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Mechanistic examination of methimazole-induced hepatotoxicity in patients with Grave’s disease: a metabolomic approach

Li, Xuesong ; Yang, Jialin ; Jin, Shasha ; Dai, Yu ; Fan, Yujuan ; Fan, Xiaofang ; Li, Zhigang ; Yang, Jianhua ; Yau, Wai-Ping ; Lin, Haishu ; Cai, Weimin ; Xiang, Xiaoqiang

Archives of toxicology, 2020, Vol.94 (1), p.231-244 [Periódico revisado por pares]

Berlin/Heidelberg: Springer Berlin Heidelberg

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Título:
Mechanistic examination of methimazole-induced hepatotoxicity in patients with Grave’s disease: a metabolomic approach
Autor: Li, Xuesong ; Yang, Jialin ; Jin, Shasha ; Dai, Yu ; Fan, Yujuan ; Fan, Xiaofang ; Li, Zhigang ; Yang, Jianhua ; Yau, Wai-Ping ; Lin, Haishu ; Cai, Weimin ; Xiang, Xiaoqiang
Assuntos: Adult ; Alanine ; Alanine transaminase ; Alanine Transaminase - blood ; Amine oxidase (flavin-containing) ; Amino acids ; Antithyroid Agents - adverse effects ; Aspartate aminotransferase ; Aspartate Aminotransferases - blood ; Biomedical and Life Sciences ; Biomedical materials ; Biomedicine ; Blood - drug effects ; Blood - metabolism ; Chemical and Drug Induced Liver Injury - etiology ; Chemical and Drug Induced Liver Injury - metabolism ; Deoxyribonucleic acid ; Disruption ; DNA ; Environmental Health ; Ethanolamine ; Fatty acids ; Fatty liver ; Female ; Gas chromatography ; Gas Chromatography-Mass Spectrometry ; Gene polymorphism ; Genotyping ; Glucuronosyltransferase ; Glucuronosyltransferase - genetics ; Graves Disease - drug therapy ; Graves Disease - metabolism ; Hepatotoxicity ; Humans ; Liver diseases ; Male ; Mass spectrometry ; Mass spectroscopy ; Metabolites ; Metabolomics ; Metabolomics - methods ; Methimazole - adverse effects ; Mitochondria ; Mitochondrial DNA ; Occupational Medicine/Industrial Medicine ; Octopamine ; Organ Toxicity and Mechanisms ; Osteoporosis ; Pathogenesis ; Pharmacology/Toxicology ; Plasma levels ; Polymorphism ; Reactive oxygen species ; Thyroid ; Treatment Outcome ; Uridine
É parte de: Archives of toxicology, 2020, Vol.94 (1), p.231-244
Descrição: Methimazole (MMI), the first-line anti-thyroid agent used in clinical practice is known to induce hepatotoxicity in patients with Grave’s disease (GD), although its exact mechanism remains largely unclear. This cohort study aimed to examine the mechanism of MMI-induced hepatotoxicity using metabolomic approach. A total of 40 GD patients with MMI-induced hepatotoxicity (responders) and 80 GD patients without MMI-induced hepatotoxicity (non-responders) were included in this study and their plasma metabolomics was profiled with targeted gas chromatography–tandem mass spectrometry (GC–MS/MS). The plasma levels of 42 metabolites, including glucuronic acid, some amino acids, fatty acids, ethanolamine and octopamine were found to be significantly different between responders and non-responders. In agreement with our previous genotyping data, the genetic polymorphism of uridine 5′-diphospho-glucuronosyltransferase (UGT) 1A1*6 , which affects the glucuronidation activity and circulating glucuronic acid level was identified as one of the determinants of MMI-induced hepatotoxicity. Plasma level of ethanolamine has a significant correlation with aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities. The pathway analyses further revealed that monoamine oxidase (MAO) inhibition, reactive oxygen species (ROS) production, mitochondria dysfunction, and DNA disruption might contribute to MMI-induced hepatotoxicity. Interestingly, the metabolomic data further suggested the responders had a higher risk of developing osteoporosis and fatty liver disease in comparison to the non-responders. This mechanistic study sheds light on the pathogenesis of MMI-induced hepatotoxicity and prompts personalized prescription of MMI based on UGT1A1*6 genotype in the management of GD.
Editor: Berlin/Heidelberg: Springer Berlin Heidelberg
Idioma: Inglês

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Mechanistic examination of methimazole-induced hepatotoxicity in patients with Grave’s disease: a metabolomic approach

Li, Xuesong ; Yang, Jialin ; Jin, Shasha ; Dai, Yu ; Fan, Yujuan ; Fan, Xiaofang ; Li, Zhigang ; Yang, Jianhua ; Yau, Wai-Ping ; Lin, Haishu ; Cai, Weimin ; Xiang, Xiaoqiang

Berlin/Heidelberg: Springer Berlin Heidelberg

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