Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto M5S3M2, Canada.
Department of Pharmacology, College of Pharmacy and Pharmaceutical Sciences, University of Toledo Health Science Campus, Toledo, Ohio 43614.
Toxicol Sci. 2021 Feb 26;180(1):17-25. doi: 10.1093/toxsci/kfaa182.
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.
甲氧苄啶（TMP）引起的皮疹和肝损伤可能涉及活性代谢物的形成。类似于奈韦拉平引起的皮疹，一种可能的活性代谢物是 TMP 的α-羟化物的硫酸盐结合物。我们合成了这种硫酸盐，并发现它在体外与蛋白质反应。我们制备了 TMP 抗血清，并发现 TMP 处理大鼠的肝中有 TMP 的共价结合。然而，我们发现α-羟化物不是人磺基转移酶的底物，并且我们在 TMP 处理的大鼠的皮肤中未检测到共价结合。尽管比硫酸盐的反应性低，但发现α-羟化物在体外与肝和皮肤蛋白共价结合。尽管与肝蛋白有共价结合，但 TMP 并未在大鼠或我们免疫耐受受损的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 处理的小鼠肝脏中 TMP 的共价结合比 TMP 处理的大鼠少得多。可能有些患者有一种磺基转移酶，可以产生活性苄基硫酸盐；但是，α-羟化物本身具有足够的反应性，可以与皮肤中的蛋白质共价结合，可能是引起 TMP 引起的皮疹的原因。TMP 代谢的种间和个体间差异可能是决定 TMP 引起的皮疹风险的一个因素。这项研究提供了理解 TMP 引起的皮疹和药物引起的皮疹的一般机制所需的重要数据。
