Abstract
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.
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Acknowledgements
We thank all of the subjects who participated in this study. This work was supported by the National Natural Science Foundation of China [81473409]; Shanghai Science and Technology Innovation Fund [18140900900]; Foundation of Shanghai Municipal Commission of Health and Family Planning [201840057]; and Science and Technology Commission of Shanghai Municipality [114119b0400].
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This study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of Minhang Hospital, Fudan University. The written informed consent forms were obtained from all the participants. This study was registered in chictr.org.cn (Registration No. 1800018388).
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Li, X., Yang, J., Jin, S. et al. Mechanistic examination of methimazole-induced hepatotoxicity in patients with Grave’s disease: a metabolomic approach. Arch Toxicol 94, 231–244 (2020). https://doi.org/10.1007/s00204-019-02618-z
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DOI: https://doi.org/10.1007/s00204-019-02618-z