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

  • Xuesong Li
  • Jialin Yang
  • Shasha Jin
  • Yu Dai
  • Yujuan Fan
  • Xiaofang Fan
  • Zhigang Li
  • Jianhua Yang
  • Wai-Ping Yau
  • Haishu Lin
  • Weimin Cai
  • Xiaoqiang XiangEmail author
Organ Toxicity and Mechanisms

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.

Keywords

Methimazole Grave’s disease Metabolomics UGT1A1*6 MAO-A Hepatotoxicity 

Notes

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].

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

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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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Endocrinology and Metabolism, Minhang HospitalFudan UniversityShanghaiPeople’s Republic of China
  2. 2.Department of Clinical Pharmacy, School of PharmacyFudan UniversityShanghaiPeople’s Republic of China
  3. 3.Department of Pharmacy, Faculty of ScienceNational University of SingaporeSingaporeSingapore
  4. 4.Department of PharmacyKashgar Prefecture Second People’s HospitalKashgarPeople’s Republic of China
  5. 5.Department of Pharmacy, The First Affiliated HospitalXinjiang Medical UniversityUrumqiPeople’s Republic of China

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