Reilly T P, Bellevue F H, Woster P M, Svensson C K
Department of Pharmaceutical Sciences, Wayne State University, Detroit, MI 48202, USA.
Biochem Pharmacol. 1998 Mar 15;55(6):803-10. doi: 10.1016/s0006-2952(97)00547-9.
The differential incidence of adverse drug reactions (ADR) between trimethoprim-sulfamethoxazole and dapsone might be explained, in part, by differences in the inherent toxicity of the hydroxylamine metabolites of sulfamethoxazole and dapsone. To test this hypothesis, the in vitro cytotoxicities of sulfamethoxazole hydroxylamine, dapsone hydroxylamine, and monoacetyldapsone hydroxylamine were compared using peripheral blood mononuclear cells (PBMC) from healthy volunteers. After 3 hr of exposure to hydroxylamine metabolites, PBMC were washed thoroughly to remove residual hydroxylamine, and viability was assessed 16 hr later by determination of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) conversion. A concentration-dependent toxicity was observed with each hydroxylamine metabolite. While dapsone hydroxylamine and monoacetyldapsone hydroxylamine were not significantly different, both showed significantly greater cytotoxic potency than sulfamethoxazole hydroxylamine (P < 0.05). This differential potency was not a function of differential stability in aqueous medium and was maintained over time. The effects of red blood cells (RBC), impermeable RBC "ghosts," and RBC lysate on hydroxylamine-induced cytotoxicity were determined using a two-compartment dialysis system. Amelioration of hydroxylamine-dependent cytotoxicity occurred when RBC were included in PBMC incubations. This apparent detoxifying effect was markedly greater using RBC lysate in comparison with impermeable "ghosts" (P < 0.05). No difference in detoxification was observed between sulfamethoxazole hydroxylamine and monoacetyldapsone hydroxylamine. Differences in the inherent cytotoxicity of their hydroxylamine metabolites do not appear to explain the differential incidence of ADR between trimethoprim-sulfamethoxazole and dapsone.
甲氧苄啶 - 磺胺甲恶唑与氨苯砜之间不良药物反应（ADR）的差异发生率，部分原因可能是磺胺甲恶唑和氨苯砜的羟胺代谢产物固有毒性的不同。为验证这一假设，使用健康志愿者的外周血单核细胞（PBMC）比较了磺胺甲恶唑羟胺、氨苯砜羟胺和单乙酰氨苯砜羟胺的体外细胞毒性。在暴露于羟胺代谢产物3小时后，彻底洗涤PBMC以去除残留的羟胺，并在16小时后通过测定3 -（4,5 - 二甲基噻唑 - 2 - 基）- 2,5 - 二苯基溴化四氮唑（MTT）转化率来评估细胞活力。每种羟胺代谢产物均观察到浓度依赖性毒性。虽然氨苯砜羟胺和单乙酰氨苯砜羟胺没有显著差异，但两者均显示出比磺胺甲恶唑羟胺显著更高的细胞毒性效力（P < 0.05）。这种差异效力不是水性介质中差异稳定性的函数，并且随时间保持不变。使用两室透析系统测定红细胞（RBC）、不可渗透的红细胞“空壳”和红细胞裂解物对羟胺诱导的细胞毒性的影响。当RBC包含在PBMC孵育中时，羟胺依赖性细胞毒性得到改善。与不可渗透的“空壳”相比，使用红细胞裂解物时这种明显的解毒作用明显更大（P < 0.05）。磺胺甲恶唑羟胺和单乙酰氨苯砜羟胺之间未观察到解毒差异。它们的羟胺代谢产物固有细胞毒性的差异似乎不能解释甲氧苄啶 - 磺胺甲恶唑与氨苯砜之间ADR的差异发生率。
