甲巯咪唑(MMI)是目前临床上应用最广泛的抗甲状腺药物之一,肝功能损害是其最常见的不良反应,并成为困扰临床医生治疗甲状腺功能亢进的难关。本文对药物性肝损伤(DILI)机制主要是甲巯咪唑致肝损伤(MMI-DILI)机制进行综述,以帮助临床医生预判应用甲巯咪唑的可能带来的风险,并为进一步研究MMI-DILI机制提供思路。
Methimazole (MMI) is currently one of the most widely used clinically anti-thyroid drugs, liver inju-ry is the most common adverse reactions, and it is a serious problem for physicians to treat hyper-thyroidism. However, the mechanism of methimazole-induced hepatotoxicity is not fully understood so far. In this paper, the mechanisms of drugs-induced liver injury (DILI) and methimazole-induced liver damage (MMI-DILI) were reviewed, in order to help clinical doctors to predict drugs’ side effect, and provide ideas for further research on mechanism of MMI-DILI.
甲巯咪唑,药物性肝损伤,药物代谢,HLA, Methimazole Drugs-Induced Liver Injury (DILI) Drug Metabolism HLA摘要
Methimazole (MMI) is currently one of the most widely used clinically anti-thyroid drugs, liver injury is the most common adverse reactions, and it is a serious problem for physicians to treat hyperthyroidism. However, the mechanism of methimazole-induced hepatotoxicity is not fully understood so far. In this paper, the mechanisms of drugs-induced liver injury (DILI) and methimazole-induced liver damage (MMI-DILI) were reviewed, in order to help clinical doctors to predict drugs’ side effect, and provide ideas for further research on mechanism of MMI-DILI.
Keywords:Methimazole, Drugs-Induced Liver Injury (DILI), Drug Metabolism, HLA
张丽芹. 甲巯咪唑致肝损伤相关因素研究进展Advances in the Study of Related Factors of Methimazole-Induced Liver Injury[J]. 临床医学进展, 2022, 12(10): 9020-9023. https://doi.org/10.12677/ACM.2022.12101304
参考文献ReferencesMcDermott, M. (2020) Hyperthyroidism. Annals of Internal Medicine, 172, ITC49-ITC64.
<br>https://doi.org/10.7326/AITC202004070刘超, 蒋琳. 抗甲状腺药物不良反应的再认识[J]. 中华内分泌代谢杂志, 2011, 27(6): 529-532.王宁, 王薇, 张红, 袁振芳, 郭晓蕙, 张俊清. 抗甲状腺药物与甲状腺功能亢进症所致肝功能异常的临床分析[J]. 中国临床药理学杂志, 2018, 34(3): 244-247.Woeber, K. (2002) Me-thimazole-Induced Hepatotoxicity. Endocrine Practice, 8, 222-224.
<br>https://doi.org/10.4158/EP.8.3.222Heidari, R., Babaei, H. and Eghbal, M. (2013) Mechanisms of Methima-zole Cytotoxicity in Isolated Rat Hepatocytes. Drug and Chemical Toxicology, 36, 403-411. <br>https://doi.org/10.3109/01480545.2012.749272巩政, 王旗. 黄素单加氧酶3的基因多态性及其在药物代谢和毒性中的作用[J]. 中国中药杂志, 2015, 40(14): 2701-2705.Heidari, R., Niknahad, H., Jamshidzadeh, A., Eghbal, M.A. and Abdoli. N. (2015) An Overview on the Proposed Mechanisms of Antithyroid Drugs-Induced Liver Injury. Advanced Pharmaceutical Bulletin, 5, 1-11.
<br>https://doi.org/10.5681/apb.2015.001殷静, 王芳, 王永艳, 汤洪策, 孙纯, 阎胜利. 甲巯咪唑致肝损害与黄素单加氧酶3E308G位点基因多态性的相关性研究[J]. 中国药学杂志, 2014. 49(15): 1338-1341.Li, X., Yang, J., Jin, S., Dai, Y., Fan, Y., Fan, X., et al. (2020) Mechanistic Examination of Methimazole-Induced Hepatotoxi-city in Patients with Grave’s Disease: A Metabolomic Approach. Archives of Toxicology, 94, 231-244.
<br>https://doi.org/10.1007/s00204-019-02618-zHeidari, R., Niknahad, H., Jamshidzadeh, A. and Abdoli, N. (2014) Factors Affecting Drug-Induced Liver Injury: Antithyroid Drugs as Instances. Clinical and Molecular Hepatolo-gy, 20, 237-248.
<br>https://doi.org/10.3350/cmh.2014.20.3.237Lang, C., Meier, Y., Stieger, B., Beuers, U., Lang, T., Kerb, R., et al. (2007) Mutations and Polymorphisms in the Bile Salt Export Pump and the Multidrug Resistance Protein 3 Associat-ed with Drug-Induced Liver Injury. Pharmacogenet Genomics, 17, 47-60. <br>https://doi.org/10.1097/01.fpc.0000230418.28091.76Choi, J.H., Ahn, B.M., Yi, J., Lee, J.H., Lee, J.H., Nam, S.W., et al. (2007) MRP2 haplotypes Confer Differential Susceptibility to Toxic Liver Injury. Pharmacogenetics and Genomics, 17, 403-415.
