Bioactivation mechanism of the cytotoxic and nephrotoxic S-conjugate S-(2-chloro-1,1,2-trifluoroethyl)-L-cysteine.
Bioactivation mechanism of the cytotoxic and nephrotoxic S-conjugate S-(2-chloro-1,1,2-trifluoroethyl)-L-cysteine.
复制标题
细胞毒性和肾毒性 S-缀合物 S-(2-氯-1,1,2-三氟乙基)-L-半胱氨酸的生物激活机制。
DOI：
10.1073/pnas.84.21.7443
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发表时间：
1987
影响因子：
11.1
通讯作者：
Anders,MW
中科院分区：
文献类型：
--
作者：
Dekant,W;Lash,LH;Anders,MW
在十六烷基三甲基溴化铵胶束中，以纯化的牛肾半胱氨酸偶联β裂解酶和N-十二烷基吡哆醛溴化物为模型体系，研究了S-(2-氯-1，1，2-三氟乙基)-L-半胱氨酸的生物活性。β-裂解酶和吡哆醛模型体系将CTFC转化为氯氟乙酸和无机氟，其结构经~(19)F核磁共振波谱确证。CTFC的代谢产物为2-氯-1，1，2-三氟乙硫醇和氯氟硫代乙基氟，分别与溴化苄基和二乙胺固定，生成2-氯-1，1，2-三氟乙基苯硫醚和N，N-二乙基氯氟硫代乙酰胺，并用气相色谱/质谱法进行鉴定。因此，CTFC的生物活化机理包括初始形成不稳定的硫醇2-氯-1，1，2-三氟乙硫醇，它失去氟化氢而形成酰化剂氯氟硫代硫乙酰氟；硫代酰氟的水解得到稳定的最终代谢物氯氟乙酸和无机氟。中间体酰化剂和氯氟乙酸可能参与了CTFC的细胞毒作用。
The bioactivation of S-(2-chloro-1,1,2-trifluoroethyl)-L-cysteine (CTFC) was studied with purified bovine kidney cysteine conjugate beta-lyase and with N-dodecylpyridoxal bromide in cetyltrimethylammonium bromide micelles as a pyridoxal model system. The beta-lyase and the pyridoxal model system converted CTFC to chlorofluoroacetic acid and inorganic fluoride, which were identified by 19F NMR spectrometry. 2-Chloro-1,1,2-trifluoroethanethiol and chlorofluorothionoacetyl fluoride were formed as metabolites of CTFC and were trapped with benzyl bromide and diethylamine, respectively, to yield benzyl 2-chloro-1,1,2-trifluoroethyl sulfide and N,N-diethyl chlorofluorothioacetamide, which were identified by gas chromatography/mass spectrometry. The bioactivation mechanism of CTFC therefore involves the initial formation of the unstable thiol 2-chloro-1,1,2-trifluoroethanethiol, which loses hydrogen fluoride to form the acylating agent chlorofluorothionoacetyl fluoride; hydrolysis of the thionoacyl fluoride affords the stable, terminal metabolites chlorofluoroacetic acid and inorganic fluoride. The intermediate acylating agent and chlorofluoroacetic acid may contribute to the cytotoxic effects of CTFC.