Sharma Amy M, Novalen Maria, Tanino Tadatoshi, Uetrecht Jack P
Leslie Dan Faculty of Pharmacy, University of Toronto , Toronto, Ontario M5S 3M2, Canada.
Chem Res Toxicol. 2013 May 20;26(5):817-27. doi: 10.1021/tx400098z. Epub 2013 May 3.
Nevirapine (NVP) treatment is associated with a significant incidence of skin rash in humans, and it also causes a similar immune-mediated skin rash in Brown Norway (BN) rats. We have shown that the sulfate of a major oxidative metabolite, 12-OH-NVP, covalently binds in the skin. The fact that the sulfate metabolite is responsible for covalent binding in the skin does not prove that it is responsible for the rash. We used various inhibitors of sulfation to test whether this reactive sulfate is responsible for the skin rash. Salicylamide (SA), which depletes 3'-phosphoadenosine-5'-phosphosulfate (PAPS) in the liver, significantly decreased 12-OH-NVP sulfate in the blood, but it did not prevent covalent binding in the skin or the rash. Topical application of 1-phenyl-1-hexanol, a sulfotransferase inhibitor, prevented covalent binding in the skin as well as the rash, but only where it was applied. In vitro incubations of 12-OH-NVP with PAPS and cytosolic fractions from the skin of rats or from human skin also led to covalent binding that was inhibited by 1-phenyl-1-hexanol. Incubation of 12-OH-NVP with PAPS and sulfotransferase 1A1*1, a human isoform that is present in the skin, also led to covalent binding, and this binding was also inhibited by 1-phenyl-1-hexanol. We conclude that salicylamide did not deplete PAPS in the skin and was unable to prevent covalent binding or the rash, while topical 1-phenyl-1-hexanol inhibited sulfation of 12-OH-NVP in the skin and did prevent covalent binding and the rash. These results provide definitive evidence that 12-OH-NVP sulfate formed in skin is responsible for NVP-induced skin rashes. Sulfotransferase is one of the few metabolic enzymes with significant activity in the skin, and it may be responsible for the bioactivation of other drugs that cause skin rashes.
奈韦拉平（NVP）治疗在人类中与皮疹的高发生率相关，并且它在褐家鼠（BN大鼠）中也会引发类似的免疫介导性皮疹。我们已经表明，主要氧化代谢产物12 - 羟基奈韦拉平（12 - OH - NVP）的硫酸盐在皮肤中发生共价结合。硫酸盐代谢产物负责皮肤中的共价结合这一事实并不证明它是皮疹的成因。我们使用了各种硫酸化抑制剂来测试这种反应性硫酸盐是否是皮疹的成因。水杨酰胺（SA）可消耗肝脏中的3'-磷酸腺苷 - 5'-磷酸硫酸（PAPS），显著降低血液中的12 - OH - NVP硫酸盐，但它并不能防止皮肤中的共价结合或皮疹。局部应用磺基转移酶抑制剂1 - 苯基 - 1 - 己醇可防止皮肤中的共价结合以及皮疹，但仅在应用部位起作用。12 - OH - NVP与PAPS以及来自大鼠皮肤或人类皮肤的胞质部分进行体外孵育也会导致共价结合，而这种结合可被1 - 苯基 - 1 - 己醇抑制。12 - OH - NVP与PAPS以及皮肤中存在的人类同工型磺基转移酶1A1*1进行孵育也会导致共价结合，并且这种结合也被1 - 苯基 - 1 - 己醇抑制。我们得出结论，水杨酰胺并未消耗皮肤中的PAPS，并且无法防止共价结合或皮疹，而局部应用的1 - 苯基 - 1 - 己醇可抑制皮肤中12 - OH - NVP的硫酸化，并确实防止了共价结合和皮疹。这些结果提供了确凿证据，表明皮肤中形成的12 - OH - NVP硫酸盐是奈韦拉平诱导皮疹的原因。磺基转移酶是少数在皮肤中具有显著活性的代谢酶之一，它可能是导致皮疹的其他药物生物活化的原因。
