Metabolic Activation of Tofacitinib Mediated by Myeloperoxidase in Vitro.,Chemical Research in Toxicology

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Metabolic Activation of Tofacitinib Mediated by Myeloperoxidase in Vitro.
Chemical Research in Toxicology ( IF 3.7 ) Pub Date : 2019-11-27 , DOI: 10.1021/acs.chemrestox.9b00280
Xiucai Guo ₁ , Yudi Jia ₁ , Lingling Han ₁ , Yanhong Zhao ₁ , Wei Li ₁ , Zhengyu Zhang ₁ , Ying Peng ₁ , Jiang Zheng _{1,

2}

Affiliation

Tofacitinib (TFT) is used for the treatment of moderately and severely active rheumatoid arthritis. Unfortunately, TFT was reported to induce leukopenia, and the underlying mechanisms remain unclear. The present study demonstrated that TFT was oxidized to a chemically reactive nitrenium ion by myeloperoxidase (MPO) occurring in neutrophils. The electrophilic ion showed chemical reactivity toward N-acetyl-cysteine (NAC) to produce two TFT-NAC conjugates (M1 and M2) in incubation of TFT with leucocytes in the presence of NAC. The generation of the nitrenium ion was verified by HClO-mediated oxidation of TFT. In addition, the nitrenium ion was found to react with sulfhydryl groups of cysteine residues of cellular protein in leucocytes after exposure to TFT. The study facilitates the understanding of the mechanisms of TFT toxic action.

中文翻译：

髓过氧化物酶介导的托法替尼的体外代谢活化。

Tofacitinib（TFT）用于治疗中度和重度活动性类风湿关节炎。不幸的是，据报道TFT会引起白细胞减少，其潜在机制仍不清楚。本研究表明，TFT被中性粒细胞中的髓过氧化物酶（MPO）氧化成化学反应性的氮离子。亲电子离子对N-乙酰基-半胱氨酸（NAC）表现出化学反应性，在存在NAC的情况下将TFT与白细胞一起孵育时会产生两种TFT-NAC共轭物（M1和M2）。硝酸根离子的产生通过HClO介导的TFT氧化来验证。另外，发现硝酸根离子在暴露于TFT后与白细胞中细胞蛋白的半胱氨酸残基的巯基反应。该研究有助于理解TFT毒性作用的机理。

更新日期：2019-11-28

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