazole-induced toxicity, including cell repair, energy production, and alteration to bile acid hemostasis. Furthermore, a metabolite panel consisting of α-ketoglutarate, glycocholate, and β-N-acetylglucosamine demonstrated better performance for detecting voriconazole-induced hepatotoxicity than conventional liver function tests. These metabolomics findings reveal that voriconazole-induced hepatotoxicity is associated with oxidative stress. ? 2020 Elsevier Inc. |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-85088636621&doi=10.1016%2fj.taap.2020.115157&partnerID=40&md5=591eeb93315a4e5f3fc39e474654ba97 https://scholars.lib.ntu.edu.tw/handle/123456789/565167 |
ISSN: | 0041008X | DOI: | 10.1016/j.taap.2020.115157 | SDG/關鍵字: | 2 oxoglutaric acid; asparagine; cysteine; glutamic acid; glutamine; glycocholic acid; n acetylglucosamine; voriconazole; antifungal agent; voriconazole; adult; aged; aplastic anemia; Article; cell regeneration; cholestasis; controlled study; DNA synthesis; energy yield; female; hematologic disease; hemostasis; human; leukemia; liver function test; liver toxicity; major clinical study; male; metabolomics; mycosis; myelodysplastic syndrome; nonhodgkin lymphoma; oxidative stress; triple quadrupole mass spectrometry; trough concentration; ultra performance liquid chromatography; blood; drug effect; metabolism; middle aged; oxidative stress; toxic hepatitis; Aged; Antifungal Agents; Chemical and Drug Induced Liver Injury; Female; Humans; Male; Metabolomics; Middle Aged; Oxidative Stress; Voriconazole |
顯示於: | 藥學系 |
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