Vyas Piyush M, Roychowdhury Sanjoy, Woster Patrick M, Svensson Craig K
Division of Pharmaceutics, College of Pharmacy, The University of Iowa, 115 S. Grand Avenue, S213 PHAR, Iowa City, IA 52242, USA.
Biochem Pharmacol. 2005 Jul 15;70(2):275-86. doi: 10.1016/j.bcp.2005.04.023.
Cutaneous drug reactions (CDR) are responsible for numerous minor to life-threatening complications. Though the exact mechanism for CDR is not completely understood, evidence suggests that bioactivation of drugs to reactive oxygen or nitrogen species is an important factor in the initiation of these reactions. Several CDR-inducing drugs having an arylamine functional group, such as sulfamethoxazole (SMX) and dapsone (DDS), undergo bioactivation to reactive arylhydroxylamine metabolites. These metabolites can generate cellular oxidative stress by forming reactive oxygen species (ROS). Several studies have demonstrated a higher cytotoxicity with DDS hydroxylamine (DDS-NOH) compared to SMX hydroxylamine (SMX-NOH). To investigate the role of differential ROS generation in the higher cytotoxicity of DDS-NOH, hydroxylamine metabolites of SMX and DDS were synthesized and ROS formation by these metabolites determined. DDS-NOH and its analogues/metabolites consistently resulted in higher ROS formation as compared to SMX-NOH. However, comparison of the ROS generation and cytotoxicity of a series of arylhydroxylamine analogues of DDS did not support a simple correlation between ROS generation and cell death. Numerous ROS scavengers were found to reduce metabolite-induced ROS formation, with differences in the potency between the agents. The decrease in DDS-NOH-induced ROS generation in NHEK with ascorbic acid, N-acetylcysteine, Trolox, and melatonin was 87, 86, 44, and 16%, respectively. Similarly, the cytotoxicity and adduct formation of DDS-NOH in NHEK was reduced in the presence of ascorbic acid. In summary, these studies show that arylhydroxylamine metabolites of SMX/DDS induce ROS generation in NHEK, though such generation is not directly related to cytotoxicity.
皮肤药物反应（CDR）会引发众多轻微至危及生命的并发症。尽管CDR的确切机制尚未完全明确，但有证据表明，药物生物活化形成活性氧或氮物种是引发这些反应的一个重要因素。几种具有芳胺官能团的CDR诱导药物，如磺胺甲恶唑（SMX）和氨苯砜（DDS），会生物活化形成活性芳基羟胺代谢物。这些代谢物可通过形成活性氧（ROS）产生细胞氧化应激。多项研究表明，与SMX羟胺（SMX-NOH）相比，DDS羟胺（DDS-NOH）具有更高的细胞毒性。为了研究ROS生成差异在DDS-NOH更高细胞毒性中的作用，合成了SMX和DDS的羟胺代谢物，并测定了这些代谢物形成ROS的情况。与SMX-NOH相比，DDS-NOH及其类似物/代谢物始终会产生更高的ROS形成。然而，对一系列DDS芳基羟胺类似物的ROS生成和细胞毒性进行比较，并不支持ROS生成与细胞死亡之间存在简单的相关性。发现多种ROS清除剂可减少代谢物诱导的ROS形成，不同清除剂的效力存在差异。在正常人表皮角质形成细胞（NHEK）中，抗坏血酸、N-乙酰半胱氨酸、生育三烯酚和褪黑素使DDS-NOH诱导的ROS生成分别减少了87%、86%、44%和16%。同样，在抗坏血酸存在的情况下，NHEK中DDS-NOH的细胞毒性和加合物形成也有所降低。总之，这些研究表明，SMX/DDS的芳基羟胺代谢物可在NHEK中诱导ROS生成，尽管这种生成与细胞毒性并无直接关联。
