Investigating the Mechanism of Trimethoprim-Induced Skin Rash and Liver Injury.
Investigating the Mechanism of Trimethoprim-Induced Skin Rash and Liver Injury.
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DOI：
10.1093/toxsci/kfaa182
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发表时间：
2021-02-26
期刊：
影响因子：
--
通讯作者：
Uetrecht J
中科院分区：
文献类型：
--
作者：
Cao Y;Bairam A;Jee A;Liu M;Uetrecht J
甲氧苄啶（TMP）诱导的皮疹和肝损伤可能涉及反应性代谢产物的形成。与奈韦拉平诱导的皮疹类似，一种可能的反应性代谢产物是α-羟基TMP的硫酸盐结合物，TMP的一种代谢产物。我们合成了这种硫酸盐，并发现它在体外与蛋白质反应。我们生产了TMP-抗血清，并发现在TMP处理的大鼠的肝脏中TMP的共价结合。然而，我们发现α-羟基TMP不是人磺基转移酶的底物，并且我们在TMP处理的大鼠皮肤中未检测到共价结合。虽然反应性低于硫酸盐，但发现α-羟基TMP在体外与肝脏和皮肤蛋白共价结合。尽管与肝脏蛋白质存在共价结合，但TMP并没有在大鼠或我们的免疫耐受受损小鼠模型中引起肝损伤，该模型已经能够揭示其他药物引起免疫介导的肝损伤的能力。这可能是因为TMP治疗小鼠肝脏中TMP的共价结合量比TMP治疗大鼠少得多。一些患者可能具有可产生反应性苄基硫酸盐的磺基转移酶;然而，α-羟基TMP本身具有足够的反应性，可与皮肤中的蛋白质共价结合，可能是TMP诱导的皮疹的原因。TMP代谢的种间和个体间差异可能是决定TMP诱导皮疹风险的一个因素。本研究提供了重要的数据，需要了解TMP诱导的皮疹和一般药物诱导的皮疹的机制。
Trimethoprim (TMP)-induced skin rash and liver injury are likely to involve the formation of reactive metabolites. Analogous to nevirapine-induced skin rash, 1 possible reactive metabolite is the sulfate conjugate of α-hydroxyTMP, a metabolite of TMP. We synthesized this sulfate and found that it reacts with proteins in vitro. We produced a TMP-antiserum and found covalent binding of TMP in the liver of TMP-treated rats. However, we found that α-hydroxyTMP is not a substrate for human sulfotransferases, and we did not detect covalent binding in the skin of TMP-treated rats. Although less reactive than the sulfate, α-hydroxyTMP was found to covalently bind to liver and skin proteins in vitro. Even though there was covalent binding to liver proteins, TMP did not cause liver injury in rats or in our impaired immune tolerance mouse model that has been able to unmask the ability of other drugs to cause immune-mediated liver injury. This is likely because there was much less covalent binding of TMP in the livers of TMP-treated mice than TMP-treated rats. It is possible that some patients have a sulfotransferase that can produce the reactive benzylic sulfate; however, α-hydroxyTMP, itself, has sufficient reactivity to covalently bind to proteins in the skin and may be responsible for TMP-induced skin rash. Interspecies and interindividual differences in TMP metabolism may be 1 factor that determines the risk of TMP-induced skin rash. This study provides important data required to understand the mechanism of TMP-induced skin rash and drug-induced skin rash in general.
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影响因子：
4.1
作者：
Mak, Alastair;Uetrecht, Jack
通讯作者：
Uetrecht, Jack
影响因子：
3.3
作者：
KOCH, UJ;SCHUMANN, KP;KEWITZ, H
通讯作者：
KEWITZ, H
DOI：
10.1007/s00044-020-02570-z
发表时间：
2020-07
期刊：
Medicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents
影响因子：
--
作者：
Nolte WM;Tessman RT;Goldman JL
通讯作者：
Goldman JL
影响因子：
5.8
作者：
Bairam AF;Rasool MI;Alherz FA;Abunnaja MS;El Daibani AA;Gohal SA;Kurogi K;Sakakibara Y;Suiko M;Liu MC
通讯作者：
Liu MC
影响因子：
4.1
作者：
Shenton, JM;Teranishi, M;Uetrecht, JP
通讯作者：
Uetrecht, JP