<br>https://doi.org/10.1097/01.fpc.0000236337.41799.b3Li, L.M., Chen, L., Deng, G.H., Tan, W.T., Dan, Y.J., Wang, R.Q., et al. (2012) SLCO1B1 *15 Haplotype Is Associated with Rifampin-Induced Liver Injury. Molecular Med-icine Reports, 6, 75-82.
<br>https://doi.org/10.3892/mmr.2012.900Jin, S., Li, X., Fan, Y., Fan, X., Dai, Y., Lin, H., et al. (2019) Associ-ation between Genetic Polymorphisms of SLCO1B1 and Susceptibility to Methimazole-Induced Liver Injury. Basic & Clinical Pharmacology & Toxicology, 125, 508-517.
<br>https://doi.org/10.1111/bcpt.13284Stephens, C. and Andrade, R.J. (2020) Genetic Predisposition to Drug-Induced Liver Injury. Clinics in Liver Disease, 24, 11-23. <br>https://doi.org/10.1016/j.cld.2019.08.003Grove, J. and Aithal, G. (2015) Human Leukocyte Antigen Genetic Risk Factors of Drug-Induced Liver Toxicology. Expert Opinion on Drug Metabolism & Toxicology, 11, 395-409. <br>https://doi.org/10.1517/17425255.2015.992414Fan, W., Shiao, M.S., Hui, R.C., Su, S.C., Wang, C.W., Chang, Y.C., et al. (2017) HLA Association with Drug-Induced Adverse Reactions. Journal of Immunology Research, 2017, Article ID: 3186328.
<br>https://doi.org/10.1155/2017/3186328Ma, Q., Yang, W., Wang, L., Ma, L., Jing, Y., Wang, J., et al. (2020) Research Advances in the Association of Drug- Induced Liver Injury with Polymorphisms in Human Leukocyte Antigen. International Immunopharmacology, 81, Article ID: 106037. <br>https://doi.org/10.1016/j.intimp.2019.106037Petros, Z., Kishikawa, J., Makonnen, E., Yimer, G., Habtewold, A. and Aklillu, E. (2017) HLA-B* 57 Allele Is Associated with Concomitant Anti-Tuberculosis and Antiretroviral Drugs Induced Liver Toxicity in Ethiopians. Frontiers in Pharmacology, 8, Article No. 90. <br>https://doi.org/10.3389/fphar.2017.00090Li, C., Rao, T., Chen, X., Zou, Z., Wei, A., Tang, J., et al. (2019) HLA-B* 35:01 Allele Is a Potential Biomarker for Predicting Polygonum multiflorum-Induced Liver Injury in Humans. Hepatology, 70, 346-357.
<br>https://doi.org/10.1002/hep.30660Nicoletti, P., Aithal, G.P., Chamberlain, T.C., Coulthard, S., Alshabeeb, M., Grove, J.I., et al. (2019) Drug-Induced Liver Injury due to Flucloxacillin: Relevance of Multiple Human Leukocyte An-tigen Alleles. Clinical Pharmacology and Therapeutics, 106, 245-253. <br>https://doi.org/10.1002/cpt.1375Fon-tana, R., Cirulli, E.T., Gu, J., Kleiner, D., Ostrov, D., Phillips, E., Schutte, R., et al. (2018) The Role of HLA-A*33:01 in Patients with Cholestatic Hepatitis Attributed to Terbinafine. Journal of Hepatology, 69, 1317-1325.
<br>https://doi.org/10.1016/j.jhep.2018.08.004Nicoletti, P., Werk, A.N., Sawle, A., Shen, Y., Urban, T.J., Coul-thard, S.A., et al. (2016) HLA-DRB1*16: 01-DQB1*05: 02 Is a Novel Genetic Risk Factor for Flupirtine-Induced Liver Injury. Pharmacogenetics and Genomics, 26, 218-224.
<br>https://doi.org/10.1097/FPC.0000000000000209Li, X., Jin, S., Fan, Y., Fan, X., Tang, Z., Cai, W., et al. (2019) Association of HLA-C*03:02 with Methimazole-Induced Liver Injury in Graves’ Disease Patients. Biomedicine & Pharmacotherapy, 117, Article ID: 109095.
<br>https://doi.org/10.1016/j.biopha.2019.109095Akmal, A. and Kung, J. (2014) Propylthiouracil, and Methi-mazole, and Carbimazole-Related Hepatotoxicity. Expert Opinion on Drug Safety, 13, 1397-1406. <br>https://doi.org/10.1517/14740338.2014.953796Clare, K., Miller, M. and Dillon, J. (2017) Genetic Factors Influencing Drug-Induced Liver Injury: Do They Have a Role in Prevention and Diagnosis? Current Hepatology Reports, 16, 258-264.
<br>https://doi.org/10.1007/s11901-017-0363-9