氨苯砜被人肝微粒体酶生物激活为细胞毒性代谢物。
Bioactivation of dapsone to a cytotoxic metabolite by human hepatic microsomal enzymes.
作者信息
Coleman M D, Breckenridge A M, Park B K
机构信息
Department of Pharmacology and Therapeutics, New Medical School, Liverpool.
出版信息
Br J Clin Pharmacol. 1989 Oct;28(4):389-95. doi: 10.1111/j.1365-2125.1989.tb03517.x.
Abstract
- Using human mononuclear leucocytes as target cells, we have investigated the bioactivation of dapsone (DDS) to a cytotoxic metabolite in the presence of microsomes from nine human livers. Values for NADPH dependent toxicity ranged from 8.8-27% (15.8 +/- 5.9%) and were similar to those for microsomes from control mice, 16-24% (19.0 +/- 4.8%). 2. Microsomes prepared from mice induced with either phenobarbitone or beta-naphthoflavone did not produce significantly more NADPH dependent toxicity than microsomes prepared from control mice. 3. Cytotoxicity was abolished not only by ascorbic acid, but also by sub-physiological concentrations of N-acetylcysteine and glutathione. 4. DDS was metabolised in vitro to a hydroxylamine (metabolic conversion 3.1 +/- 1.5%), which was oxidised further to a cytotoxic metabolite which also became irreversibly bound to protein.
摘要
- 以人单核白细胞作为靶细胞，我们研究了在来自九个人肝脏的微粒体存在下，氨苯砜（DDS）生物活化成细胞毒性代谢物的情况。依赖于NADPH的毒性值范围为8.8 - 27%（15.8±5.9%），与来自对照小鼠的微粒体的毒性值相似，为16 - 24%（19.0±4.8%）。2. 用苯巴比妥或β - 萘黄酮诱导制备的小鼠微粒体，产生的依赖于NADPH的毒性并不比从对照小鼠制备的微粒体显著更高。3. 细胞毒性不仅被抗坏血酸消除，而且被亚生理浓度的N - 乙酰半胱氨酸和谷胱甘肽消除。4. DDS在体外代谢为羟胺（代谢转化率3.1±1.5%），其进一步氧化为细胞毒性代谢物，该代谢物也不可逆地与蛋白质结合。
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