Shear N H, Spielberg S P, Grant D M, Tang B K, Kalow W
Ann Intern Med. 1986 Aug;105(2):179-84. doi: 10.7326/0003-4819-105-2-179.
Individual differences in metabolism of the sulfonamides may predispose patients to idiosyncratic reactions. Sulfonamides are metabolized by N-acetylation (mediated by a genetically polymorphic enzyme) and oxidation to potentially toxic metabolites. We examined 6 patients who had severe reactions to sulfonamides and compared them with 20 controls. Acetylator phenotype was determined with caffeine, a safe in-vivo probe of enzyme activity. All 6 patients were slow acetylators (expected, 55%; p less than 0.05). Detoxification of oxidative metabolites was studied in vitro with a lymphocyte assay evaluating cell death from metabolites generated by a murine hepatic microsomal system. Cells from each patient showed increased toxicity from sulfonamide metabolites but not from the drugs themselves. Cells from parents of 3 patients had intermediate toxicity from sulfonamide metabolites, whereas cells from a sibling of 1 patient had a normal response. Susceptibility to sulfonamide reactions may be due to interaction of metabolic pathways, possibly under genetic control, regulating N-acetylation and specific detoxification of toxic metabolites of the drugs.
磺胺类药物代谢的个体差异可能使患者易发生特异反应。磺胺类药物通过N - 乙酰化（由一种基因多态性酶介导）和氧化代谢为潜在的有毒代谢产物。我们研究了6名对磺胺类药物有严重反应的患者，并将他们与20名对照者进行比较。用咖啡因（一种安全的体内酶活性探针）确定乙酰化表型。所有6名患者均为慢乙酰化者（预期比例为55%；p小于0.05）。用淋巴细胞试验在体外研究氧化代谢产物的解毒作用，该试验评估由小鼠肝微粒体系统产生的代谢产物导致的细胞死亡。每位患者的细胞对磺胺类药物代谢产物的毒性增加，但对药物本身无此反应。3名患者父母的细胞对磺胺类药物代谢产物有中等毒性，而1名患者兄弟姐妹的细胞反应正常。对磺胺类药物反应的易感性可能是由于代谢途径的相互作用，可能受基因控制，调节N - 乙酰化和药物有毒代谢产物的特定解毒过程。
