Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Canada M5S 3M2.
Department of Pharmacology, College of Pharmacy and Pharmaceutical Sciences, University of Toledo Health Science Campus, Toledo, Ohio 43614, United States.
Chem Res Toxicol. 2023 Nov 20;36(11):1711-1716. doi: 10.1021/acs.chemrestox.3c00187. Epub 2023 Nov 3.
The mechanism of drug-induced skin rash is not well understood. Circumstantial evidence suggests that the covalent binding of a reactive metabolite is involved in the mechanism of most idiosyncratic drug reactions. However, there is a limited quantity of drug metabolizing enzymes in the skin, except for sulfotransferases. It is possible that some drugs are metabolized to reactive sulfate metabolites that are responsible for skin rashes. For example, nevirapine-induced skin rash involves metabolism of nevirapine to 12-hydroxy-nevirapine, which is further metabolized by sulfotransferase in the skin to a reactive benzylic sulfate that covalently binds to proteins. The working hypothesis is that lamotrigine, valdecoxib, and sertraline skin rashes involve the formation of reactive sulfate in the skin. Lamotrigine--oxide, hydroxy-valdecoxib, and hydroxy-sertraline were tested as substrates with known human sulfotransferases. Hydroxy-valdecoxib and the benzylic alcohol metabolite of sertraline were not substrates for human sulfotransferases. Therefore, this pathway is presumably not involved in the mechanism by which they cause skin rashes. In contrast, lamotrigine--oxide is a substrate for several human sulfotransferases and the sulfate is chemically reactive. Furthermore, lamotrigine--sulfate not only alkylates proteins as we described previously but also forms the sulfate of tyrosine, suggesting another possible mechanism for protein modification. This study has further added to the understanding of the potential of the sulfotransferase pathways and protein sulfation to play a role in drug-induced skin rash.
药物性皮疹的发病机制尚不清楚。间接证据表明，大多数药物特异质反应的机制与反应性代谢物的共价结合有关。然而，皮肤中除了磺基转移酶外，代谢药物的酶数量有限。某些药物可能代谢为反应性硫酸代谢物，从而导致皮疹。例如，奈韦拉平引起的皮疹涉及奈韦拉平代谢为 12-羟基奈韦拉平，后者进一步被皮肤中的磺基转移酶代谢为反应性苄基硫酸酯，与蛋白质共价结合。工作假说认为拉莫三嗪、伐地考昔和舍曲林皮疹涉及皮肤中形成的活性硫酸酯。拉莫三嗪-氧化物、羟基伐地考昔和羟基舍曲林被测试为已知的人类磺基转移酶的底物。羟基伐地考昔和舍曲林的苄醇代谢物不是人磺基转移酶的底物。因此，这条途径大概不是它们引起皮疹的机制。相比之下，拉莫三嗪-氧化物是几种人类磺基转移酶的底物，硫酸酯具有化学活性。此外，拉莫三嗪-硫酸盐不仅如我们之前所述烷基化蛋白质，还形成酪氨酸的硫酸盐，提示了另一种可能的蛋白质修饰机制。这项研究进一步加深了对磺基转移酶途径和蛋白质磺化在药物性皮疹中的作用的理解。
